Phytomedicine 104 (2022) 154263

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Phytomedicine
journal homepage: www.elsevier.com/locate/phymed

Review

A systematic review and meta-analysis for the primary prevention of high

risk of stroke by Nao-an capsules
Liuding Wang , Xueming Fan , Wanqing Du , Xiao Liang , Yifan Chen , Jingzi Shi , Linjuan Sun ,
Wei Shen *, Yunling Zhang *
Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China

A R T I C L E I N F O A B S T R A C T

Keywords: Background: To date, Nao-an capsules are the only Chinese patent medicine primarily prescribed for the primary
Aspirin prevention of stroke.
Traditional Chinese medicine Purpose: To evaluate the efficacy and safety of Nao-an capsules in the primary prevention of stroke in high-risk
Stroke prevention
patients.
Incidence of stroke
Bleeding risks
Study design: A systematic review and meta-analysis of randomized controlled trials.
Methods: We searched 7 electronic databases and 2 registries from inception to January 13, 2022 for relevant
randomized controlled trials. Two independent investigators selected trials, collected data, and judged the risk of
bias. We performed a meta-analysis using the Review Manager software.
Results: Nine randomized controlled trials involving 14 744 patients at high risk of stroke were included. Nao-an
capsules reduced the risk of first stroke compared with no intervention (risk ratio [RR] = 0.49, 95 % confidence
interval [CI] 0.29 to 0.82, p = 0.006) or aspirin (RR50 mg qd = 0.47, 95 % CI 0.25 to 0.91, p = 0.03; RR100 mg qd =
0.46, 95 % CI 0.22 to 0.99, p = 0.05), without increased bleeding risks. The certainty of evidence was evaluated
as moderate to very low.
Conclusion: In addition to controlling specific risk factors, Nao-an capsules might provide additional preventive
effects on first stroke with an acceptable safety profile for populations at high risk of stroke. However, as current
evidence is too weak, a firm recommendation depends on further confirmation from more studies with more
rigorous methodology.

Introduction strategies to relieve this substantial burden. Controlling the levels of

Stroke is a life-threatening disease associated with a high lifetime
risk. According to a national population-based survey (Wang et al.,
2017), approximately 2.4 million patients suffer from first-ever stroke
and 1.1 million patients die annually from stroke in China. In addition,
an astonishing 3.88% of American adults will have experienced a stroke
in less than a decade (Ovbiagele et al., 2013). In the UK, the societal cost
is projected to almost triple between 2015 and 2035 (King et al., 2020).
As a major cause of disability-adjusted life-years globally, stroke is
causing an increasing burden. Due to the worldwide rising prevalence of
stroke, more effective prevention strategies are urgently needed.
Primary prevention approaches of new strokes are the principal
identified risk factors in high-risk individuals remains the most recom­
mended effective approach (Diener and Hankey, 2020). In addition,
antiplatelet therapy has gradually advanced from secondary to primary
prevention in recent years, but the net benefit of treatment with aspirin
in preventing first stroke remains widely controversial. Based on the
latest systematic review (Guirguis-Blake et al., 2022), the United States
Preventive Services Task Force (USPSTF) has recommended that for
adults aged 40 to 59 with a 10% or greater 10-year risk of atherosclerotic
cardiovascular disease (ASCVD), it should be an individual
decision-making to initiate the administration of low-dose aspirin for the
primary prevention of cardiocerebrovascular events, due to the small
net benefit, whereas for adults aged 60 or older this primary prevention

Abbreviations: AHA/ASA, American Heart Association/American Stroke Association; ASCVD, atherosclerotic cardiovascular disease; ADP, adenosine diphosphate;
bid, twice daily; CVHI, cerebral vascular hemodynamic indexes; GRADE, Grading of Recommendations Assessment, Development and Evaluation; HPLC, high
performance liquid chromatography; qd, once daily; qn, once a night; qod, every other day; RCTs, randomized controlled trials; tid, three times daily.
* Corresponding authors.
E-mail addresses: 676665709@qq.com (W. Shen), yunlingzhang2004@163.com (Y. Zhang).

https://doi.org/10.1016/j.phymed.2022.154263
Received 10 April 2022; Received in revised form 5 June 2022; Accepted 8 June 2022
Available online 15 June 2022
0944-7113/© 2022 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
L. Wang et al.
strategy should be opposed (Davidson et al., 2022). Although it is
generally accepted that the benefits, such as reduced incidence of stroke,
outweigh the bleeding risks when the ASCVD 10-year risk is >10%,
balancing the benefits and harms from the use of low-dose aspirin re­
mains a difficult challenge (Mora and Manson, 2016). This is reflected
not only in the USPSTF update of the previous recommendation (Bib­
bins-Domingo and Force, 2016), but also in the extremely limited
applicable population that can follow these recommendations made by
the American Heart Association/American Stroke Association
(AHA/ASA) (Meschia et al., 2014). In addition to people with a suffi­
ciently high risk, AHA/ASA guidelines recommend the use of aspirin for
women (81 mg daily or 100 mg every other day) and chronic renal
disease sufferers (Meschia et al., 2014). However, except for these spe­
cial populations, other people at high risk of stroke identified by
screening risk factors alone do not benefit from aspirin (Uchiyama et al.,
2016; Judge et al., 2020). Given the clinical dilemma, there is an urgent
need for a novel prevention strategy with clear net benefits and wider
coverage.
In China, a complete stroke prevention system is gradually
advancing from an accurate prediction tool to a promising primary
prevention therapy. As part of the National Key Technologies R&D
Program of China, the stroke prevention collaboration group established
the cerebral vascular hemodynamic indexes (CVHI), also known as the
cerebrovascular function score, further confirming CVHI as an inde­
pendent risk factor of stroke (Wang and Huang, 2002), and verified the
sensitivity and specificity of CVHI for the early detection of stroke to be
as high as 80.77% and 67.55%, respectively, in a multicenter extended
study (Zhen, 2008). The latest study showed that CVHI has been vali­
dated to predict the 10-year risk of first stroke (Huang et al., 2021). By
searching publicly available information such as the biding of the testing
instrument for cerebrovascular function, it can be seen that CVHI may be
applied in 18 provinces, 3 municipalities directly under the central
government, and 3 autonomous regions under the recommendation of
the guidelines for the primary prevention of cerebrovascular diseases in
China (Chinese Society of Neurology and Chinese Stroke Society, 2019).
The price of each test varies between different cities, ranging from $18
to $28, with some regions, such as Beijing and Henan Province,
including it in the scope of medical insurance. Although the monitoring
of first stroke has been widely popularized, in terms of stroke preven­
tion, there is a lack of authoritative recommendations on using Nao-an
capsules, which have been suggested as the primary preventive medi­
cation for stroke. From reducing the annual average incidence rate of
stroke in Nanhui District of Shanghai by 40.5% 2 decades ago (Huang,
2002) to its advantage over aspirin (50 or 75 mg) reported in a Cochrane
systematic review in 2010 (Yang et al., 2010), Nao-an capsules are the
only evidence-based Chinese patent medicine that prevents first stroke.
Nao-an capsules were derived from the famous traditional prescription,
Buyang Huanwu Decoction. They consist of Conioselinum anthriscoides
"Chuanxiong" [Apiaceae; Chuanxiong Rhizoma], Angelica sinensis (Oliv.)
Diels [Apiaceae; Angelicae Sinensis Radix], Carthamus tinctorius L.
[Asteraceae; Carthami Flos], Panax ginseng C.A.Mey. [Araliaceae;
Ginseng Radix et Rhizoma], and Dryobalanops aromatica C.F.Gaertn.
[Dipterocarpaceae; Borneolum] (Supplementary Table 1). Ferulic
acid, the main active component in Nao-an capsules, is the standard
compound for evaluation of preparation quality (Li, 2018). The con­
centration of ferulic acid and ginsenoside in each Nao-an capsule should
be no less than 60 μg and 0.20 mg, respectively, as indicated by high
performance liquid chromatography (HPLC). The active components,
sodium ferulate and ligustrazine, have been demonstrated to possess
various therapeutic activities, including improving microcirculation by
affecting antiplatelet aggregation (Li et al., 2019), protecting the
endothelium (Wang et al., 2004; Wu et al., 2012), alleviating oxidative
stress (Amić et al., 2020; Jiang et al., 2011), and preventing athero­
sclerosis. Over the past decade, several new randomized controlled trials
(RCTs) performing a comparison between Nao-an capsules and aspirin
(100 mg) have emerged. Based on the wide application of CVHI in
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Phytomedicine 104 (2022) 154263
China, this primary prevention strategy, that is, the combination of
Nao-an capsules and CVHI, is highly implementable. Therefore, we
aimed to evaluate the effects of Nao-an capsules, a promising alternative
medication, on preventing first stroke in high-risk patients by focusing
on stroke incidence.
Methods
We registered the protocol for this systematic review in the inter­
national prospective register of systematic reviews (PROSPERO) under
the registration number CRD42021271692. This systematic review was
performed according to the Preferred Reporting Items for Systematic
Review and Meta-Analyses (PRISMA) 2020 statement (Page et al.,
2021).
Literature search and study selection
We searched MEDLINE OVID (1946 to January 13, 2022), EMBASE
OVID (1974 to January 13, 2022), and the Cochrane Central Register of
Controlled Trials (CENTRAL) of The Cochrane Library (Issue 12 of 12,
December 2021) to identify published studies. We also searched Chinese
databases (from inception to January 13, 2022), including the China
National Knowledge Infrastructure (CNKI), Chinese Scientific Journals
Database (VIP), WanFang database, and Chinese Biomedical Literature
Service System (SinoMed). We did not implement any restrictions
regarding the language of publications. The following terms and Bool­
ean operators were used as the search strategy and modified to suit each
database: (cerebrovasc$ or cerebral vasc$ or cerebr$ or brain$ cardio$
or cardia$ or hypertensive$ or blood pressure or hyperlipid$ or
cholesterol$ or diabet$).tw. and (Nao an).tw. Detailed search strategies
comprising complete subject headings and free-text terms for the
aforementioned databases are listed in Supplementary Table 2.
Regarding other resources, ClinicalTrials.gov and the Chinese Clin­
ical Trial Register were searched for unpublished studies. We further
checked the references of relevant reviews for potentially eligible trials.
Eligibility criteria
We included RCTs evaluating the use of Nao-an capsules for primary
prevention of stroke. We included participants with CVHI < 75. CVHI is
the recommended risk assessment tool for first stroke in the 2019 Chi­
nese guidelines. Participants with a history of stroke were excluded.
Intervention groups were treated with Nao-an capsules in combina­
tion with controlling risk factors. There were no limitations regarding
the dosage or treatment duration of Nao-an capsules. Control groups
were treated with aspirin, placebo, or no additional treatment combined
with controlling risk factors. All participants underwent the same
routine approaches for controlling risk factors, including health educa­
tion and guidance for controlling hypertension, diabetes, dyslipidemia,
and other modifiable risk factors.
The primary outcome of interest was the incidence of fatal or
nonfatal stroke. The secondary outcome was CVHI. CVHI is measured by
clinicians using a special noninvasive device, the cerebrovascular
function detector. As for the evaluation process, the cerebral blood flow
information and arterial elasticity indexes are collected at the bilateral
common carotid arteries through the ultrasonic Doppler probe and
pressure probe; the score of CVHI is automatically calculated based on
the following collected indexes: cerebrovascular average blood flow,
maximum flow velocity, minimum flow velocity, average flow velocity,
peripheral resistance, characteristic impedance, pulse wave velocity,
dynamic resistance, expansibility, critical pressure level, and the dif­
ference between diastolic and critical pressure (Huang et al., 2021).
Safety outcomes were the incidences of hemorrhagic stroke, gastroin­
testinal bleeds, and other adverse events.
L. Wang et al.
Study selection
Duplicates in all records retrieved were removed by NoteExpress3.2.
Two authors (Liuding Wang and Xueming Fan) independently screened
titles and abstracts first, and obtained full text articles to finalize the
articles meeting eligibility criteria. Any disagreements were settled by
consensus.
Data extraction
Two researchers (Liuding Wang and Yifan Chen) used a pilot tested
extraction form to conduct data extraction independently. Discrepancies
were settled by consensus.
We extracted the following data: (1) publication information: au­
thors, country, journal name, and publication year; (2) study designs:
sample size, methods of randomization and blinding; (3) participant
details; (4) details of intervention and comparator; and (5) outcome
measures (dichotomous data, such as incidence of stroke, were extracted
as the number of participants and that of events; continuous data, such
as CVHI score, were extracted as the number of participants, mean value
and standard deviation). When an article provided questionable data,
we contacted the authors for confirmation.
Assessment of risk of bias
Two independent authors (Liuding Wang and Yifan Chen) used the
Cochrane risk of bias tool 2.0 to appraise the quality of included trials.
We evaluated 5 domains as follows: randomization process, deviations
from intended interventions, missing outcome data, outcome measure­
ments, and selective reporting. Finally, we judged them as "low risk of
bias", "some concerns", or "high risk of bias". In cases of any disagree­
ments, we consulted with a specialist (Wei Shen) in our team.
Data synthesis
We used the Review Manager software (RevMan, Version 5.4) to
conduct statistical analyses. According to the characteristics of included
trials, such as age, interventions, and outcome measurement types, we
first assessed clinical heterogeneity. If the baseline characteristics were
comparable, we then assessed statistical heterogeneity using the I2.
When statistical heterogeneity was acceptable (heterogeneity test, I2 ≤
80%), the data were pooled. Otherwise, we used descriptive analysis.
When statistical heterogeneity was insignificant (I2 ≤ 50%), we selected
a fixed-effects model; otherwise (50% < I2 ≤ 80%), we applied a
random-effects model. Finally, the sources of heterogeneity were fully
explored. Risk ratio (RR) was used for dichotomous data (for example,
incidence of stroke), whereas standardized mean difference (SMD) or
weighted mean difference (WMD) was used for continuous variables (for
example, CVHI score). We calculated them with 95% confidence in­
tervals (CI), and considered a p < 0.05 to be statistical significance.
To compare the efficacy between Nao-an capsules and different doses
of aspirin and reduce heterogeneity, we performed subgroup analyses
according to the treatments of control groups. To further explore the
sources of heterogeneity, we performed a sensitivity analysis, omitting
one trial at a time. If the statistical heterogeneity changed significantly
after a trial was omitted, we reread the full-texts of trials, focusing on the
potential factors that might have led to clinical and methodological
heterogeneity, such as the geographical location of the study area,
random sequence generation, and allocation concealment method. To
explore the effect of a high risk of bias on the results, we excluded the
trials with low quality and reexamined the meta-analysis to determine
whether the findings were noticeably changed. If the findings changed
insignificantly, this indicated that our results were robust. If they
changed significantly, this indicated that the results might be unreliable.
To detect publication bias, we planned to perform quantitative tests.
Nevertheless, as these methods are unreliable when the number of
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included trials is fewer than 10, we did not perform the detection.
Certainty of evidence
Two reviewers (Liuding Wang and Wanqing Du) independently used
the Grading of Recommendations Assessment, Development, and Eval­
uation (GRADE) approach to evaluate the quality of evidence (Balshem
et al., 2011). We downgraded the certainty for 5 limitations (high risk of
bias, substantial heterogeneity, detected publication bias, imprecision,
and indirectness).
Results
Literature search
The PRISMA flow diagram illustrates how trials were identified
(Fig. 1). Our search strategy retrieved 462 records: 461 identified in
electronic databases and 1 identified in the Chinese Clinical Trial Reg­
ister. After removing 249 duplicates using NoteExpress3.2, we screened
titles and abstracts and excluded 188 ineligible records. Of the
remaining 25 trials that required full-text review, 16 trials that appeared
to be eligible were excluded for the following reasons: nonrandom
design, duplicate publication, unreported CVHI, and unknown dosage of
Nao-an capsules or treatment course (Supplementary Table 3). Ulti­
mately, 9 trials (Liu et al., 2018; Huang et al., 2015; Li and Liu, 2014;
Yang et al., 2013; Liu et al., 2012; Huang et al., 2009; Guo et al., 2008;
Guo et al., 2007; Fan et al., 2007) met our eligibility criteria.
Study characteristics
We included 9 trials in our review. All trials included participants at
high risk of stroke with CVHI < 75 and excluded participants with
previous incidences of stroke. In total, 14 744 participants were ran­
domized, with 6329 classified in the Nao-an capsules group and 8415 in
the control group. All RCTs took place in China, including Shanghai,
Beijing, Guangzhou, Xiamen, Changsha, Xiangtan, Chengdu, and Qin­
huangdao. Regarding the setting, 6 trials took place in communities,
whereas 3 trials took place in hospitals. Seven trials were two-arm trials,
whereas 2 were three-arm trials. None of the included trials compared
the effect of Nao-an capsules with that of other interventions with an
unknown effect. All trials compared the use of Nao-an capsules with that
of aspirin (50 mg, 75 mg, or 100 mg) or no intervention on the basis of
general measures to control risk factors. Five trials used the incidence of
stroke as the primary outcome, among which only 2 reported hemor­
rhagic and ischemic stroke. We summarized the details of exposure and
outcomes in each trial in Table 1.
Methodological quality
We judged the overall bias as "high risk of bias" in 6 trials (Liu et al.,
2018; Yang et al., 2013; Liu et al., 2012; Huang et al., 2009; Guo et al.,
2008, 2007), whereas identified it as "some concerns" in 3 trials. We
summarized these results in Fig. 2.
We judged the randomization process as "some concerns" because 7
trials reported few details regarding the methods of random sequence
generation or allocation concealment. In contrast, we rated 2 trials
(Huang et al., 2009; Guo et al., 2007) as "low risk of bias" because their
allocation sequences were stored by epidemiologists who did not
participate in the observation. We identified deviations from the
intended interventions in all trials because they did not report blinded
participants and personnel. Hence, in this domain, we rated 3 trials (Liu
et al., 2018; Yang et al., 2013; Huang et al., 2009) as "high risk of bias"
because the per-protocol principle was applied in analyses. However, we
rated 6 trials as "some concerns" because they used appropriate analyses,
such as intention-to-treat and random sampling. Regarding the risk of
bias due to missing outcome data, we rated 1 trial (Liu et al., 2018) as
L. Wang et al.
Fig. 1. PRISMA flow diagram for review of primary prevention of high risk of stroke by Nao-an capsules.
"high risk of bias" because of the unbalanced numbers of patients lost to
follow-up between the Nao-an capsule and aspirin groups. In addition,
we rated 1 trial (Yang et al., 2013) as "some concerns" because of a large
drop-out rate of 11%. In other studies rated as "low risk of bias", we
detected negligible losses to follow-up, the missing data were balanced
between the 2 groups, or there was no reported loss to follow-up. In the
case of the measurement of outcomes, no trials blinded outcome asses­
sors. Whether they reported a stroke generally depended on their
judgment of images. Moreover, if more imaging studies were performed
in the control group, more asymptomatic infarction would be diagnosed.
Therefore, we rated trials reporting the incidence of stroke as "high risk
of bias". Considering that CVHI score is the result of an automated test,
we rated other trials as "low risk of bias". Regarding the selection of
reported results, we rated 4 trials (Huang et al., 2015; Li and Liu, 2014;
Yang et al., 2013; Liu et al., 2012) as "some concerns" because the
adverse events were not mentioned in the results. Other trials with "low
risk of bias" completely reported observations planned in the methods of
articles despite lack of a protocol.
Efficacy outcomes
Incidence of fatal or nonfatal stroke
We found that 5 trials reported the incidence of fatal or nonfatal
stroke, including 3 trials that compared the use of Nao-an capsules with
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Phytomedicine 104 (2022) 154263
that of aspirin and 2 trials that compared the use of Nao-an capsules with
no intervention.
Nao-an capsules vs. no intervention
When compared with participants who only controlled for risk fac­
tors, the pooled results of 2 large-sample RCTs demonstrated a ~50%
decreased incidence of stroke in participants taking Nao-an capsules
(RR = 0.49, 95% CI 0.29–0.82, p = 0.006) (Fig. 3A). We detected
insignificant heterogeneity among these 2 trials (p = 0.4, I2 = 0 %).
Nao-an capsules vs. aspirin
Three trials administrated aspirin in different doses or frequencies,
including 100 mg daily, 100 mg once every other day, 75 mg daily, and
50 mg daily. To eliminate clinical heterogeneity, we performed sub­
group analyses according to the daily dose of aspirin. We detected
insignificant heterogeneity among these 3 trials (p = 0.71, I2 = 0%);
therefore, we applied a fixed-effects model.
When compared with participants taking aspirin, the consolidated
results from 3 RCTs revealed a significantly decreased incidence of
stroke in participants taking Nao-an capsules (RR = 0.56, 95% CI
0.39–0.80, p = 0.001) (Fig. 3B). However, we noticed that in subgroup
analysis, the reductions in 75 mg daily and 100 mg once every other day
 L. Wang et al.
Table 1
Basic characteristics of included trials.
Study Sample size Male/ female Age/ (year) Cerebrovascular Intervention group Control Duration/ Outcomes Methodological quality assessment
function scores group (month)
T C T C T C T C Nao-an capsule Combined Random Allocation Blind
therapy method concealment

Liu et al., 559 529 259/ 236/ 69.4± 69.7± 45.2± 47.2± 0.8 g bid CTs aspirin 100 24 1) 2) 4) Cluster Unclear None
2018 272 229 6.7 6.4 19.7 18.9 mg qod+CTs random
Huang 42 40 20/22 20/20 62.25 64.12 38.12± 37.90± For CVHI < 75, 0.8 g bid; CTs CTs 3 2) Computer Unclear None
et al., ± 7.82 ± 9.82 13.80 14.37 for CVHI < 25, 0.8 g tid. sequence
2015
Li and 83 83 - - 50-84 48.18± 45.90± 0.8 g bid CTs CTs 12 2) Unclear Unclear None
Liu, 14.69 14.53
2014
Yang 555 576 - - 64.46 66.95 36.49± 39.95± 0.8 g bid CTs CTs 18 2) 4) Unclear Unclear None
et al., ± 8.26 ± 9.67 17.64 20.88
2013
Liu et al., 2000 2069 1497/2572 62.94±7.86 < 75 0.8 g bid CTs CTs 24 1) 3) 4) Cluster Unclear None
2012 random
5

Huang 162 158 94/ 91/ 66±8 66±10 49±13 49±12 0.8 g bid CTs aspirin 100 24-36 1) 2) 3) 4) Random Kept by None
et al., 162 158 mg qd+CTs number table statisticians
2009
Guo et al., 132 146 79/53 85/61 62±10 62±9 63±15 64±14 For CVHI < 75, 0.4 g bid; CTs CTs 24 1) Random Unclear None
2008 for CVHI < 50, 0.8 g bid; for number table
CVHI < 25, 0.8 g bid + 0.4 g
qn.
Guo et al., 1656 1348 598/ 446/ 63±9 62±9 < 75 0.4-0.8 g bid CTs aspirin 50 16 1) 4) Random Unclear None
2007 1058 902 mg qd+CTs number table
Guo et al., 1656 1411 598/ 440/ 63±9 62±9 < 75 0.4-0.8 g bid CTs aspirin 75 16 1) 4) Random Unclear None
2007 1058 971 mg qd+CTs number table
Fan et al., 1140 1007 - - 45.21± 46.52± For CVHI < 75, 0.4 g bid; CTs aspirin 50 12 2) Cluster Unclear None
2007 19.68 18.05 for CVHI < 50, 0.4 g tid; for mg qd+CTs random
CVHI < 25, 0.8 g bid.
Fan et al., 1140 1048 - - 45.21± 45.26± For CVHI < 75, 0.4 g bid; CTs aspirin 75 12 2) Cluster Unclear None
2007 19.68 19.47 for CVHI < 50, 0.4 g tid; for mg qd+CTs random
CVHI < 25, 0.8 g bid.

Note. qd, once daily; qn, once a night; qod, every other day; bid, twice daily; tid, three times daily; CTs, conventional therapies for special risk factors, including diabetes, hypertension, and dyslipidemia; C, control group;
T, intervention group; (1), incidence of fatal or non-fatal stroke; (2), CVHI; (3), incidence of hemorrhagic stroke; (4), adverse events.

Phytomedicine 104 (2022) 154263

L. Wang et al.
Fig. 2. Risk of bias graph: judgements about each risk of bias item presented across all included studies.
subgroups were not statistically significant (RR75 mg qd = 0.60, 95 % CI
0.30–1.18, p = 0.14; RR100 mg qod = 0.81, 95% CI 0.37–1.75, p = 0.59)
(Fig. 3B). Conversely, in the subgroups of 50 mg aspirin daily and 100
mg aspirin daily, Nao-an capsules were shown to be superior to aspirin
in lowering the incidence of stroke with statistical significance (RR50 mg
qd = 0.47, 95 % CI 0.25–0.91, p = 0.03; RR100 mg qd = 0.46, 95% CI
0.22–0.99, p = 0.05) (Fig. 3B).
CVHI
We noticed that 6 trials reported CVHI after treatments to evaluate
the efficacy of Nao-an capsules in controlling this independent risk
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Phytomedicine 104 (2022) 154263
factor of stroke and improving cerebrovascular function. We performed
subgroup analyses based on the treatments of comparators.
Nao-an capsules vs. no intervention
When comparing the use of Nao-an capsules and no intervention, we
detected substantial heterogeneity among the 3 trials (p < 0.00001, I2 =
93%). We carefully revisited full texts and further conducted a subgroup
analysis according to the mean value of CVHI before treatments. We
accordingly found that heterogeneity was significantly decreased. In
particular, we found that for patients with relatively high CVHI (CVHI
scores before treatments: 48.18 ± 14.69; 45.90 ± 14.53), treatment
L. Wang et al.
Fig. 3. Forest plots of the incidence of stroke. (A) Nao-an capsules vs. no intervention; (B) Nao-an capsules vs. aspirin.
with Nao-an capsules was associated with statistically significant im­
provements in CVHI compared with that in the control (MD = 17.81,
95% CI 12.99–22.63, p < 0.00001) (Fig. 4A). However, for patients with
relatively low CVHI (CVHI scores before treatments: 38.12 ± 13.80;
37.90 ± 14.37; 36.49 ± 17.64; 39.95 ± 20.88), the difference was not
statistically significant (MD = 2.04, 95% CI –1.03–5.10, p = 0.19)
(Fig. 4A).
Nao-an capsules vs. aspirin
When comparing the use of Nao-an capsules and that of aspirin, we
detected that the CVHI scores before treatments in the 3 trials were
comparable (45.2 ± 19.7; 47.2 ± 18.9; 49 ± 13; 49 ± 12; 45.21 ±
19.68; 46.52 ± 18.05; 45.26 ± 19.47), exhibiting insignificant hetero­
geneity among the 4 subgroups of various aspirin doses (p = 0.2, I2 =
36%). The consolidated results from 3 RCTs demonstrated that treat­
ment with Nao-an capsules was associated with statistically significant
improvements in CVHI (MD = 10.45, 95% CI 8.94–11.97, p < 0.00001)
(Fig. 4B). Moreover, our subgroup analysis indicated that Nao-an cap­
sules were superior to any dose of aspirin in improving cerebrovascular
function (MD100 mg qod = 8.00, 95% CI 4.79–11.21, p < 0.00001; MD100
mg qd = 12.00, 95% CI 9.79–14.21, p < 0.00001; MD75 mg qd = 9.06, 95%
CI 5.21–12.91, p < 0.00001; MD50 mg qd = 10.67, 95% CI 6.77–14.57, p
< 0.00001) (Fig. 4B).
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Phytomedicine 104 (2022) 154263
Safety outcomes
Incidence of hemorrhagic stroke
We identified 2 trials that reported the incidence of hemorrhagic
stroke after exposure to Nao-an capsules.
Nao-an capsules vs. no intervention
We found that there were 3 episodes of hemorrhagic stroke reported
in the Nao-an capsule group compared to the same number in the blank
group (no intervention) (RR = 1.03, 95% CI 0.21–5.12, p = 0.97)
(Fig. 5A).
Nao-an capsules vs. aspirin
Compared with 10 episodes of hemorrhagic stroke in the aspirin
group (100 mg daily), there were only 3 episodes reported in the Nao-an
capsule group (RR = 0.29, 95% CI 0.08–1.04, p = 0.06) (Fig. 5B).
These results indicated that Nao-an capsules did not increase the risk
of hemorrhagic stroke and were thus safer than aspirin.
Incidence of gastrointestinal bleeds
We noticed that none of the included trials reported any gastroin­
testinal bleeding.
L. Wang et al. Phytomedicine 104 (2022) 154263

Fig. 4. Forest plots of CVHI score. (A) Nao-an capsules vs. no intervention; (B) Nao-an capsules vs. aspirin.

Fig. 5. Forest plots of the incidence of hemorrhagic stroke. (A) Nao-an capsules vs. no intervention; (B) Nao-an capsules vs. aspirin.

Adverse events in the Nao-an capsule groups, from high- to low-frequency, included
gastrointestinal symptoms, dizziness, headache, and gingival bleeding;
We found 5 trials that reported adverse events. In particular, 1 trial however, all these symptoms were mild and disappeared after drug
recorded no serious adverse reactions (Liu et al., 2018). Adverse events withdrawal.

8
L. Wang et al.
Compared with aspirin, Nao-an capsules were associated with a
significantly lower incidence of gastrointestinal symptoms (RR = 0.24,
95% CI 0.16–0.34, p < 0.00001) and extracranial bleeding events (RR =
0.04, 95% CI 0.00–0.64, p < 0.00001) (Fig. 6). Gastrointestinal symp­
toms in the aspirin group were relieved after oral administration of
sucralfate. Extracranial bleeding events without a description of specific
locations were likely to include gastrointestinal hemorrhage. However,
Nao-an capsules were associated with a significantly higher incidence of
headache (RR = 46.87, 95% CI 7.24–303.64, p < 0.0001) (Fig. 7).
Quality of evidence
We assessed the certainty of evidence using the GRADE system
(Table 2). We rated the quality of evidence as moderate to very low,
mainly due to the high risk of bias and imprecision.
Discussion
Summary of findings
When evaluating the efficacy of Nao-an capsules compared with no
intervention in the primary prevention of stroke, our results demon­
strated a 51% reduction in the incidence of stroke. Based on current
evidence, Nao-an capsules are to this day the only Chinese patent
medicine demonstrated to be effective in preventing first stroke. Certain
studies have shown that the major preventive mechanism of Nao-an
capsules was the inhibition of vascular endothelial cell apoptosis,
which reversed atherosclerosis (Zhang et al., 2004; 2008).
Importantly, the comparison between Nao-an capsules and aspirin
deserves more attention. First, we found that Nao-an capsules achieved a
significant decrease in stroke incidence compared with 50 mg aspirin
daily. Although the use of low-dose aspirin has been advocated owing to
reduced bleeding risks, a study indicated that on carotid atherosclerosis
50 mg aspirin daily might be inadequate in the presence of risk factors
due to the dose-dependent effect (Ranke et al., 1993). Second, Nao-an
capsules were associated with a reduced incidence of stroke compared
with 100 mg aspirin every 2 days and 75 mg aspirin daily, but without
statistical significance. A large RCT among 39 876 women receiving 100
mg of aspirin or placebo every other day found that aspirin significantly
decreased the incidence of stroke (Ridker et al., 2005). This effect might
explain the difference between the significant reduction in the incidence
of stroke in the Nao-an capsule group compared with that in the no
intervention group and the slight reduction compared with that in the
100 mg aspirin every other day group, despite the clinical heterogeneity
in subjects. Third, another encouraging result was that Nao-an capsules
Fig. 6. Forest plot of gastrointestinal symptoms and bleedings (Nao-an capsules vs. aspirin).
9
Phytomedicine 104 (2022) 154263
significantly lowered the risk of stroke compared with that of 100 mg
aspirin daily. Regarding the efficacy of 100 mg aspirin daily, the Japa­
nese Primary Prevention Project of 14 464 elderly Japanese participants
with risk factors for stroke found that a daily dose of 100 mg aspirin had
no net benefit in preventing first stroke (Uchiyama et al., 2016). We
were concerned that the increased risk of hemorrhagic stroke would
likely offset the reduced risk of ischemic stroke at this dose of aspirin.
However, according to our results, Nao-an capsules did not increase the
risk of hemorrhagic stroke. Therefore, the aforementioned findings
combined with the results of CVHI suggested additional mechanistic
advantages of Nao-an capsules over the antiplatelet effect of aspirin. In
particular, Nao-an capsules have also been shown to prevent vascular
endothelial cell damage. Regarding the comparison of its mechanism
with that of aspirin, in a study exploring the effect of antithrombosis, the
reduction in thrombus wet weight in the high-dose Nao-an capsule
extraction group (80 mg kg-1) was not statistically lower than that in the
aspirin-receiving positive control group (300 mg kg-1) (Zhang et al.,
2002). In addition, Nao-an capsules were reported to not only have the
same antithrombotic effect as aspirin but also inhibit adenosine
diphosphate (ADP)-induced thrombosis (Chen et al., 1998), likely
because they do not prevent the release of prostacyclin (Xu et al., 1984).
Regarding the safety evaluation, Nao-an capsules were safer than
aspirin in terms of adverse events, such as extracranial hemorrhage and
gastrointestinal stimulation. Nevertheless, Nao-an capsules might
induce headache and dizziness, likely because of blood pressure fluc­
tuations. Although these symptoms are mild and easy to relieve, patients
with hypertension should monitor their blood pressure.
Comparison with other studies
Compared with the published literature, the novelty and innovative
potential of our meta-analysis is given in the following points: (1) To our
best knowledge, this review is the first to focus on a certain Chinese
patent medicine for the primary prevention of stroke. Compared with
the previous Cochran systematic review of Chuanxiong preparations for
preventing stroke 10 years ago, our research question is more clearly
defined in terms of participants with CVHI < 75, Nao-an capsules,
comparators, and outcomes. (2) To facilitate the formation of recom­
mendations, the risk of bias tool 2.0 was used to strictly assess included
trials, while GRADE was used to evaluate the level of evidence in a
standardized manner.
Limitations of included trials
The included trials had a few limitations. First, the risk of stroke was
L. Wang et al. Phytomedicine 104 (2022) 154263

Fig. 7. Forest plot of headache (Nao-an capsules vs. aspirin).

Table 2
GRADE summary of outcomes for Nao-an capsules in patients at high risk of stroke.
Outcomes No. of Participants Anticipated Absolute Effects (95% CI) Relative Effect Certainty of the
(studies) Risk with CG Risk difference with EG (95% CI) Evidence (GRADE)

Incidence of fatal or non-fatal stroke (Nao-an 4374 (2) 20 per 1000 10 fewer per 1,000 (14 fewer to 4 RR 0.49 (0.29 ⨁⨁⨁◯
capsule vs. No intervention) fewer) to 0.82) MODERATEa
Incidence of fatal or non-fatal stroke (Nao-an 7387 (3) 22 per 1000 10 fewer per 1,000 (14 fewer to 4 RR 0.56 (0.39 ⨁⨁⨁◯
capsule vs. Aspirin) fewer) to 0.80) MODERATEa
Incidence of fatal or non-fatal stroke (Nao-an 3004 (1) 18 per 1000 9 fewer per 1,000 (13 fewer to 2 RR 0.47 (0.25 ⨁⨁⨁◯
capsules vs. 50 mg aspirin daily) fewer) to 0.91) MODERATEa
Incidence of fatal or non-fatal stroke (Nao-an 320 (1) 120 per 1000 65 fewer per 1,000 (94 fewer to 1 RR 0.46 (0.22 ⨁◯◯◯
capsules vs. 100 mg aspirin daily) fewer) to 0.99) VERY LOWa,b,c
Incidence of fatal or non-fatal stroke (Nao-an 996 (1) 28 per 1000 5 fewer per 1,000 (18 fewer to 21 RR 0.81 (0.37 ⨁⨁◯◯
capsules vs. 100 mg aspirin every other day) more) to 1.75) LOWa,c
Incidence of fatal or non-fatal stroke (Nao-an 3067 (1) 14 per 1000 6 fewer per 1,000 (10 fewer to 3 RR 0.60 (0.30 ⨁⨁◯◯
capsules vs. 75 mg aspirin daily) more) to 1.18) LOWa,c
Incidence of hemorrhagic stroke (Nao-an 320 (1) 63 per 1000 45 fewer per 1,000 (58 fewer to 3 RR 0.29 (0.08 ⨁◯◯◯
capsule vs. 100 mg aspirin daily) more) to 1.04) VERY LOWa,b,c
Incidence of hemorrhagic stroke (Nao-an 4069 (1) 1 per 1000 0 fewer per 1,000 (1 fewer to 6 more) RR 1.03 (0.21 ⨁⨁◯◯
capsule vs. no intervention) to 5.12) LOWa,c
CVHI (Nao-an capsule vs. aspirin) 3014 (3) The mean CVHI The mean CVHI in the EG was 10.45 - ⨁⨁⨁◯
ranged from 53.7 to higher (8.94 higher to 11.97 higher) MODERATEa
70
CVHI (Nao-an capsule vs. no intervention) 1379 (3) The mean CVHI The mean CVHI in the EG was 7.72 - ⨁⨁◯◯
ranged from 48.7 to higher (3.31 lower to 18.74 higher) LOWa,d
54.33
Gastrointestinal symptoms (Nao-an capsule vs. 4735 (2) 70 per 1000 53 fewer per 1,000 (59 fewer to 46 RR 0.24 (0.16 ⨁⨁⨁◯
aspirin) fewer) to 0.34) MODERATEa

Note. CG, control group; CI, confidence interval; EG, experimental group; RR, relative risks; a, poor methodology, including the method of randomization and blinding;
b, small sample sizes; c, CI overlaps no effect or CI boundary close to no effect (for example, CI includes RR of 1.0 or CI boundary is RR of 0.99); d, I2 ≥ 50% for
heterogeneity.

judged only by CVHI. Although CVHI has been demonstrated to predict
the 10-year risk of first stroke, AHA/ASA guidelines recommend the use
of aspirin for cardiovascular (including stroke) prophylaxis in people
with a 10-year ASCVD risk ≥ 10% (Meschia et al., 2014). There is no
evidence that CVHI < 75 is equivalent to a 10-year ASCVD risk ≥ 10%;
therefore, we failed to ensure that this risk level of included subjects in
the aspirin groups was sufficiently high for the benefits to outweigh the
risks associated with treatment. As a result, the efficacy of Nao-an
capsules might have been exaggerated compared with that of aspirin.
Second, the short-term follow-up time was not sufficiently long to fully
observe the endpoint of first stroke. Few studies have assessed the effects
of Nao-an capsules on participants at high risk of stroke with a follow-up
period longer than 3 years. Third, most trials did not report the classi­
fication of the occurred stroke. There has been a lack of information for
separately analyzing the benefit of ischemic stroke and risk of hemor­
rhagic stroke associated with Nao-an capsules. In some trials, no adverse
events were reported, which is questionable. Fourth, the included trials
suffered from key methodological limitations; the potential high risk of
bias associated with nonblinding weakened the inference of the effects
of Nao-an capsules.
Limitations of the review
According to the recommendations of AHA/ASA (Meschia et al.,
2014), the benefit of aspirin for the primary prevention of stroke is
limited to several selected population groups, such as women, chronic
renal disease patients, or people with an ASCVD 10-year risk ≥ 10%.
However, we failed to perform subgroup analyses based on these factors
because no information was available. Although we conducted subgroup
analyses based on the dose of aspirin, and the dose of Nao-an capsules
was 0.8 g twice daily in most trials, the dose of Nao-an capsules also
exhibited certain clinical heterogeneity.
Differences from protocol
In our protocol, we planned to include modifiable risk factors of
stroke, including glucose, lipids, and blood pressure, as secondary out­
comes. However, when conducting the meta-analysis for the efficacy of
controlling blood pressure, significant heterogeneity was detected
among trials. Therefore, we reconsidered whether these risk factors
were reasonable for the efficacy evaluation of Nao-an capsules. In
addition to being affected by the use of Nao-an capsules and aspirin,
blood pressure and lipids are mainly controlled by antihypertensive and
lipid-lowering drugs. These risk factors were different from CVHI, an
independent risk factor of stroke; therefore, we removed these outcomes
because of substantial clinical heterogeneity regarding the usage of
drugs. Additionally, we added safety outcomes for a more comprehen­
sive evaluation of the application of Nao-an capsules in the primary
prevention of stroke.

10
L. Wang et al.
Implications for practical application
Our review demonstrated that Nao-an capsules might have preven­
tive effects on populations at high risk of stroke, whereas the results of
subgroup analysis showed that these effects might be not significant in
the higher-risk group (populations with lower CVHI). Therefore, in
addition to therapeutic changes in the lifestyle and certain targeted
treatments of risk factors, Nao-an capsules are recommended for the
primary prevention of stroke in patients with CVHI between 40 and 75.
However, whether Nao-an capsules should be used in low-risk in­
dividuals with CVHI > 75 or very high-risk individuals with CVHI < 40
needs to be further confirmed.
At least 2691 patients were treated with Nao-an capsules for 2 years,
and therefore we suggest that Nao-an capsules could be safely admin­
istrated for at least 2 years. According to the dosage provided by most
trials, the adequate dosage of Nao-an capsules should be 0.8 g twice
daily; whether this is the optimum dosage remains unclear.
Implications for future research
Our findings supported Nao-an capsules as a promising preventive
medication for improving cerebral vascular function and reducing the
incidence of first stroke in populations at high risk of stroke. Conse­
quently, further investigations of the optimum dosage of Nao-an cap­
sules are needed to provide that these observed protective effects are
warranted. Although Nao-an capsules appear to be safe with no
increased risk of craniocerebral and extracranial hemorrhage, the re­
ported adverse reaction of headache suggests the continuous exploration
to identify people who will benefit from the use of Nao-an capsules.
The significantly reduced relative risk might not mean that the
reduction in absolute risk is always significant. Especially, as Nao-an
capsules were found to have relatively insignificant effects on the
higher-risk group with lower CVHI, it is very necessary to conduct a cost-
effectiveness evaluation of taking Nao-an capsules and measuring CVHI
for a long period in primary prevention of stroke; although a previous
study suggested that this strategy is cost-effective (Huang et al., 2003).
In future RCTs, allocation concealment methods should be rigorously
applied to avoid random invalidation, and double-blind methods should
be strictly implemented to control the bias of performance and detec­
tion. Furthermore, ischemic, hemorrhagic, fatal, and nonfatal stroke
should be evaluated separately when reporting primary endpoints, and
any adverse event should be recorded, with particular attention to the
characteristics of patients with headache or dizziness. Most importantly,
the protocol should be prospectively registered, and the findings should
be reported in strict accordance with the CONSORT-CHM Formulas
2017. In addition, a patient registry study is more flexible for endpoints
requiring a long follow-up duration. Our research group will be moni­
toring large-sample trials of Nao-an capsules to update this systematic
review with any emerging high-quality evidence.
Conclusion
In populations at high risk of stroke, administration of Nao-an cap­
sules in addition to the management of specific risk factors has been
shown to provide additional preventive effects on first stroke, without
increased bleeding risks. Although current evidence has supported Nao-
an capsules as a promising agent against first stroke, the positive effects
have been severely limited by the high risk of bias. Because these limi­
tations have further weakened the reliability of evidence from a few
studies, more RCTs with more rigorous methodological designs and
longer follow-up periods are warranted to upgrade the level of evidence
and contribute to clinical decision-making. Considering this and the
minor benefits in the very high-risk individuals, clinicians might pre­
scribe Nao-an capsules for patients who have received CVHI measure­
ment with a score within 40− 75 and are willing to accept the associated
cost.
11
Phytomedicine 104 (2022) 154263
Data availability statement
All data were generated in-house, and no paper mill was used. All
authors agree to be accountable for all aspects of work ensuring integrity
and accuracy.
Funding
This work was supported by the China Academy of Chinese Medical
Sciences (No. CI2021B006; CI2021A01301; CI2021A01310); and the
State Administration of Traditional Chinese Medicine (No. ZYYCXTD-C-
202007; NATCM Personnel and Education Department [2018] No. 12;
ZZ13-024-3).
CRediT authorship contribution statement
Liuding Wang: Conceptualization, Software, Visualization, Investi­
gation, Validation, Writing – original draft. Xueming Fan: Methodol­
ogy, Supervision, Data curation, Software. Wanqing Du: Methodology,
Visualization, Investigation. Xiao Liang: Visualization, Investigation.
Yifan Chen: Methodology, Data curation, Software. Jingzi Shi: Visu­
alization, Investigation. Linjuan Sun: Visualization, Investigation. Wei
Shen: Conceptualization, Writing – review & editing, Supervision.
Yunling Zhang: Writing – review & editing, Supervision, Project
administration, Funding acquisition.
Declaration of Competing Interest
The authors declare no conflicts of interest.
Supplementary materials
Supplementary material associated with this article can be found, in
the online version, at doi:10.1016/j.phymed.2022.154263.
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