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Efficacy and safety of Chinese herbal medicine Xiao Yao San in hypertension: A systematic review and meta-analysis

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Background: Xiao Yao San (XYS) is thought to be beneficial for the treatment of hypertension in China. Purpose: A systematic review and meta-analysis was performed to evaluate the efficacy and safety of XYS in hypertension. Study design: A comprehensive literature search was conducted in 7 electronic databases for randomized controlled trials from their inception until January 7, 2019. Methods: Methodological quality was assessed independently using the Cochrane Handbook for Systematic Reviews of Interventions. Results: A total of 17 trials including 1460 hypertensive patients met the selection criteria. Pooled analysis favored XYS plus antihypertensive drugs on blood pressure (BP), Hamilton anxiety scale, self-rating anxiety scale, self-rating depression scale, 9-item patient health questionnaire scale, total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, homocysteine, and C-reactive protein. No significant difference between XYS plus antihypertensive drugs and antihypertensive drugs on major cardiovascular and cerebrovascular events was identified. XYS was well tolerated in the treatment of hypertension. Conclusion: XYS adjuvant to antihypertensive drugs maybe beneficial for hypertensive patients in lowering BP, improving depression, regulating blood lipids, and inhibiting inflammation. However, the efficacy and safety of XYS are still uncertain due to methodological shortcomings. More long-term, randomized, double-blinded clinical trials are needed in future studies.
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Phytomedicine
journal homepage: www.elsevier.com/locate/phymed
Review
Efficacy and safety of Chinese herbal medicine Xiao Yao San in
hypertension: A systematic review and meta-analysis
Xiong Xingjiang
a,1,
, Wang Pengqian
b
, Duan Lian
a,1
, Liu Wei
c,1
, Chu Fuyong
c
, Li Shengjie
d,e
,
Li Xiaoke
f
, Su Kelei
g
, You Hu
h,i,⁎⁎
, Xing Yanwei
a,
a
Department of Cardiology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
b
Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
c
Department of Cardiology, Traditional Chinese Medicine Hospital of Beijing, Beijing University of Chinese Medicine, Beijing, China
d
Department of Biological Science and Technology, School of Life Sciences, Tsinghua University, Beijing, China
e
Department of Molecular Biology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
f
Bio-organic and Natural Products Laboratory, McLean Hospital, Harvard Medical School, Belmont, USA
g
Department of Respiration, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
h
Department of Chinese Medicine, Nanjing Benq Hospital, Nanjing Medical University, Nanjing, China
i
College of Basic Medicine, Nanjing University of Chinese Medicine, Nanjing, China
ARTICLE INFO
Keywords:
Hypertension
Blood pressure
Traditional Chinese medicine
Xiao Yao San
Systematic review
Meta-analysis
ABSTRACT
Background: Xiao Yao San (XYS) is thought to be beneficial for the treatment of hypertension in China.
Purpose: A systematic review and meta-analysis was performed to evaluate the efficacy and safety of XYS in
hypertension.
Study design: A comprehensive literature search was conducted in 7 electronic databases for randomized con-
trolled trials from their inception until January 7, 2019.
Methods: Methodological quality was assessed independently using the Cochrane Handbook for Systematic
Reviews of Interventions.
Results: A total of 17 trials including 1460 hypertensive patients met the selection criteria. Pooled analysis
favored XYS plus antihypertensive drugs on blood pressure (BP), Hamilton anxiety scale, self-rating anxiety
scale, self-rating depression scale, 9-item patient health questionnaire scale, total cholesterol, triglycerides, high-
density lipoprotein cholesterol, low-density lipoprotein cholesterol, homocysteine, and C-reactive protein. No
significant difference between XYS plus antihypertensive drugs and antihypertensive drugs on major cardio-
vascular and cerebrovascular events was identified. XYS was well tolerated in the treatment of hypertension.
Conclusion: XYS adjuvant to antihypertensive drugs maybe beneficial for hypertensive patients in lowering BP,
improving depression, regulating blood lipids, and inhibiting inflammation. However, the efficacy and safety of
XYS are still uncertain due to methodological shortcomings. More long-term, randomized, double-blinded
clinical trials are needed in future studies.
Introduction
Hypertension is an important public-health challenge worldwide
(Lawes et al., 2008). The Global Burden of Disease Study identified
elevated blood pressure (BP) as the leading risk factor for death and
disability-adjusted life-years lost during 2010 (Lim et al., 2012). It has
been well recognized as a major independent risk factor for coronary
heart disease, heart failure, stroke, peripheral vascular disease,
https://doi.org/10.1016/j.phymed.2019.152849
Received 19 September 2018; Received in revised form 15 January 2019; Accepted 26 January 2019
Abbreviations: AEs, adverse events; BP, blood pressure; CI, confidence interval; CRP, C-reactive protein; DBP, diastolic blood pressure; HAMA, Hamilton anxiety
scale; Hcy, homocysteine; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; LSI, life style intervention; MCCE, major cardi-
ovascular and cerebrovascular events; PHQ-9, 9-item patient health questionnaire scale; RCT, randomized controlled trial; REM, random effects model; RR, risk ratio;
SAS, self-rating anxiety scale; SBP, systolic blood pressure; SDS, self-rating depression scale; TC, total cholesterol; TG, triglycerides; TCM, traditional Chinese
medicine; WMD, weighted mean difference; XPAD, Xiao Yao San plus antihypertensive drugs; XPLSI, Xiao Yao San plus life style intervention; XYS, Xiao Yao San
Corresponding authors.
⁎⁎
Co-corresponding author.
E-mail addresses: xiongxingjiangtcm@163.com (X. Xiong), 364577807@qq.com (H. You), xingyanwei12345@163.com (Y. Xing).
1
These authors contributed equally.
Phytomedicine 61 (2019) 152849
0944-7113/ © 2019 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/BY-NC-ND/4.0/).
T
cognitive impairment, renal impairment, and visual impairment, which
brings about a heavy economic burden to countries and individuals
(Vasan et al., 2001; Go et al., 2014; MacMahon et al., 1990). It is also
predicted that the number of patients with hypertension is increased by
about 60% to a total of 1.56 billion by 2025 (Kearney et al., 2005).
Antihypertensive therapy has been widely used, but the hypertension
awareness, management, and control remained poor due to adverse
effects and intolerance of antihypertensive drugs by hypertensive pa-
tients (Guo et al., 2012). Additionally, depression and anxiety, which
are commonly co-existing psychological states, could influence physical
health undoubtedly. Co-occurrence of depression with hypertension is
not rare currently. Currently, the association between depression and
hypertension has been established by an increasing number of epide-
miological studies and systematic reviews (Aaron et al., 2015; Kayano
et al., 2015; Maatouk et al., 2016; Neupane et al., 2015; Ho et al.,
2015). Therefore, depression is probably an independent risk factor
of hypertension (Meng et al., 2012). Patients with depression are at
high risk for developing hypertension, as well as more likely to have
poor BP control (Moise et al., 2014). Therefore, it is important to take
depression into consideration during the process of prevention and
treatment of hypertension. As a result, the benefits of complementary
and alternative therapies for both hypertension and depression are
being explored (Brook et al., 2013; Sharifi-Rad et al., 2016; Vogel et al.,
2005; Xiong et al., 2013a; Xiong 2015; Zhang et al., 2012).
Chinese herbal medicine has been widely used to treat hypertension
with a long history in East Asian (Wang and Xiong, 2012a; Xiong et al.,
2014). In traditional Chinese medicine (TCM), hypertension is nearly
equivalent to the domain of “vertigo” and “headache” which is re-
corded in Inner Canon of Yellow Emperor (Huang Di Nei Jing in Chi-
nese), a classical literature from the Warring States period (475–221
BCE) (Xiong et al., 2013b). Hypertension can be divided into different
categories or syndromes based on various clinical signs and symptoms
(Wang and Xiong, 2013). In TCM, “liver qi stagnation”, “spleen defi-
ciency”, and “fluid retention” are acknowledged to be the basic pa-
thogenesis of hypertension (Wang and Xiong, 2012b). Xiao Yao San
(XYS), originated in the Formulae of the Bureau of People's Welfare
Pharmacies (Taiping Huimin Hejiju Fang in Chinese) in the Song Dynasty
of China (960–1127 CE), is one of the most utilized TCM classic herbal
formulae. It could relieve liver qi stagnancy, tonify spleen qi, and dis-
sipate excessive fluid. The XYS decoction is composed of 8 crude herbs,
including Thorowax Root (Chaihu, Radix Bupleuri), Chinese Angelica
Root (Danggui, Radix Angelicae Sinensis), White Peony Root (Baishao,
Radix Albus Paeoniae Lactiflorae), White Atractylodes Rhizome
(Baizhu, Rhizoma Atractylodis Macrocephalae), Poria (Fuling, Scier-
otium Poriae Cocos), Liquoric Root (Gancao, Radix Glycyrrhizae), Field
Mint (Bohe, Herba Menthae Haplocalycis), and Fresh Ginger Rhizome
(Shengjiang, Fresh Rhizoma Zingiberis). Various chemical compounds,
such as total glucosides of paeony, volatile oil of radix angelicae si-
nensis, quercetin, liquiritin, saikosaponins, curcumin, isorhamnetin,
and kaempferol, are contained in XYS (Li and Xiang, 2010; Chen et al.,
2016; Li et al., 2015).
XYS is widely used for the treatment of depression by TCM physi-
cians now (Zhang et al., 2012). Recently, evidence from human trials
suggested that XYS has been considered to be effective for the treatment
of hypertension. The animal experiments indicated that XYS could not
only lower BP (Mao, 2011), but also reduce blood sugar, improve in-
sulin sensitivity, reduce cholesterol, triglyceride, low density lipopro-
tein, and increase high density lipoprotein (Zhu, 2013). The anti-
hypertensive pharmacological effects are mainly related to total
glucosides of paeony, volatile oil of radix angelicae sinensis, etc. The
total glucosides of paeony could lower BP and blood sugar, improve
insulin sensitivity, in insulin resistance rats (Chen and Zhu, 2013) and
metabolic syndromic-hypertension rats (Feng et al., 2010). The essen-
tial oil of Angelica sinensis can lower BP through decrease the level of
peripheral plasma rennin, endothelin-1, and vascular endothelial
growth factor, and up regulation the expression of ACE2/Ang1-7/Mas
receptor axis (Wang et al., 2018; Yi et al., 2017). However, conflicting
results regarding the BP-lowering effect of XYS have been identified in
other studies. Although so many systematic reviews and meta-analysis
on Chinese herbal medicines for hypertension have been conducted, the
efficacy and safety of XYS haven't been evaluated until now. What's
more, no systematic reviews and meta-analysis assessed the efficacy of
Chinese herbal medicines on both blood pressure and depression so far.
Therefore, this study aims to evaluate the efficacy and safety of XYS on
BP and other cardiovascular risk factors in patients with hypertension
in this study.
Methods
This study was conducted following the Preferred Reporting Items
for Systematic Reviews and Meta-analyses (PRISMA) (Moher et al.,
2009).
Search strategy
Randomized controlled trials (RCTs) that evaluated the effect of XYS
for hypertension were searched in the following 7 electronic databases
from their inception until January 7, 2019: the Chinese National
Knowledge Infrastructure (CNKI, from 1980 to 2018), Chinese
Scientific Journal Database (VIP, from 1989 to 2018), Chinese
Biomedical Literature Database (CBM, from 1978 to 2018), Wanfang
Database (from 1998 to 2018), Cochrane Library (from 1996 to 2018),
PubMed (from 1959 to 2018), and EMBASE (from 1980 to 2018). We
used the following terms: (“blood pressure” OR “high blood pressure”
OR “primary hypertension” OR “hypertension” OR “essential hy-
pertension”) AND (“xiao yao” OR “xiao yao san” OR “xiao yao powder
OR “xiaoyao” OR “xiaoyaosan” OR “xiaoyao powder”) AND (“clinical
trial” OR “randomized controlled trial” OR “randomised controlled
trial”). Reference of important articles were searched manually for
possible relevant studies. No restriction on language was applied.
Study selection
Type of studies
Only RCTs investigating the association between intake of XYS and
BP were included in this review. Studies were excluded if: (a) they were
not randomized; (b) the control group was not used; (c) they were
animal experiments; (d) outcomes regarding the BP data were not re-
ported; and (e) no enough data could be extracted for statistical
pooling.
Type of participants
Trials were considered eligible for inclusion if they were conducted
in patients with hypertension, with no restriction on age, gender, or
nationality. Studies were excluded if patients with secondary hy-
pertension were enrolled.
Type of interventions
According to the personalized treatment principle in TCM basic
theory, XYS could be modified based on the chief complaint and ac-
companying symptoms when seeing a doctor. However, Thorowax Root
(Chaihu, Radix Bupleuri), one of the most critical herb in XYS (also
named “Jun” herb in TCM), can't be removed. RCTs that compared XYS
or modified XYS as the active intervention in the treatment group vs.
placebo, life style intervention (LSI), or antihypertensive drugs in the
control group were included. RCTs that tested XYS plus anti-
hypertensive drugs (XPAD) vs. antihypertensive drugs and XYS plus LSI
(XPLSI) vs. LSI were also considered. However, trials were excluded if
any other medications, including qigong, Tai Chi, acupuncture, cupping,
moxibustion, and massage, were used as co-interventions. No restric-
tion on dosage of each herb in XYS was preset. The treatment duration
should be at least 2 weeks.
X. Xiong, et al. Phytomedicine 61 (2019) 152849
2
Type of outcome measures
The primary outcome was defined as BP including categorical BP,
systolic blood pressure (SBP), and diastolic blood pressure (DBP). The
secondary outcomes included major cardiovascular and cere-
brovascular events (MCCE), Hamilton anxiety scale (HAMA), self-rating
anxiety scale (SAS), self-rating depression scale (SDS), 9-item patient
health questionnaire scale (PHQ-9), total cholesterol (TC), triglycerides
(TG), high-density lipoprotein cholesterol (HDL-C), low-density lipo-
protein cholesterol (LDL-C), homocysteine (Hcy), C-reactive protein
(CRP), and adverse events (AEs).
Data extraction
The titles and abstracts of potentially eligible studies were in-
dependently screened by 2 reviewers (XJX, PQW) according to the pre-
described search strategy. Then, full texts of the possible studies were
retrieved and reviewed based on the inclusion and exclusion criteria.
Subsequently, data of the included trials was extracted independently
by 2 reviewers (WL, FYC). The following information was retrieved:
title, first author's name, publication year, sample size, mean partici-
pant age, sex distribution, study design, diagnostic criteria, baseline BP,
interventions in the treatment and control groups, composition of XYS
or modified XYS, dosage, duration, dropouts, and outcome measures.
Any discrepancy was discussed with the third party (HY, YWX).
Methodological quality assessment
The methodological quality of each included trials was graded in-
dependently by 2 reviewers (SJL, XKL) according to the Cochrane col-
laboration tool. It is comprised of 7 domains: adequate sequence gen-
eration, concealment of allocation, blinding of participants and
personnel, incomplete outcome data, selective reporting, and other
biases (Higgins and Green, 2014). Three levels were used to assess the
methodological quality: “low risk of bias” (+), “high risk of bias” (−),
and “unclear risk of bias” (?). Consensus on this issue was researched
under the help of a third party (LD, KLS, YH) when necessary.
Data synthesis and analysis
Summary relative risk (RR) and 95% confidence intervals (CIs) were
calculated for MCCE, categorical BP, and AEs. Weighted mean differ-
ence (WMD) and 95% CIs were calculated for SBP, DBP, HAMA, SAS,
SDS, PHQ-9, TC, TG, HDL-C, LDL-C, Hcy, and CRP. The heterogeneity
was estimated by chi-squared test, and it was presented as significant
when I
2
statistics >50% or p< 0.05 (Higgins et al., 2003). The random
effects model (REM) was applied for the meta-analysis if significant
heterogeneity was identified; otherwise, the fixed effects model was
applied. Subgroup analyses according to the type of treatment or con-
trol group were conducted. The treatment groups were classified into
XYS used alone, XPAD, and XPLSI. The control groups were classified
Fig. 1. PRISMA 2009 flow diagram.
X. Xiong, et al. Phytomedicine 61 (2019) 152849
3
Table 1
Characteristics of the 17 studies included in the meta-analysis.
Author(s) Sample size
(randomized/
analyzed)
Trial design Diagnostic criteria Experimental Control Duration Adverse
events report
Outcome measures
Sun and Liu (2015) 60/60 Single
center;
parallel
FMCM; HAMA Modified XYS (1
dose/300 ml/d)+C
Nifedipine controlled release tablet (30 mg, qd) and
doxepin (50 mg, tid)
2 weeks N SBP, DBP, and HAMA
Gong (2010) 60/60 Single
center;
parallel
CGMH-2005;
GCRNDTCM
XYS (1 dose/d)+C Extended release nifedipine tablet (10 mg, bid) 8 weeks Y SBP, DBP, HAMA, blood
lipids (TC, TG, HDL-C, LDL-
C), CRP, and MCCE
Teng (2009) 59/59 Single
center;
parallel
CGMH-2005; HAMA Modified XYS (1 dose/d)+C Extended release nifedipine tablet (10 mg, bid) 6 weeks N SBP, DBP, and HAMA
Ye (2014) 60/60 Single
center;
parallel
CGMH-2010 XYS (3 g, tid)+C Amlodipine besylate tablet (5 mg, qd) 6 weeks N SBP, DBP, SAS and SDS
Lin (2012) 158/158 Single
center;
parallel
NR XYS (3 g, tid)+C Amlodipine besylate tablet (5 mg, qd) 12 weeks N SBP and DBP
Ma and Li (2015) 46/46 Single
center;
parallel
CGMH-2010;
CCDCD
Modified XYS (300 ml/d) and
amlodipine besylate tablet (5 mg,
qd)
Amlodipine besylate tablet (5 mg, qd) and
lorazepam tablet (1 mg, tid)
4 weeks N SBP, DBP and HAMA
Zhou (2015) 73/73 Single
center;
parallel
WHO-ISH GMH-
1999
Modified XYS (1 dose/d)+C Nifedipine (10 mg, qd) and fluoxetine (20 mg, qd) 4 weeks N SBP, DBP and SDS
Liu and Dong (2008) 165/165 Single
center;
parallel
WHO-ISH GMH-
1999; HAMA
Modified XYS (12 g, tid)+C Dihydrochlorothiazide (10 mg, qd), nifedipine
controlled release tablet (20 mg, qd), and
maprotiline (25–250 mg, qd)
12 weeks Y SBP, DBP and HAMA
Wang and Dong (2012) 60/60 Single
center;
parallel
CGMH-2005;
HAMA; GDTCIDCM
Modified XYS (1 dose/d) and
antihypertensive drugs
Antihypertensive drugs and buspirone
hydrochloride tablet (5–10 mg, tid)
4 weeks N SBP, DBP and HAMA
Li et al. (2012) 79/79 Single
center;
parallel
ESH/ESC-2007;
TNTOGD
Modified XYS (6 g, bid)+CValsartan (50 mg, qd) 12 weeks N SBP, DBP, Hcy, and HDL-C
Liu et al. (2009) 106/106 Single
center;
parallel
WHO-ISH GMH-
1999
Modified XYS (1 dose/d)+C Amlodipine besylate tablet (5 mg, qd), nimodipine
(10 mg, tid), and metoprolol (25 mg, bid)
4 weeks N BP
Zhou and Qi (2006) 130/130 Single
center;
parallel
WHO-ISH GMH-
1999
T1: XYS (6–8 g, bid-tid)+CMetoprolol (25 mg, bid) 4 weeks N BP
T2: XYS (6–8 g, bid-tid)
Xie (2006) 50/50 Single
center;
parallel
WHO-ISH GMH-
1999; HAMA
XYS (6 g, tid)+C Enalapril (5 mg, bid) 8 weeks N BP and HAMA
Gong et al. (2014) 84/84 Single
center;
parallel
CGMH-2005; PHQ-9 Modified XYS (6–9 g, bid)+C Antihypertensive drugs (diuretic, CCB, ACEI, and
ARB)
12 weeks Y BP and PHQ-9
Wu and Chen (2003) 84/84 Single
center;
parallel
WHO-ISH GMH-
1999; SDCEDSCM
Modified XYS (1 dose/d) Oryzanol (20 mg, tid), Vitamine B1 (10 mg, tid), and
nifedipine (10 mg, tid)
3 weeks N BP
(continued on next page)
X. Xiong, et al. Phytomedicine 61 (2019) 152849
4
into LSI used alone and antihypertensive drugs. Potential publication
bias was also assessed by visual inspection of a funnel plot. An asym-
metric inverted funnel-shape scatter plot of the effects of XYS against a
measure would indicate the existence of potential publication bias
(Sterne and Egger, 2001). Review Manager, Version 5.3 (The Nordic
Cochrane Centre, Copenhagen, Denmark) was used for data synthesis
and analysis. p< 0.05 was considered statistically significant, except
where otherwise specified.
Results
Study identification
Based on the search strategy, 222 potential relevant articles were
searched by both electronic and manual search in the 7 databases. After
removal of 110 duplicates, 112 reports were retrieved. After going
through the titles and abstracts, 81 articles were excluded because they
failed to meet the inclusion criteria, and the remaining 31 articles were
retrieved in full text for further assessment. After further reading, 14
articles were excluded for the reasons listed in Fig. 1. Finally, a total of
17 eligible studies were included in this meta-analysis (Sun and Liu,
2015; Gong, 2010; Teng, 2009; Ye, 2014; Lin, 2012; Ma and Li, 2015;
Zhou, 2015; Liu and Dong, 2008; Wang and Dong, 2012; Li et al., 2012;
Liu et al., 2009; Zhou and Qi, 2006; Xie, 2006; Gong et al., 2014; Wu
and Chen, 2003; Wang et al., 2014; Li, 2015).
Study characteristics
The basic characteristics of the 17 included studies were summar-
ized in Tables 1 and 2. All trials were conducted in China. In general,
1460 hypertensive patients were included. The sample size ranged from
46 to 165 participants. One trial was a three-arm design, with 2 treat-
ment groups and 1 control group (Zhou and Qi, 2006). In the treatment
groups, 14 studies used XPAD (Sun and Liu, 2015; Gong, 2010; Teng,
2009; Ye, 2014; Lin, 2012; Ma and Li, 2015; Zhou, 2015; Liu and Dong,
2008; Wang and Dong, 2012; Li et al., 2012; Liu et al., 2009; Zhou and
Qi, 2006; Xie, 2006; Gong et al., 2014), 3 studies used XYS alone (Zhou
and Qi, 2006; Wu and Chen, 2003; Wang et al., 2014), and 1 study used
XPLSI (Li, 2015). Detailed information about the ingredients of XYS
used in all the 17 studies was listed in Table 3. In terms of control
conditions, 16 studies used antihypertensive drugs (Sun and Liu, 2015;
Gong, 2010; Teng, 2009; Ye, 2014; Lin, 2012; Ma and Li, 2015; Zhou,
2015; Liu and Dong, 2008; Wang and Dong, 2012; Li et al., 2012; Liu
et al., 2009; Zhou and Qi, 2006; Xie, 2006; Gong et al., 2014; Wu and
Chen, 2003; Wang et al., 2014) and 1 study used LSI (Li, 2015). The
efficacy and safety of XYS for hypertension was reported in all 17 in-
cluded studies. BP as the primary outcome measure was reported in all
studies, with continuous BP in 11 studies (Sun and Liu, 2015; Gong,
2010; Teng, 2009; Ye, 2014; Lin, 2012; Ma and Li, 2015; Zhou, 2015;
Liu and Dong, 2008; Wang and Dong, 2012; Li et al., 2012; Li, 2015)
and categorical BP in 6 studies (Liu et al., 2009; Zhou and Qi, 2006; Xie,
2006; Gong et al., 2014; Wu and Chen, 2003; Wang et al., 2014). In
terms of secondary outcome measures, MCCE was observed in 1 study
(Gong, 2010). The change of HAMA was observed in 7 studies (Sun and
Liu, 2015; Gong, 2010; Teng, 2009; Ma and Li, 2015; Liu and Dong,
2008; Wang and Dong, 2012; Xie, 2006), SAS was observed in 1 study
(Ye, 2014), SDS was observed in 2 studies (Ye, 2014; Zhou, 2015), PHQ-
9 was observed in 1 study (Gong et al., 2014), blood lipids including TC
(Gong, 2010), TG (Gong, 2010), HDL-C (Gong, 2010; Li et al., 2012),
LDL-C (Gong, 2010) were observed in 2 studies (Gong, 2010; Li et al.,
2012), Hcy was observed in 1 study (Li et al., 2012), CRP was observed
in 1 study (Gong, 2010), and AEs were reported in 4 studies (Gong,
2010; Liu and Dong, 2008; Gong et al., 2014; Wang et al., 2014), re-
spectively. Although no detailed information on dosage of each herb
was provided in 7 studies (Gong et al., 2014; Li et al., 2012; Lin, 2012;
Liu and Dong, 2008; Xie, 2006; Ye, 2014; Zhou and Qi, 2006), the daily
Table 1 (continued)
Author(s) Sample size
(randomized/
analyzed)
Trial design Diagnostic criteria Experimental Control Duration Adverse
events report
Outcome measures
Wang et al. (2014) 90/90 Single
center;
parallel
PIM; SDCEDSCM Modified XYS (1 dose/d) Amlodipine besylate tablet (5–10 mg, qd) 3 weeks Y BP
Li (2015) 96/96 Single
center;
parallel
WHO-ISH GMH-
1999; GCRNDTCM
Modified XYS (1 dose/d)+C Exercise, diet control, improving the lifestyle,
quitting smoking, and limiting alcohol
8 weeks N SBP and DBP
Abbreviations: ACEI: angiotensin converting enzyme inhibitor; ARB: angiotensin receptor blocker; BP: blood pressure; C: control group; CCB: calcium channel blocker; CCDCD: Chinese classification and diagnostic criteria
of mental disorders; CGMH: Chinese guidelines for the management of hypertension; CRP: C-reactive protein; DBP: diastolic blood pressure; FMCM: Fuwai manual of cardiovascular medicine; GCRNDTCM: guidelines of
clinical research of new drugs of traditional Chinese medicine; GDTCIDCM: guidelines for diagnosis and treatment of common internal diseases in Chinese medicine; HAMA: Hamilton anxiety scale; Hcy: homocysteine;
HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; MCCE: major cardiovascular and cerebrovascular events; N: no; NR: not reported; PIM: practice of internal medicine; PHQ-9: 9-
item patient health questionnaire scale; SAS: self-rating anxiety scale; SBP: systolic blood pressure; SDCEDSCM: standard of diagnosis and curative effect of disease and syndrome of Chinese medicine; SDS: self-rating
depression scale; TC: total cholesterol; TG: triglycerides; TNTOGD: the new treatment of obstetrics and gynecology diseases; WHO-ISH GMH: World Health Organization-international society of hypertension guidelines
for the management of hypertension; XYS: xiao yao san; and Y: yes.
X. Xiong, et al. Phytomedicine 61 (2019) 152849
5
dosage of XYS was reported in Table 1. All of included studies reported
the treatment duration. It ranged from 2 to 12 weeks. Among them,
only 4 trials have a long term follow up with more than 12 weeks (Gong
et al., 2014; Li et al., 2012; Lin, 2012; Liu and Dong, 2008).
Risk of bias
The methodological quality of 17 included studies was summarized
in Table 4. The risk of bias across studies was evaluated by criteria from
Cochrane Handbook for Systematic Reviews of Interventions
(Higgins and Green, 2014). Although randomization was declared in all
the included studies, 8 studies reported the method of random se-
quences generation, including random number table (Gong, 2010;
Teng, 2009; Ye, 2014; Ma and Li, 2015; Liu and Dong, 2008; Wang and
Dong, 2012; Li et al., 2012; Li, 2015). However, no details were iden-
tified in the domains of random allocation concealment, blinding of
participants, personnel and outcome assessors, and selective outcome
reporting. Because no preregistered protocols could be obtained from
the primary authors, the selective reporting was considered to be un-
clear.
Primary outcome
BP, either categorical or continuous BP, was reported in all the in-
cluded trials and subgroup analysis was performed. Meta-analysis of 14
trials (Sun and Liu, 2015; Gong, 2010; Teng, 2009; Ye, 2014; Lin, 2012;
Ma and Li, 2015; Zhou, 2015; Liu and Dong, 2008; Wang and Dong,
2012; Li et al., 2012; Liu et al., 2009; Zhou and Qi, 2006; Xie, 2006;
Gong et al., 2014) comparing XPAD with antihypertensive drugs re-
vealed a significant lowering effect of XPAD in SBP (10 trials, n= 821;
WMD: −8.94 mmHg; 95% CI: −13.06 to −4.81; I
2
=89%,
p< 0.0001; Fig. 2a), DBP (10 trials, n= 821; WMD: −4.93 mmHg;
95% CI: −7.03 to −2.83; I
2
=72%, p< 0.00001; Fig. 2b), and BP (4
trials, n= 264; RR: 1.24; 95% CI: 1.11–1.39; I
2
=6%, p= 0.0001;
Fig. 2c). However, there is no significant difference between XYS and
antihypertensive drugs on BP (3 trials, n= 256; RR: 1.01; 95% CI: 0.93
to 1.09; I
2
=0%, p= 0.90; Fig. 3). Compared with LSI, XPLSI exhibited
significant lowering effects on SBP (1 trial, n= 96; WMD:
−13.39 mmHg; 95% CI: −17.89 to −8.89; p< 0.00001), but no sig-
nificant difference on DBP (1 trial, n= 96; WMD: −2.53 mmHg; 95%
CI: −5.48 to 0.42; p = 0.09).
Secondary outcomes
MCCE
MCCE was reported in only 1 trial conducted by Gong (2010). At the
end of the trial, no patient suffered from MCCE in both treatment and
control groups. Therefore, no significant difference between XPAD and
antihypertensive drugs was identified.
HAMA, SAS, SDS, and PHQ-9
HAMA at baseline and after intervention was reported in 7 trials
(Sun and Liu, 2015; Gong, 2010; Teng, 2009; Ma and Li, 2015; Liu and
Dong, 2008; Wang and Dong, 2012; Xie, 2006) that compared XPAD
with antihypertensive drugs. The meta-analysis revealed a significant
reduction by XPAD in HAMA (7 trials, n= 500; WMD: −6.67; 95% CI:
Table 2
Basic characteristics of included subjects in the 17 studies.
References T/C (M/F) Age (years) SBP (mmHg) DBP (mmHg) Baseline difference
BT AT BT AT
Sun and Liu (2015) T: 30 (20/10) T: 60.22 ± 12.52 T: 163.30 ± 12.60 T: 130.60 ± 10.70 T: 101.60 ± 8.40 T: 82.80 ± 7.80 NSD
C: 30 (22/8) C: 62.20 ± 17.33 C: 162.50 ± 13.40 C: 143.40 ± 11.50 C: 103.40 ± 7.80 C: 91.90 ± 9.80
Gong (2010) T: 30 (18/12) T: 49.20 ± 6.60 T: 162.40 ± 18.20 T: 128.50 ± 17.40 T: 99.80 ± 9.20 T: 85.40 ± 9.10 NSD
C: 30 (17/13) C: 50.50 ± 5.40 C: 161.60 ± 17.90 C: 140.60 ± 17.20 C: 100.50 ± 9.40 C: 86.10 ± 9.00
Teng (2009) T: 30 (M/F: NR) T: 45.43 ± 8.37 T: 151.20 ± 7.46 T: 130.67 ± 7.27 T: 88.00 ± 6.00 T: 75.67 ± 6.99 NSD
C: 29 (M/F: NR) C: 45.20 ± 8.09 C: 151.38 ± 7.60 C: 142.41 ± 6.25 C: 88.28 ± 5.51 C: 84.62 ± 4.73
Ye (2014) T: 30 (14/16) T: 60.70 ± 6.50 T: 159.33 ± 14.17 T: 145.50 ± 11.08 T: 89.50 ± 11.24 T: 80.59 ± 6.09 NSD
C: 30 (19/11) C: 59.80 ± 6.40 C: 157.50 ± 15.16 C: 147.83 ± 12.57 C: 90.33 ± 9.54 C: 85.27 ± 7.61
Lin (2012) T: 80 (M/F: NR) 45–55 T: 155.10 ± 10.30 T: 117.50 ± 9.20 T: 102.20 ± 8.30 T: 82.10 ± 6.10 NSD
C: 79 (M/F: NR) T/C: NR C: 153.60 ± 9.80 C: 135.20 ± 10.20 C: 103.50 ± 8.10 C: 87.60 ± 8.90
Ma and Li (2015) T: 23 (16/7) T: 63.82 ± 9.43 T: 164.70 ± 15.10 T: 136.60 ± 11.80 T: 109.00 ± 6.30 T: 89.80 ± 5.40 NSD
C: 23 (14/9) C: 60.34 ± 10.66 C: 165.10 ± 14.40 C: 148.40 ± 10.50 C: 107.90 ± 7.00 C: 97.50 ± 8.50
Zhou (2015) T: 38 (27/11) T: 56.90 ± 3.50 T: 162.70 ± 9.70 T: 154.30 ± 9.20 T: 89.50 ± 9.60 T: 81.40 ± 8.70 NSD
C: 35 (21/14) C: 57.40 ± 3.80 C: 160.50 ± 11.80 C: 158.10 ± 8.60 C: 90.80 ± 10.10 C: 87.20 ± 10.50
Liu and Dong (2008) T: 80 (28/52) T: 46.00 ± 9.10 T: 146.20 ± 11.60 T: 130.30 ± 9.80 T: 100.30 ± 3.40 T: 85.70 ± 8.10 NSD
C: 85 (30/55) C: 47.50 ± 8.30 C: 143.30 ± 11.20 C: 130.30 ± 11.20 C: 100.60 ± 4.90 C: 86.70 ± 6.80
Wang and Dong (2012) T: 30 (11/19) T: 51.40 ± 8.60 T: 166.80 ± 13.06 T: 155.53 ± 11.60 T: 87.57 ± 8.37 T: 80.83 ± 9.36 NSD
C: 30 (10/20) C: 53.70 ± 7.20 C: 163.73 ± 11.72 C: 162.13 ± 11.65 C: 90.93 ± 9.43 C: 86.93 ± 11.61
Li et al. (2012) T: 39 (M/F: NR) T: 50.80 ± 3.90 T: 156.40 ± 11.60 T: 131.80 ± 6.60 T: 93.40 ± 9.50 T: 81.70 ± 8.50 NSD
C: 40 (M/F: NR) C: 51.10 ± 4.70 C: 152.10 ± 14.30 C: 142.70 ± 7.90 C: 95.00 ± 7.70 C: 82.50 ± 7.30
Liu et al. (2009) T: 59 (M/F: NR) T: 49.60 NR NR NR NR NSD
C: 47 (M/F: NR) C: 49.20
Zhou and Qi (2006) T1: 48 (M/F: NR) 44–56
T2: 40 (M/F: NR) NR NR NR NR NSD
C: 42 (M/F: NR) T1/T2/C: NR
Xie (2006) T: 25 (10/15) T: 35–65 NR NR NR NR NSD
C: 25 (12/13) C: 33–66
Gong et al. (2014) T: 42 (M/F: NR) 30–62 NR NR NR NR NSD
C: 42 (M/F: NR) T/C: NR
Wu and Chen (2003) T: 42 (M/F: NR) T: 45–65 NR NR NR NR NSD
C: 42 (M/F: NR) C: 46–64
Wang et al. (2014) T: 45 (25/20) T: 51.00 ± 0.50 NR NR NR NR NSD
C: 45 (24/21) C: 52.00 ± 0.40
Li (2015) T: 48 (M/F: NR) 43.46 ± 6.89 T: 157.32 ± 10.46 T: 131.87 ± 11.02 T: 95.32 ± 8.16 T: 87.79 ± 7.26 NSD
C: 48 (M/F: NR) T/C: NR C: 156.78 ± 11.26 C: 145.26 ± 11.48 C: 94.89 ± 8.16 C: 90.32 ± 7.49
Abbreviations: AT: after treatment; BT: before treatment; C: control group; DBP: diastolic blood pressure; F: female; M: male; NR: no reported; NSD: no significant
difference; SBP: systolic blood pressure; and T: treatment group.
X. Xiong, et al. Phytomedicine 61 (2019) 152849
6
Table 3
The ingredients of Xiao Yao San used in the 17 studies.
References CHM Ingredients of XYS
Sun and Liu (2015) Modified XYS Thorowax Root (Chaihu, Radix Bupleuri) 15 g, Chinese Angelica Root (Danggui, Radix Angelicae Sinensis) 15 g, Poria (Fuling,
Scierotium Poriae Cocos) 15 g, White Peony Root (Baishao, Radix Albus Paeoniae Lactiflorae) 15 g, White Atractylodes Rhizome
(Baizhu, Rhizoma Atractylodis Macrocephalae) 15 g, Field Mint (Bohe, Herba Menthae Haplocalycis) 9 g, Cortex of the Peony Tree Rote
(Danpi, Cortex Radicis Moutan) 12 g, Gardenia (Zhizi, Fructus Gardeniae Jasminoidis) 12 g, Fresh Ginger Rhizome (Shengjiang, Fresh
Rhizoma Zingiberis) 6 g, and Liquoric Root (Gancao, Radix Glycyrrhizae) 6 g. If dizziness and headache are identified, Gastrodia
(Tianma, Gastrodiae Rhizoma) and Szechuan Lovage Root (Chuanxiong, Rhizoma Ligustici Chuanxiong) should be added. If bitter taste
and dry mouth are identified, Chinese Gentian Root (Longdancao, Radix Gentianae Longdancao) and Trichosanthes Root (Tianhuafen,
Trichosanthis Radix) should be added. If palpitation and insomnia are identified, Flowey Knotweed Stem (Yejiaoteng, Polygoni
Multiflori Caulis) and Chinese Senega Root (Yuanzhi, Radix Polygalae Tenuifoliae) should be added.
Gong (2010) XYS Thorowax Root (Chaihu, Radix Bupleuri) 12 g, Chinese Angelica Root (Danggui, Radix Angelicae Sinensis) 10 g, Poria (Fuling,
Scierotium Poriae Cocos) 10 g, White Peony Root (Baishao, Radix Albus Paeoniae Lactiflorae) 10 g, White Atractylodes Rhizome
(Baizhu, Rhizoma Atractylodis Macrocephalae) 10 g, Fresh Ginger Rhizome (Shengjiang, Fresh Rhizoma Zingiberis) 6 g, Liquoric Root
(Gancao, Radix Glycyrrhizae) 3 g, and Field Mint (Bohe, Herba Menthae Haplocalycis) 3 g.
Teng (2009) Modified XYS Thorowax Root (Chaihu, Radix Bupleuri) 10 g, Chinese Angelica Root (Danggui, Radix Angelicae Sinensis) 10 g, Poria (Fuling,
Scierotium Poriae Cocos) 10 g, White Peony Root (Baishao, Radix Albus Paeoniae Lactiflorae) 10 g, White Atractylodes Rhizome
(Baizhu, Rhizoma Atractylodis Macrocephalae) 10 g, Liquoric Root (Gancao, Radix Glycyrrhizae) 3 g, and Field Mint (Bohe, Herba
Menthae Haplocalycis) 6 g. If stagnated heat is identified, Cortex of the Peony Tree Rote (Danpi, Cortex Radicis Moutan), Gardenia
(Zhizi, Fructus Gardeniae Jasminoidis), and Baical Skullcap Root (Huangqin, Radix Scutellariae Baicalensis) should be added. If phlegm
accumulation is identified, Pinellia Rhizome (Banxia, Rhizoma Pinelliae Tematae), Magnolia Bark (Houpu, Cortex Magnoliae
Officinalis)and Honey-fried Tatarian Aster Root (Ziyuan, Radix Asteris Tatarici) should be added. If blood deficiency is identified,
Rehmannia (Dihuang, Radix Rehmanniae Glutinosae), Spiny Jujube Kernel (Suanzaoren, Ziziphi Spinosi Semen), and Szechuan Lovage
Root (Chuanxiong, Rhizoma Ligustici Chuanxiong) should be added; however, Field Mint (Bohe, Herba Menthae Haplocalycis) should be
removed. If deficiency of both qi and blood is identified, Field Mint (Bohe, Herba Menthae Haplocalycis) should be removed; however,
Rehmannia (Dihuang, Radix Rehmanniae Glutinosae), Codonopsis Root (Dangshen, Radix Codonopsitis Pilosulae), Szechuan Lovage
Root (Chuanxiong, Rhizoma Ligustici Chuanxiong), Spiny Jujube Kernel (Suanzaoren, Ziziphi Spinosi Semen), Flesh of the Longan Fruit
(Longyanrou, Arillus Euphoriae Longanae) and Costus Root (Muxiang, Radix Aucklandiae Lappae) should be added. If yin-deficiency and
fire-hyperactivity is identified, Gardenia (Zhizi, Fructus Gardeniae Jasminoidis), Cortex of the Peony Tree Rote (Danpi, Cortex Radicis
Moutan), Spiny Jujube Kernel (Suanzaoren, Ziziphi Spinosi Semen) and Rehmannia (Dihuang, Radix Rehmanniae Glutinosae) should be
added.
Ye (2014) XYS Thorowax Root (Chaihu, Radix Bupleuri), Chinese Angelica Root (Danggui, Radix Angelicae Sinensis), White Peony Root (Baishao, Radix
Albus Paeoniae Lactiflorae), White Atractylodes Rhizome (Baizhu, Rhizoma Atractylodis Macrocephalae), Poria (Fuling, Scierotium
Poriae Cocos), Liquoric Root (Gancao, Radix Glycyrrhizae), Field Mint (Bohe, Herba Menthae Haplocalycis), and Fresh Ginger Rhizome
(Shengjiang, Fresh Rhizoma Zingiberis).
Lin (2012) XYS Thorowax Root (Chaihu, Radix Bupleuri), Chinese Angelica Root (Danggui, Radix Angelicae Sinensis), White Peony Root (Baishao, Radix
Albus Paeoniae Lactiflorae), White Atractylodes Rhizome (Baizhu, Rhizoma Atractylodis Macrocephalae), Poria (Fuling, Scierotium
Poriae Cocos), Liquoric Root (Gancao, Radix Glycyrrhizae), Field Mint (Bohe, Herba Menthae Haplocalycis), and Fresh Ginger Rhizome
(Shengjiang, Fresh Rhizoma Zingiberis).
Ma and Li (2015) Modified XYS Thorowax Root (Chaihu, Radix Bupleuri) 15 g, Tangerine Peel (Chenpi, Pericarpium Citri Reticulatae) 10 g, Szechuan Lovage Root
(Chuanxiong, Rhizoma Ligustici Chuanxiong) 12 g, Immature Bitter Orange (Zhishi, Fructus Citri Seu Ponciri Immaturus) 12 g, White
Peony Root (Baishao, Radix Albus Paeoniae Lactiflorae) 12 g, Chinese Angelica Root (Danggui, Radix Angelicae Sinensis) 12 g, Nut Grass
Rhizome (Xiangfu, Rhizoma Cyperi Rotundi) 6 g, and Liquoric Root (Gancao, Radix Glycyrrhizae) 6 g. If dizziness and headache are
identified, Gastrodia (Tianma, Gastrodiae Rhizoma), Field Mint (Bohe, Herba Menthae Haplocalycis), and Gambir Vine Stems and
Thorns (Gouteng, Ramulus Uncariae Cum Uncis) should be added. If bitter taste and dry mouth are identified, Chinese Gentian Root
(Longdancao, Radix Gentianae Longdancao) and Trichosanthes Root (Tianhuafen, Trichosanthis Radix) should be added. If palpitation
and insomnia are identified, Flowey Knotweed Stem (Yejiaoteng, Polygoni Multiflori Caulis), Chinese Senega Root (Yuanzhi, Radix
Polygalae Tenuifoliae), and Acorus Root (Shichangpu, Acori Rhizoma) should be added.
Zhou (2015) Modified XYS Flowey Knotweed Stem (Yejiaoteng, Polygoni Multiflori Caulis) 30 g, Oyster Shell (Muli, Concha Ostreae) 30 g, Thorowax Root (Chaihu,
Radix Bupleuri) 15 g, White Peony Root (Baishao, Radix Albus Paeoniae Lactiflorae) 15 g, Poria (Fuling, Scierotium Poriae Cocos) 12 g,
Gardenia (Zhizi, Fructus Gardeniae Jasminoidis) 10 g, Cortex of the Peony Tree Rote (Danpi, Cortex Radicis Moutan) 10g, Fresh Ginger
Rhizome (Shengjiang, Fresh Rhizoma Zingiberis) 9 g, Field Mint (Bohe, Herba Menthae Haplocalycis) 6 g, and Liquoric Root (Gancao,
Radix Glycyrrhizae) 6 g. If blood stasis is identified, Cortex of the Peony Tree Rote (Danpi, Cortex Radicis Moutan) and Gardenia (Zhizi,
Fructus Gardeniae Jasminoidis) should be removed; however, Orange Fruit (Zhike, Fructus Aurantii) and Szechuan Lovage Root
(Chuanxiong, Rhizoma Ligustici Chuanxiong) should be added. If restlessness is identified, Spiny Jujube Kernel (Suanzaoren, Ziziphi
Spinosi Semen) and Chinese Senega Root (Yuanzhi, Radix Polygalae Tenuifoliae) should be added. If insomnia is identified, Chinese
Magnoliavine Fruit (Wuweizi, Fructus Schisandrae Chinensis) and Wheat Grain (Not Yet Ripe) (Fuxiaomai, Fructus Levis Tritici Aestivi)
should be added. If hyperhidrosis is identified, Chinese Date (Dazao, Fructus Zizyphi Jujubae) should be added. If qi deficiency is
identified, Astragalus (Huangqi, Radix Astragali Membranacei) and Codonopsis Root (Dangshen, Radix Codonopsitis Pilosulae) should
be added.
Liu and Dong (2008) Modified XYS Thorowax Root (Chaihu, Radix Bupleuri), Chinese Angelica Root (Danggui, Radix Angelicae Sinensis), White Peony Root (Baishao, Radix
Albus Paeoniae Lactiflorae), White Atractylodes Rhizome (Baizhu, Rhizoma Atractylodis Macrocephalae), Poria (Fuling, Scierotium
Poriae Cocos), Liquoric Root (Gancao, Radix Glycyrrhizae), Field Mint (Bohe, Herba Menthae Haplocalycis), Fresh Ginger Rhizome
(Shengjiang, Fresh Rhizoma Zingiberis), Cortex of the Peony Tree Rote (Danpi, Cortex Radicis Moutan), and Gardenia (Zhizi, Fructus
Gardeniae Jasminoidis).
Wang and Dong (2012) Modified XYS Cortex of the Peony Tree Rote (Danpi, Cortex Radicis Moutan) 10 g, Gardenia (Zhizi, Fructus Gardeniae Jasminoidis) 10 g, Thorowax
Root (Chaihu, Radix Bupleuri) 15 g, White Peony Root (Baishao, Radix Albus Paeoniae Lactiflorae) 15 g, Chinese Angelica Root
(Danggui, Radix Angelicae Sinensis) 10 g, Poria (Fuling, Scierotium Poriae Cocos) 12 g, Flowey Knotweed Stem (Yejiaoteng, Polygoni
Multiflori Caulis) 30 g, White Atractylodes Rhizome (Baizhu, Rhizoma Atractylodis Macrocephalae) 10 g, Fossilized Mammal Bones
(Longgu, Os Draconis) 30 g, Oyster Shell (Muli, Concha Ostreae) 30 g, Fresh Ginger Rhizome (Shengjiang, Fresh Rhizoma Zingiberis) 9 g,
Field Mint (Bohe, Herba Menthae Haplocalycis) 6 g, and Liquoric Root (Gancao, Radix Glycyrrhizae) 6 g. If blood stasis is identified,
Cortex of the Peony Tree Rote (Danpi, Cortex Radicis Moutan), Gardenia (Zhizi, Fructus Gardeniae Jasminoidis), and White Peony Root
(Baishao, Radix Albus Paeoniae Lactiflorae) should be removed; however, Red Peony Root (Chishao, Radix Rubrus Paeoniae Lactiflorae)
15 g, Orange Fruit (Zhike, Fructus Aurantii) 9 g, Szechuan Lovage Root (Chuanxiong, Rhizoma Ligustici Chuanxiong) 12 g, Peach Kernel
(Taoren, Persicae Semen) 12 g, and Safflower Flower (Honghua, Flos Carthami Tinctorii) 10 g should be added. If restlessness is
identified, Spiny Jujube Kernel (Suanzaoren, Ziziphi Spinosi Semen) 15 g and Chinese Senega Root (Yuanzhi, Radix Polygalae
(continued on next page)
X. Xiong, et al. Phytomedicine 61 (2019) 152849
7
−10.41 to −2.93; I
2
=98%, p = 0.0005; Fig. 4a).
SAS at baseline and after intervention was reported in only 1 trial
(Ye, 2014). Compared with antihypertensive drugs, SAS was sig-
nificantly lower in the XPAD group (1 trial, n= 60; WMD: −4.62; 95%
CI: −8.06 to −1.18; p = 0.008).
SDS at baseline and after intervention was reported in 2 trials (Ye,
2014; Zhou, 2015). Compared with antihypertensive drugs, meta-ana-
lysis showed a significant lowering effect of XPAD (2 trials, n= 133;
WMD: −1.23; 95% CI: −1.75 to −0.70; I
2
=0%, p< 0.00001;
Fig. 4b).
PHQ-9 at baseline and after intervention was reported in only 1 trial
(Gong et al., 2014). Reduction in PHQ-9 was significantly greater for
XPAD than antihypertensive drugs used alone (1 trial, n= 84; WMD:
−34.79; 95% CI: −36.61 to −32.97; p< 0.00001).
Blood lipids (TC, TG, HDL-C, and LDL-C)
The effect of XYS on serum TC level was reported by 1 trial
(Gong, 2010). Compared with antihypertensive drugs, XPAD showed a
significant TC-lowering effect (1 trial, n= 60; WMD: −0.87 mmol/l;
95% CI: −1.02 to −0.72; p< 0.00001).
Serum TG level was also reported by the same trial as TC that
compared XPAD with antihypertensive drugs (Gong, 2010). A sig-
nificant reduction of serum TG level was observed by XPAD (1 trial,
n= 60; WMD: −0.77 mmol/l; 95% CI: −0.96 to −0.58; p< 0.00001).
2 trials (Gong, 2010; Li et al., 2012) evaluated the effect of XPAD on
serum HDL-C level compared with the antihypertensive drugs. The
meta-analysis revealed a significant increasing effect of HDL-C by XPAD
(2 trials, n= 139; WMD: 0.15mmol/l; 95% CI: 0.10 to 0.20; I
2
=95%,
p< 0.00001; Fig. 4c).
The serum LDL-C level at baseline and after intervention was re-
ported in only 1 trial (Gong, 2010). Compared with antihypertensive
drugs, serum LDL-C level was significantly lower in the XPAD group (1
trial, n= 60; WMD: −0.23 mmol/l; 95% CI: −0.44 to −0.02;
p = 0.03).
Table 3 (continued)
References CHM Ingredients of XYS
Tenuifoliae) 6 g should be added. If insomnia is identified, Wheat Grain (Not Yet Ripe) (Fuxiaomai, Fructus Levis Tritici Aestivi) 30 g,
Chinese Magnoliavine Fruit (Wuweizi, Fructus Schisandrae Chinensis) 10 g, and Mimosa Tree Bark (Hehuanpi, Cortex Albizziae
Julibrissinis)10 g should be added. If hyperhidrosis is identified, Wheat Grain (Not Yet Ripe) (Fuxiaomai, Fructus Levis Tritici Aestivi)
60 g and Chinese Date (Dazao, Fructus Zizyphi Jujubae) 10 should be added. If qi deficiency is identified, Astragalus (Huangqi, Radix
Astragali Membranacei)30 g and Codonopsis Root (Dangshen, Radix Codonopsitis Pilosulae) 12 g should be added. If fire syndrome due
to qi stagnation is identified, Anemarrhena Rhizome (Zhimu, Rhizoma Anemarrhenae Aspheloidis) 6 g, Coptis Rhizome (Huanglian,
Rhizoma Coptidis) 6 g, and Cinnamon Bark (Rougui, Cinnamomi Cortex) 3 g should be added.
Li et al. (2012) Modified XYS Thorowax Root (Chaihu, Radix Bupleuri), Chinese Angelica Root (Danggui, Radix Angelicae Sinensis), White Peony Root (Baishao, Radix
Albus Paeoniae Lactiflorae), White Atractylodes Rhizome (Baizhu, Rhizoma Atractylodis Macrocephalae), Poria (Fuling, Scierotium
Poriae Cocos), Liquoric Root (Gancao, Radix Glycyrrhizae), Cortex of the Peony Tree Rote (Danpi, Cortex Radicis Moutan), an Gardenia
(Zhizi, Fructus Gardeniae Jasminoidis).
Liu et al. (2009) Modified XYS Thorowax Root (Chaihu, Radix Bupleuri) 12 g, Chinese Angelica Root (Danggui, Radix Angelicae Sinensis) 12 g, White Peony Root
(Baishao, Radix Albus Paeoniae Lactiflorae) 12 g, White Atractylodes Rhizome (Baizhu, Rhizoma Atractylodis Macrocephalae) 12 g,
Poria (Fuling, Scierotium Poriae Cocos) 15 g, and Liquoric Root (Gancao, Radix Glycyrrhizae) 6 g. If headache is identified, Szechuan
Lovage Root (Chuanxiong, Rhizoma Ligustici Chuanxiong) and Dahurian Angelica Root (Baizhi, Radix Angelicae Dahuricae) should be
added. If insomnia and dreaminess are identified, Spiny Jujube Kernel (Suanzaoren, Ziziphi Spinosi Semen) and Chinese Senega Root
(Yuanzhi, Radix Polygalae Tenuifoliae) should be added. If irregular menstruation and fever are identified, Cortex of the Peony Tree
Rote (Danpi, Cortex Radicis Moutan) and Gardenia (Zhizi, Fructus Gardeniae Jasminoidis) should be added.
Zhou and Qi (2006) XYS Thorowax Root (Chaihu, Radix Bupleuri), Chinese Angelica Root (Danggui, Radix Angelicae Sinensis), White Peony Root (Baishao, Radix
Albus Paeoniae Lactiflorae), White Atractylodes Rhizome (Baizhu, Rhizoma Atractylodis Macrocephalae), Poria (Fuling, Scierotium
Poriae Cocos), Liquoric Root (Gancao, Radix Glycyrrhizae), Field Mint (Bohe, Herba Menthae Haplocalycis), and Fresh Ginger Rhizome
(Shengjiang, Fresh Rhizoma Zingiberis).
Xie (2006) XYS Thorowax Root (Chaihu, Radix Bupleuri), Chinese Angelica Root (Danggui, Radix Angelicae Sinensis), White Peony Root (Baishao, Radix
Albus Paeoniae Lactiflorae), White Atractylodes Rhizome (Baizhu, Rhizoma Atractylodis Macrocephalae), Poria (Fuling, Scierotium
Poriae Cocos), Liquoric Root (Gancao, Radix Glycyrrhizae), Field Mint (Bohe, Herba Menthae Haplocalycis), and Fresh Ginger Rhizome
(Shengjiang, Fresh Rhizoma Zingiberis).
Gong et al. (2014) Modified XYS Thorowax Root (Chaihu, Radix Bupleuri), Chinese Angelica Root (Danggui, Radix Angelicae Sinensis), White Peony Root (Baishao, Radix
Albus Paeoniae Lactiflorae), White Atractylodes Rhizome (Baizhu, Rhizoma Atractylodis Macrocephalae), Poria (Fuling, Scierotium
Poriae Cocos), Liquoric Root (Gancao, Radix Glycyrrhizae), Field Mint (Bohe, Herba Menthae Haplocalycis), Fresh Ginger Rhizome
(Shengjiang, Fresh Rhizoma Zingiberis), Cortex of the Peony Tree Rote (Danpi, Cortex Radicis Moutan), and Gardenia (Zhizi, Fructus
Gardeniae Jasminoidis).
Wu and Chen (2003) Modified XYS Thorowax Root (Chaihu, Radix Bupleuri) 10 g, White Peony Root (Baishao, Radix Albus Paeoniae Lactiflorae) 20 g, Chinese Angelica
Root (Danggui, Radix Angelicae Sinensis) 6 g, Poria (Fuling, Scierotium Poriae Cocos) 15 g, White Atractylodes Rhizome (Baizhu,
Rhizoma Atractylodis Macrocephalae) 15 g, Field Mint (Bohe, Herba Menthae Haplocalycis) 9 g, Privet Fruit (Nvzhenzi, Fructus Ligustri
Lucidi) 15 g, Achyranthes Root (Niuxi, Achyranthis Bidentatae Radix) 15 g, Chrysanthemum Flower (Juhua, Flos Chrysanthemi
Morifolii) 15 g, Gambir Vine Stems and Thorns (Gouteng, Ramulus Uncariae Cum Uncis) 20 g, Chinese Taxillus Twig (Sangjisheng, Herba
Taxilli) 20 g, Salvia Root (Danshen, Radix Salviae Miltiorrhizae) 15 g, and Abalone Shell (Shijueming, Haliotidis Concha) 15 g.
Wang et al. (2014) Modified XYS Cortex of the Peony Tree Rote (Danpi, Cortex Radicis Moutan) 12 g, Gardenia (Zhizi, Fructus Gardeniae Jasminoidis) 12 g, Thorowax
Root (Chaihu, Radix Bupleuri) 12 g, Chinese Angelica Root (Danggui, Radix Angelicae Sinensis) 15 g, Abalone Shell (Shijueming,
Haliotidis Concha) 21 g, Gambir Vine Stems and Thorns (Gouteng, Ramulus Uncariae Cum Uncis) 15 g, Gastrodia (Tianma, Gastrodiae
Rhizoma) 15 g, Prunella (Xiakucao, Spica Prunellae Vulgaris) 9 g, Tumeric Tuber (Yujin, Tuber Curcumae) 12 g, White Peony Root
(Baishao, Radix Albus Paeoniae Lactiflorae) 15 g, Chrysanthemum Flower (Juhua, Flos Chrysanthemi Morifolii) 12 g, and Mimosa Tree
Bark (Hehuanpi, Cortex Albizziae Julibrissinis) 18 g. If severe yin deficiency is identified, Rehmannia (Dihuang, Radix Rehmanniae
Glutinosae) and Privet Fruit (Nvzhenzi, Fructus Ligustri Lucidi) should be added. If vexation and insomnia are identified, Salvia Root
(Danshen, Radix Salviae Miltiorrhizae) and Flowey Knotweed Stem (Shouwuteng, Polygoni Multiflori Caulis) should be added.
Li (2015) Modified XYS Cortex of the Peony Tree Rote (Danpi, Cortex Radicis Moutan) 12 g, Gardenia (Zhizi, Fructus Gardeniae Jasminoidis) 12 g, Chinese
Angelica Root (Danggui, Radix Angelicae Sinensis) 10 g, White Peony Root (Baishao, Radix Albus Paeoniae Lactiflorae) 10 g, Thorowax
Root (Chaihu, Radix Bupleuri) 10 g, Poria (Fuling, Scierotium Poriae Cocos) 10 g, White Atractylodes Rhizome (Baizhu, Rhizoma
Atractylodis Macrocephalae) 10 g, Field Mint (Bohe, Herba Menthae Haplocalycis) 10 g, Liquoric Root (Gancao, Radix Glycyrrhizae)
6 g, and Fresh Ginger Rhizome (Shengjiang, Fresh Rhizoma Zingiberis) 6 g.
Abbreviations: CHM: Chinese herbal medicine; XYS: Xiao Yao San.
X. Xiong, et al. Phytomedicine 61 (2019) 152849
8
Hcy
The Hcy level at baseline and after intervention was reported in only
1 trial (Li et al., 2012). Compared with antihypertensive drugs, XPAD
showed a significant lowering effect on serum Hcy level (1 trial, n= 79;
WMD: −5.51 umol/l; 95% CI: −7.14 to −3.88; p< 0.00001).
CRP
The effect of XYS on CRP level was reported in the same trial as TC
(Gong, 2010). A significant lowering effect on serum CRP level by
XPAD was identified compared with antihypertensive drugs (1 trial,
n= 60; WMD: −0.12 mg/l; 95% CI: −0.20 to −0.04; p = 0.003)
AEs
Four trials (4/17, 23.53%) reported information about AEs (Gong,
2010; Liu and Dong, 2008; Gong et al., 2014; Wang et al., 2014), in-
cluding ankle edema (Gong, 2010), dizziness (Gong, 2010; Liu and
Dong, 2008; Wang et al., 2014), anorexia (Gong, 2010; Liu and Dong,
2008; Gong et al., 2014), diarrhea (Liu and Dong, 2008), constipation
(Liu and Dong, 2008; Gong et al., 2014), blurred vision (Liu and
Dong, 2008), insomnia (Liu and Dong, 2008; Gong et al., 2014), and
flushed face (Wang et al., 2014). One trial reported no AEs of XYS
(Wang et al., 2014). The aggregated results including 4 trials suggested
that the incidences of AEs were significantly reduced by XPAD or XYS
compared with antihypertensive drugs (4 trials, n= 399; RR: 0.23; 95%
CI: 0.14–0.39; I
2
=0%, p< 0.00001; Fig. 5). Meta-analysis revealed
that XPAD had lower incidence of anorexia (3 trials, n= 309; RR: 0.13;
95% CI: 0.02–0.72; I
2
=0%, p= 0.02) and insomnia (2 trials, n= 249;
RR: 0.07; 95% CI: 0.01–0.49; I
2
=0%, p= 0.008) than anti-
hypertensive drugs. Nevertheless, meta-analysis showed no significant
difference between XPAD or XYS and antihypertensive drugs alone for
ankle edema (1 trial, n= 60; RR: 0.50; 95% CI: 0.10–2.53; p= 0.40),
dizziness (3 trials, n= 315; RR: 0.23; 95% CI: 0.02–2.25; I
2
=66%,
p= 0.21), diarrhea (1 trial, n= 165; RR: 5.31; 95% CI: 0.26–108.91;
p= 0.28), constipation (2 trials, n= 249; RR: 0.56; 95% CI: 0.23–1.36;
I
2
=0%, p= 0.20), blurred vision (1 trial, n= 165; RR: 0.10; 95% CI:
0.01–1.72; p= 0.11), and flushed face (1 trial, n= 90; RR: 0.33; 95%
CI: 0.01–7.97; p= 0.50). All the reported AEs were not severe and
disappeared without further treatment.
Publication bias
Funnel plot analysis of 10 trials for the outcomes of SBP and DBP
were performed to explore the publication bias (Fig. 6). The plot was
asymmetrical suggesting the existence of publication bias.
Discussion
Summary of evidence
Herbal medicine has been recommended as a therapeutic regimen to
enhance the quality of life (Xiong et al., 2015a), improve hypertension
related symptoms (Wang et al., 2015), and lower BP (Xiong et al.,
2015b; Xiong et al., 2015c) in China and other countries. However,
whether XYS is beneficial for hypertension is not well recognized until
now. This is the first systematic review and meta-analysis of the cur-
rently published RCTs to summarize the effect of XYS for the treatment
of hypertension and provide a new level of evidence for patients, policy
makers, and clinicians.
In this systematic review, we assessed the efficacy and safety of XYS
as adjuvant therapy or used alone vs. antihypertensive drugs or LSI for
hypertension. A total of 17 trials with 1460 hypertensive patients were
included. In general, the findings from these studies demonstrated a
superior cardioprotective effect of XYS as adjuvant therapy than anti-
hypertensive drugs in improving BP, depression scale (HAMA, SAS,
SDS, and PHQ-9), blood lipids (TC, TG, HDL-C, and LDL-C), Hcy, and
CRP, and patients treated by XYS were more likely to experience less
incidence rate of AEs.
The therapeutic goals for patients with hypertension are to reduce
BP, cardiovascular risk factors, and thus MCCE (James et al., 2014;
Chobanian et al., 2003). Our primary finding revealed that XYS as
adjuvant therapy resulted in significantly greater benefit in lowering
BP. According to the estimation of World Health Organization, the
suboptimal BP (>115 mm Hg SBP) is responsible for 62% of cere-
brovascular disease and 49% of ischemic heart disease, with little
variation by sex (World Health Report, 2002). Beginning at 115/
75 mmHg, mortality from both ischemic heart disease and stroke dou-
bles for each increment of 20/10 mmHg. Framingham Heart Study also
reported that BP levels in 130–139/85–89 mmHg range are associated
with a more than 2-fold increase in relative risk from cardiovascular
disease compared with those with BP levels below 120/80 mmHg. BP
lowering significantly reduces vascular risk across various base-
line BP levels and comorbidities (Ettehad et al., 2016). A large number
of studies have confirmed the benefits of lowering BP, which was as-
sociated with reductions in stroke incidence by 35–40%, myocardial
infarction by 20–25%, and heart failure by 50% (Neal et al., 2000;
Ogden et al., 2000). It was also supported by the primary results of the
Systolic Blood Pressure Intervention Trial (SPRINT), which compared
the benefit of lowering SBP to a target of <120 mmHg with <140 mm
Hg (The SPRINT Research Group, 2015). In this review, all the included
studies reported XYS intervention on BP outcomes. Meta-analysis by
subgroups showed that, compared to antihypertensive drugs used
alone, XYS as adjuvant therapy significantly decrease SBP by
8.94 mmHg and DBP by 4.93 mmHg. This suggested that the combi-
nation of XYS and antihypertensive drugs may be optimal for hy-
pertensive patients who are partially insensitive to the pharmacologic
treatment alone, especially if they failed to tolerate conventional
treatment. However, when compared to antihypertensive drugs, XYS
used alone showed no significant difference on BP outcome. When
compared to LSI, XYS as adjuvant therapy significantly decreased SBP
by 13.39 mmHg but showed no significant difference on DBP. As only
limited number of trials in the subgroups comparing XYS with anti-
hypertensive drugs and comparing XPLSI with LSI were identified, no
confirmed conclusion regarding whether XYS could be used as alter-
native therapy to antihypertensive drugs or complementary therapy to
LSI is still unknown.
Another valuable finding of this review was the estimation on the
efficacy of XYS as adjuvant therapy for other cardiovascular risk fac-
tors, including blood lipids, Hcy, and CRP. Hypertension, dyslipidemia,
Table 4
Methodological quality of the 17 studies according to the Cochrane handbook.
References A B C D E F G H
Sun and Liu (2015) ? ? ? ? ? + ? ?
Gong (2010) + ? ? ? ? + ? ?
Teng (2009) + ? ? ? ? + ? ?
Ye (2014) + ? ? ? ? + ? ?
Lin (2012) ? ? ? ? ? + ? ?
Ma and Li (2015) + ? ? ? ? + ? ?
Zhou (2015) ? ? ? ? ? + ? ?
Liu and Dong (2008) + ? ? ? ? + ? ?
Wang and Dong (2012) + ? ? ? ? + ? ?
Li et al. (2012) + ? ? ? ? + ? ?
Liu et al. (2009) ? ? ? ? ? + ? ?
Zhou and Qi (2006) ? ? ? ? ? + ? ?
Xie (2006) ? ? ? ? ? + ? ?
Gong et al. (2014) ? ? ? ? ? + ? ?
Wu and Chen (2003) ? ? ? ? ? + ? ?
Wang et al. (2014) ? ? ? ? ? + ? ?
Li (2015) + ? ? ? ? + ? ?
Abbreviations: A: adequate sequence generation; B: concealment of allocation; C:
blinding (patient); D: blinding (investigator); E: blinding (assessor); F: in-
complete outcome data addressed (ITT analysis); G: free of selective reporting;
H: other potential threat to validity; +: low risk; -: high risk; ?: unclear.
X. Xiong, et al. Phytomedicine 61 (2019) 152849
9
and various inflammatory markers such as Hcy and CRP are important
risk factors for cardiovascular diseases (Otsuka et al., 2016). Coex-
istence of these cardiovascular risk factors is commonly observed in
daily clinical practice, which significantly increases the incidence of
cardiovascular diseases. Management of these co-existing risk factors in
hypertensive patients is essential. Several studies have suggested a
positive association between high BP level and blood lipids (Sesso et al.,
2005; Halperin et al., 2006; Laaksonen et al., 2008; Borghi et al., 2016;
Fig. 2. Forest plot of the trials that compared XPAD with antihypertensive drugs for (a) SBP, (b) DBP, and (c) BP.
Abbreviations: AD: antihypertensive drugs; BP: blood pressure; DBP: diastolic blood pressure; SBP: systolic blood pressure; XPAD: Xiao Yao San plus antihypertensive
drugs.
Fig. 3. Forest plot of the trials that compared XYS with antihypertensive drugs for BP.
Abbreviations: AD: antihypertensive drugs; BP: blood pressure; XYS: Xiao Yao San.
X. Xiong, et al. Phytomedicine 61 (2019) 152849
10
Nakamura et al., 2006; Yokoyama et al., 2007; Shepherd et al., 1995).
In our meta-analysis, pooled analysis suggested that XYS as adjuvant
therapy exhibited a significantly lowering effects on serum TC (de-
creased by 0.87 mmol/l), TG (decreased by 0.77 mmol/l), and LDL-C
(decreased by 0.23 mmol/l), and raising effect on HDL-C (increased by
0.15 mmol/l). Elevations in Hcy and CRP, two emerging risk factors,
were associated with a higher cardiovascular event rate. The meta-
analysis showed a significant lowering effect on Hcy (decreased by
5.51 umol/l) and CRP (decreased by 0.12 mg/l). Similar modulating
effect of the co-existing cardiovascular risk factors with multiple in-
gredients, multiple targets, and multiple ways could also be identified
in other herbal medicines in the treatment of hypertension (Xiong et al.,
2015d). These results supported the use of XYS as complementary
therapy for hypertensive patients complicated with multiple cardio-
vascular risk factors. However, as only few studies reporting outcomes
on cardiovascular risk factors were included in the subgroup analysis,
more credible evidence is warranted in future.
In TCM basic theory, “liver qi stagnation” is considered to be the
basic pathogenesis of depression, which could just be treated by XYS.
Depression scales are widely used for both clinical and research pur-
poses to estimate the subjective feeling for patients with depression,
with the higher total scores being indicative of higher severity of de-
pressive symptoms. In this review, we set them as our secondary out-
comes, including HAMA, SAS, SDS, and PHQ-9. Subgroup with 10
studies evaluating the efficacy of XYS as adjuvant therapy compared to
antihypertensive drugs in hypertensive patients with depression were
identified. Pooled analysis indicated that XYS possess a better anti-
depressant effect as complementary approach on HAMA (decreased by
6.67 points), SAS (decreased by 4.62 points), SDS (decreased by 1.23
points), and PHQ-9 (decreased by 34.79 points). The explicit
Fig. 4. Forest plot of the trials that compared XPAD with antihypertensive drugs for (a) HAMA, (b) SDS, and (c) HDL-C.
Abbreviations: AD: antihypertensive drugs; HAMA: hamilton anxiety scale; HDL-C: high-density lipoprotein cholesterol; SDS: self-rating depression scale; XPAD: Xiao
Yao San plus antihypertensive drugs.
Fig. 5. Forest plot of the trials that reported AEs.
Abbreviations: AEs: adverse events; AD: antihypertensive drugs; XYS: Xiao Yao San.
X. Xiong, et al. Phytomedicine 61 (2019) 152849
11
mechanism of XYS for hypertensive patients with depression is unclear,
but the possible modes for depression include inhibiting locus coer-
uleus-norepinephrine neurons activity, downregulating corticotrophin
releasing hormone receptor 2, upregulating BDNF/TrkB, phosphor-
ylating mTOR, and regulating the dysfunctions of energy metabolism,
amino acid metabolism, and gut microflora changes (Ding et al., 2014;
Zhu et al., 2014; Liu et al., 2012; Dai et al., 2010). However, ex-
planation the regulation mechanism for hypertensive patients with
depression still need more experimental and clinical studies. This sug-
gested that, beside cardiovascular protective effects, XYS possesses an
additional beneficial effect or better interaction with antihypertensive
drugs regarding depression, which is important for hypertensive pa-
tients accompanied with depression.
Limitations
Before recommending the conclusion of this systematic review to
clinical physicians, the following limitations should be paid close at-
tention to in our study. Firstly, the ultimate therapeutic goal of anti-
hypertensive therapy is not only lowering BP itself, but also reducing
MCCE (James et al., 2014; Chobanian et al., 2003). In our review, be-
cause only 1 study reported the efficacy of XYS on MCCE, no reliable
conclusion about XYS on primary outcome measures could be drew
based on current evidence. Secondly, the methodological quality was
assessed to be generally low in this review. No details were declared in
the domains of random allocation concealment, blinding of partici-
pants, personnel and outcome assessors, and selective outcome re-
porting. Small sample size and potential publication bias were also
identified in the included studies, which might weaken the level of
evidence. Thirdly, AEs of herbal medicine is a problem that can easily
be ignored (Efferth and Kaina, 2011). Most included trials paid no at-
tention to both recording and reporting of AEs. Thus, although a sig-
nificantly fewer AEs were identified in the XYS intervention groups, it
should be treated with cautious. More clinical data regarding AEs of
XYS are needed.
Conclusion
This systematic review provided evidence that XYS adjuvant to
antihypertensive drugs maybe beneficial for hypertensive patients in
lowering BP, improving depression, regulating blood lipids, and in-
hibiting inflammation. However, given the poor methodological design,
significant heterogeneity, and publication bias, the efficacy and safety
of XYS are still uncertain. More long-term, randomized, double-blinded
clinical trials focusing on the effect of XYS with long-term outcomes are
warranted to support their clinical recommendation in future studies.
Studies revealing the mechanism by which XYS benefits hypertensive
patients is also required.
Conflict of interest
We wish to confirm that there are no known conflicts of interest
associated with this publication and there has been no significant fi-
nancial support for this work that could have influenced its outcome.
Acknowledgments
This study was supported by the National Natural Science
Foundation Project of China (No. 81403375), Young Elite Scientists
Sponsorship Program by the China Association for Science and
Technology (Grant number: 2017QNRC001), and Special Fund for
Seedling Raising of Chinese Academy of Chinese Medicine. The funder
had no role in study design, data collection and analysis, decision to
publish, or preparation of the manuscript.
Author contributions
X.J.X. designed the study, carried out the statistical analysis, drew
the tables and pictures, and wrote the manuscript. L.D., P.Q.W., W.L.,
F.Y.C., S.J.L., X.K.L., K.L.S., Y.W.X., and H.Y. separately conducted the
literature searches, data extraction, methodological quality evaluation
of each study and helped to draft the manuscript.
References
Aaron, K.H., et al., 2015. Association of anxiety and depression with hypertension con-
trol: a U.S. multi-disciplinary group practice observational study. J. Hypertens. 33,
2215–2222.
Borghi, C., et al., 2016. The association between blood pressure and lipid levels in Europe:
european study on cardiovascular risk prevention and management in usual daily
practice. J. Hypertens. 34, 2155–2163.
Brook, R.D., et al., 2013. Beyond medications and diet: alternative approaches to low-
ering blood pressure. Hypertension 61, 1360–1383.
Chen, J.H., et al., 2016. Estrogenic effects of flavonoid components in Xiaoyao powder.
Genet. Mol. Res. 15, 1–9.
Chen, X.X., Zhu, Y., 2013. Effect of total glucosides of paeony on hyperglycemia and
hypertension in insulin resistance rats. Neimonggu. J. Tradit. Chin. Med. 32, 37–39.
Chobanian, A.V, et al., 2003. The seventh report of the joint national committee on
prevention, detection, evaluation, and treatment of high blood pressure: the JNC 7
report. J. Am. Med. Assoc. 289, 2560–2572.
Dai, Y, et al., 2010. Metabolomics study on the anti-depression effect of xiaoyaosan on rat
model of chronic unpredictable mild stress. J. Ethnopharmacol. 128, 482–489.
Ding, X.F, et al., 2014. Xiao Yao San improves depressive-like behaviors in rats with
Fig. 6. Funnel plot of the trials that compared XPAD with antihypertensive drugs for (a) SBP and (b) DBP.
Abbreviations: AD: antihypertensive drugs; BP: blood pressure; DBP: diastolic blood pressure; SBP: systolic blood pressure; XPAD: Xiao Yao San plus antihypertensive
drugs.
X. Xiong, et al. Phytomedicine 61 (2019) 152849
12
chronic immobilization stress through modulation of locus coeruleus-norepinephrine
system. Evid. Based Complement. Alternat. Med. 2014, e605914.
Efferth, T., Kaina, B., 2011. Toxicities by herbal medicines with emphasis to traditional
Chinese medicine. Curr. Drug Metab. 12, 989–996.
Ettehad, D, et al., 2016. Blood pressure lowering for prevention of cardiovascular disease
and death: a systematic review and meta-analysis. Lancet 387, 957–967.
Feng, R.E, et al., 2010. Effects of total glucosides of paeong on improving insulin sensi-
tivity, lowering blood pressure and enhancing antioxidation in metabolic syndrome-
hypertensive rats. Chin. J. Clin. Pharmacol. Ther. 15, 154–159.
Go, A.S, et al., 2014. Heart disease and stroke statistics — 2014 update: a report from the
American heart association. Circulation 129, 28–292.
Gong, C.Q., 2010. Effect of Xiao Yao San on hypertensive patients with liver stagnation
and spleen deficiency syndrome. Guangxi Univ. Chin. Med. 1–56.
Gong, X., et al., 2014. Efficacy and safety of Dan Zhi Xiao Yao Wan in treating hy-
pertension with anxiety disorders. Cardio. Dise. J. Integr. Tradit. Chin. West Med. 2,
173–174.
Guo, F., et al., 2012. Trends in prevalence, awareness, management, and control of hy-
pertension among United States adults, 1999–2010. J. Am. Coll. Cardiol. 60, 599–606.
Halperin, R.O, et al., 2006. Dyslipidemia and the risk of incident hypertension in men.
Hypertension 47, 45–50.
Higgins, J.P, et al., 2003. Measuring inconsistency in meta-analyses. BMJ 327, 557–560.
Higgins, J.P.T. & Green, S. 2014. Cochrane Reviewers’ Handbook 5.3.0 [updated March
2014], Review Manager (RevMan) [Computer program]. Version 5.3.0. Available
from www.cochrane-handbook.org.
Ho, A.K, et al., 2015. Association of anxiety and depression with hypertension control: a
US multidisciplinary group practice observational study. J. Hypertens. 33,
2215–2222.
James, P.A, et al., 2014. 2014 Evidence-based guideline for the management of high
blood pressure in adults: report from the panel members appointed to the Eighth
Joint National Committee (JNC 8). J. Am. Med. Assoc. 311, 507–520.
Kayano, H, et al., 2015. Impact of depression on masked hypertension and variability in
home blood pressure in treated hypertensive patients. Hypertens. Res. 38, 751–757.
Kearney, P.M, et al., 2005. Global burden of hypertension: analysis of worldwide data.
Lancet 365, 217–223.
Laaksonen, D.E, et al., 2008. Dyslipidaemia as a predictor of hypertension in middle-aged
men. Eur. Heart J. 29, 2561–2568.
Lawes, C.M., et al., 2008. Global burden of blood-pressure-related disease, 2001. Lancet
371, 1513–1518.
Li, E.M., 2015. Clinical observation on Dan Zhi Xiao Yao San in treating 45 cases of
patients with early hypertension by Yuepeng Xing. Shizhen. Med. Materia Medica Res.
26, 476–477.
Li, M.T., Xiang, H., 2010. Advances in effective ingredients and pharmacological action of
Xiaoyao Pill or Xiaoyao San research. J. Chin. Med. Mater. 33, 1968–1972.
Li, N, et al., 2015. TCM formula Xiaoyaosan decoction improves depressive-like behaviors
in rats with type 2 diabetes. Evid. Based Complement. Alternat. Med. 2015, e415243.
Li, Y.Y., et al., 2012. Clinical observation of modified Xiaoyao powder combined with
valsartan for treatment of climacteric hypertension. J. New Chin. Med. 44, 63–65.
Lim, S.S, et al., 2012. A comparative risk assessment of burden of disease and injury
attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: a
systematic analysis for the Global Burden of Disease Study 2010. Lancet 380,
2224–2260.
Lin, C., 2012. Effect of Xiao Yao Wan combined with amlodipine besylate table in the
treatment of menopausal hypertension. J. Front. Med. 5, 203–204.
Liu, P., et al., 2009. Effect of Xiao Yao Wan combined with western medicine in treating
59 cases of patients with menopausal hypertension. Shanxi J. Tradit. Chin. Med. 30,
789–790.
Liu, X.J, et al., 2012. Anti-depressant effects of Xiaoyaosan on rat model of chronic un-
predictable mild stress: a plasma metabonomics study based on NMR spectroscopy. J.
Pharm. Pharmacol. 64, 578–588.
Liu, Y.L., Dong, S.L., 2008. Effect of Dan Zhi Xiao Yao Wan in treating hypertension with
anxiety disorders. Chin. J. Integr. Tradit. West Med. 28, 280–281.
Ma, Y.Y., Li, C.X., 2015. Clinical observation on hypertension with anxiety symptom
treated with traditional Chinese combine with western medicine. J. Shanxi Coll.
Tradit. Chin. Med. 16, 67–68.
Maatouk, I, et al., 2016. Association of hypertension with depression and generalized
anxiety symptoms in a large population-based sample of older adults. J. Hypertens.
34, 1711–1720.
MacMahon, S, et al., 1990. Blood pressure, stroke, and coronary heart disease. Part 1,
Prolonged differences in blood pressure: prospective observational studies corrected
for the regression dilution bias. Lancet 335, 765–774.
Mao, Y.X., 2011. Preliminary study on the effect and mechanism of Xiao Yao Wan on
gastrointestinal smooth muscle, heart, and blood pressure. Jinan 1–45.
Meng, L., et al., 2012. Depression increases the risk of hypertension incidence: a meta-
analysis of prospective cohort studies. J. Hypertens. 30, 842–851.
Moher, D., et al., 2009. Preferred reporting items for systematic reviews and meta-ana-
lyses: the PRISMA statement. Plos Med. 6, e1000097.
Moise, N., et al., 2014. Depression and clinical inertia in patients with uncontrolled hy-
pertension. JAMA Intern. Med. 174, 818–819.
Nakamura, H, et al., 2006. Primary prevention of cardiovascular disease with pravastatin
in Japan (MEGA study): a prospective randomised controlled trial. Lancet 368,
1155–1163.
Neal, B., et al., 2000. Effects of ACE inhibitors, calcium antagonists, and other blood-
pressure-lowering drugs: results of prospectively designed overviews of randomised
trials. Blood pressure lowering treatment trialists’ collaboration. Lancet 356,
1955–1964.
Neupane, D, et al., 2015. Prevalence of undiagnosed depression among persons with
hypertension and associated risk factors: a cross-sectional study in urban Nepal. PLoS
One 10, e0117329.
Ogden, L.G., et al., 2000. Long-term absolute benefit of lowering blood pressure in hy-
pertensive patients according to the JNC VI risk stratification. Hypertension 35,
539–543.
Otsuka, T, et al., 2016. Dyslipidemia and the risk of developing hypertension in a
working-age male population. J. Am. Heart Assoc. 5, e003053.
Sesso, H.D., et al., 2005. A prospective study of plasma lipid levels and hypertension in
women. Arch. Intern. Med. 165, 2420–2427.
Sharifi-Rad, M, et al., 2016. Inhibitory activity on type 2 diabetes and hypertension key-
enzymes, and antioxidant capacity of Veronica persica phenolic-rich extracts. Cell
Mol. Biol. 62, 80–85.
Shepherd, J, et al., 1995. Prevention of coronary heart disease with pravastatin in men
with hypercholesterolemia. West of Scotland coronary prevention study group. N.
Engl. J. Med. 333, 1301–1307.
Sterne, J.A., Egger, M., 2001. Funnel plots for detecting bias in meta-analysis: guidelines
on choice of axis. J. Clin. Epidemiol. 54, 1046 1045.
Sun, C.L., Liu, C.H., 2015. Clinical observation on treatment of 60 cases of hypertension
with anxiety symptoms by integrative medicine. J. New Chin. Med. 47, 60–61.
Teng, C.X., 2009. Effect of modified Xiao Yao San on 30 cases of hypertensive patients
with anxiety. Hunan J. Tradit. Chin. Med. 25, 44–46.
The SPRINT Research Group, 2015. A randomized trial of intensive versus standard
blood-pressure control. N. Engl. J. Med. 373, 2103–2116.
Vasan, R.S, et al., 2001. Impact of high-normal blood pressure on the risk of cardiovas-
cular disease. N. Engl. J. Med. 345, 1291–1297.
Vogel, J.H, et al., 2005. American college of cardiology foundation task force on clinical
expert consensus documents (Writing committee to develop an expert consensus
document on complementary and integrative medicine). Integrating complementary
medicine into cardiovascular medicine. A report of the American College of
Cardiology Foundation Task Force on Clinical Expert Consensus Documents (Writing
Committee to Develop an Expert Consensus Document on Complementary and
Integrative Medicine). J. Am. Coll. Cardiol. 46, 184–221.
Wang, J., Xiong, X.J., 2012a. Current situation and perspectives of clinical study in in-
tegrative medicine in China. Evid. Based Complement. Alternat. Med. 2012, e268542.
Wang, J., Xiong, X.J., 2012b. Control strategy on hypertension in Chinese medicine. Evid.
Based Complement. Alternat. Med. 2012, e284847.
Wang, J., Xiong, X.J., 2013. Evidence-based Chinese medicine for hypertension. Evid.
Based Complement. Alternat. Med. 2013, e978398.
Wang, L, et al., 2018. Effects of volatile oil of Angelica sinensis on the expression levels of
ET-1, PGI2 and VEGF in spontaneously hypertensive rats. J. Clin. Cardio. 34,
297–300.
Wang, P.Q., et al., 2015. Efficacy and safety of a traditional Chinese herbal formula Xuefu
Zhuyu Decoction for hypertension: a systematic review and meta-analysis. Medicine
94, e1850.
Wang, Z.S., Dong, L., 2012. Effect of modified Dan Zhi Xiao Yao Wan in treating 30 cases
of hypertension with anxiety disorders. Tradit. Chin. Med. Res. 25, 22–24.
Wang, W.H., et al., 2014. Clinical observation on 45 cases of patients with essential hy-
pertension treated by body and mind adjustment combined with modified Dan Zhi
Xiao Yao San. Hebei J. Tradit. Chin. Med. 36, 519–520.
World Health Report, 2002. Reducing risks, Promoting Healthy Life 2002 World Health
Organization, Geneva, Switzerland. http://www.who.int/whr/2002.
Wu, H., Chen, X.K., 2003. Clinical observation on 42 cases of patients with menopausal
hypertension treated by modified Xiao Yao San. Clin. J. Anhui Tradit. Chin. Med. 15,
479.
Xie, H., 2006. Effect of integrative medicine in treating hypertension with anxiety dis-
orders. Zhejiang J. Integr. Tradit. Chin. West Med. 16, 237–239.
Xiong, X.J, et al., 2013a. Chinese herbal formulas for treating hypertension in traditional
Chinese medicine: perspective of modern science. Hypertens. Res. 36, 570–579.
Xiong, X.J, et al., 2013b. Trends in the treatment of hypertension from the perspective of
traditional Chinese medicine. Evid. Based Complement. Alternat. Med. 2013, e275279.
Xiong, X.J, et al., 2014. Herbal medicines for cardiovascular diseases. Evid. Based
Complement. Alternat. Med. 2014, e809741.
Xiong, X.J., 2015. Integrating traditional Chinese medicine into Western cardiovascular
medicine: an evidence-based approach. Nat. Rev. Cardiol. 12, e374.
Xiong, X.J., et al., 2015a. Effects of traditional Chinese patent medicine on essential
hypertension: a systematic review. Medicine 94, e442.
Xiong, X.J, et al., 2015b. Garlic for hypertension: a systematic review and meta-analysis
of randomized controlled trials. Phytomedicine 32, 352–361.
Xiong, X.J., et al., 2015c. The effect of Chinese herbal medicine Jian Ling Decoction for
the treatment of essential hypertension: a systematic review. BMJ Open 5, e006502.
Xiong, X.J., et al., 2015d. The effects of red yeast rice dietary supplement on blood
pressure, lipid profile and C-reactive protein in hypertension: a systematic review.
Crit. Rev. Food Sci. Nutr. 57, 1831–1851.
Ye, L.L., 2014. Effect of Xiao Yao Wan on blood pressure, anxiety and depression in hy-
pertensive patients. Clin. J. Chin. Med. 6, 26–27.
Yi, L, et al., 2017. Effects of volatile oil of Angelica sinensis on ACE2/Ang1-7/Mas re-
ceptor axis in spontaneously hypertensive rats. J Clin. Cardio. 33, 584–587.
Yokoyama, M, et al., 2007. Effects of eicosapentaenoic acid on major coronary events in
hypercholesterolaemic patients (JELIS): a randomised openlabel, blinded endpoint
analysis. Lancet 369, 1090–1098.
Zhang, Y.Q., et al., 2012. Chinese herbal formula Xiao Yao San for treatment of depres-
sion: a systematic review of randomized controlled trials. Evid. Based Complement.
Alternat. Med. 2012, e931636.
Zhou, B.Q., 2015. Clinical observation on hypertension with depression treated by in-
tegrative medicine. Cardio. Dise. J. Integr. Tradit. Chin. West Med. 3, 32–33.
Zhou, X.Q., Qi, T.S., 2006. Clinical observation on 59 cases of patients with menopausal
hypertension treated by integrative medicine. Sichuan Med. J. 27, 1271–1272.
Zhu, X, et al., 2014. Xiao Yao San improves depressive-like behavior in rats through
modulation of β-arrestin 2-mediated pathways in hippocampus. Evid. Based
Complement. Alternat. Med. 2014, e902516.
Zhu, Y.F., 2013. Effect of Modified Xiao Yao Wan on Insulin Resistance in T2DM Mice
Under Chronic Psychological Stress. Guangzhou University of Chinese Medicine,
Guangzhou, pp. 1–80.
X. Xiong, et al. Phytomedicine 61 (2019) 152849
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... However, preliminary surveys revealed that there was an absence of studies on the anti-inflammatory effects of CHM in PWH to enable a systematic review or meta-analyses to be performed to address this question. Most current meta-analyses either focused on CHM for the treatment of AIDS (60) or investigated the effects of CHM with or without co-interventions on CVD management, but their favorable outcomes were blood lipid profiles (61), quality of life (62) or other specific parameters of the investigated conditions (e.g., blood pressure) (63), and not inflammatory biomarkers. The available studies were not sufficient to conduct a systematic review: only two RCTs and one parallel controlled study were returned after a comprehensive search of English and Chinese databases. ...
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Inflammation drives cardiovascular disease (CVD) in individuals with underlying chronic inflammatory diseases, including People with HIV (PWH), independently of dyslipidemia. Adjunctive treatments that lower inflammation may be useful to lower CVD risk in such populations. There is very little data on the efficacy of Chinese herbal medicine (CHM) in reducing inflammation in PWH to address its potential in reducing this CVD risk factor, therefore we evaluated its impact on inflammatory biomarkers relevant to CVD risk in the general population. Six English and Chinese databases were searched for studies investigating CHM’s effects on inflammatory biomarkers relevant to CVD from respective inceptions to February 2022. A systematic review and meta-analysis of randomized controlled trials (RCTs) were conducted and the most-frequently prescribed herbs were identified. Thirty-eight RCTs involving 4,047 participants were included. Greater than or equal to 50% of included studies had a low risk of bias in five domains (random sequence generation, detection, attrition, reporting and other bias) and 97% had a high risk of performance bias. CHM provided significant additive effects on attenuating relevant inflammatory indices including hs-CRP (SMD −2.05, 95% CI −2.55 to −1.54), IL-6 (SMD −1.14, 95% CI −1.63 to −0.66) and TNF-α levels (SMD −0.88, 95% CI −1.35 to −0.41), but no significant effects on hs-CRP were found between CHM and placebo when co-treating with Western drugs (MD 0.04, 95% CI −1.66 to 1.74). No severe adverse events were reported in CHM groups. The two most prevalent herbs present in formulae demonstrating reduction of at least one inflammatory biomarker were Dan shen (Salviae Miltiorrhizae Radix et Rhizoma) and Huang qi (Astragali Radix). CHM, in combination with standard anti-inflammatory medications, may depress inflammation and reduce the risk of inflammatory conditions such as CVD. Rigorously-conducted trials and adequate reporting are needed to provide more robust evidence supporting the use of CHM to reduce CVD risk in people with underlying chronic inflammation such as PWH.
... Patients with such disorders might be at a higher risk of developing HTN, and this may explain the frequent prescription of JWXYS for HTN. Its modified formulation, Xiao-Yao-San (XYS), is beneficial for hypertensive patients in lowering BP, improving depression, regulating blood lipid levels, and inhibiting inflammation (28). So far, no studies have mentioned that JWXYS can prevent HF. ...
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Background Hypertension (HTN) is the leading preventable risk factor for cardiovascular disease worldwide. Patients with HTN are at higher risk for heart failure (HF). The currently available therapeutic approaches for HTN do not always optimally control blood pressure or are not suitable for hypertensive patients who have a higher number of comorbidities. This study aimed to determine whether Chinese herbal medicine (CMH)-based interventions could reduce the risk of HF in hypertensive patients. Methods This retrospective study randomly selected 2 million enrollees from the National Health Insurance Research Database and identified 507,608 patients who were newly diagnosed with HTN in 2000–2017. After 1:1 frequency-matching by age, sex, index year, income, urbanization, duration of HTN, comorbidities and antihypertensive medications, we selected 8,912 eligible patients in each group. During 16 years of follow-up, 380 CHM users and 426 CHM non-users developed HF, representing incidence rates of 6.29 and 7.43 per 1,000 person-years, respectively. Results CHM users had significantly lower HF risk compared with CHM non-users (adjusted HR = 0.85, 95% CI 0.74–0.98). The markedly predominant effect was observed in those receiving CHM products for more than 180 days (adjusted HR = 0.65). The frequently prescribed formula, Jia-Wei-Xiao-Yao-San, and the single herbs Ge Gen, Huang Qi, Du Zhong, Huang Qin, and Chuan Xiong were significantly associated with lower risk of HF. Conclusions This population-based study revealed decreased HF risk in hypertensive patients with CHM use. These findings may provide a reference for HF prevention strategies and support the integration of CHM into clinical intervention programs that provide a favorable prognosis for hypertensive patients.
... Once getting rancid, the active components of CMMs are affected, and there is a certain degree of loss of medicinal properties, which is harmful to clinical safety and efficacy, and even produces toxicity (Olatunji et al., 2018). However, for the changes in medicinal materials and the loss of quality during storage, most of the current research studies are limited to the detection of one or a class of chemical compounds, which cannot represent the overall quality of CMMs, and there are deficiencies (Xu et al., 2017;Beckerman and Persaud, 2019;Wang and Zhu, 2019;Zhang et al., 2019;Yu et al., 2021), this will, to a large extent, cause "deteriorated CMMs" being consumed in the markets and pharmacies, seriously threatening public health (Xin et al., 2015;Dong et al., 2019;Xiong et al., 2019;Zhang, 2020). ...
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In recent years, the domestic and international trade volumes of Chinese medicinal materials (CMMs) keep increasing. By the end of 2019, the total amount of exported CMMs reached as high as US $1.137 billion, while imported was US $2.155 billion. A stable and controllable quality system of CMMs apparently becomes the most important issue, which needs multifaceted collaboration from harvesting CMMs at a proper season to storing CMMs at a proper temperature. However, due to imperfect storage conditions, different kinds of deteriorations are prone to occur, for instance, get moldy or rancid, which not only causes a huge waste of CMM resources but also poses a great threat to clinical medication safety and public health. The key issue is to quickly and accurately distinguish deteriorated CMM samples so as to avoid consuming low-quality or even harmful CMMs. However, some attention has been paid to study the changing quality of deteriorated CMMs and a suitable method for identifying them. In this study, as a medicine and food material which easily becomes rancid, armeniacae semen amarum (ASA) was chosen as a research objective, and experimental ASA samples of different rancidness degrees were collected. Then, various kinds of analytical methods and technologies were applied to explore the changing rules of ASA quality and figure out the key indicators for the quality evaluation of ASA in the rancid process, including the human panel, colorimeter, electronic nose, and GC/MS. This study aims to analyze the correlation between the external morphological features and the inner chemical compounds, to find out the specific components from “quantitative change” to “qualitative change” in the process of “getting rancid,” and to discover the dynamic changes in the aforementioned key indicators at different stages of rancidness. The results showed since ASA samples began to get rancid with the extension of storage time, morphological features, namely, surface color and smell, changed significantly, and the degree of rancidness further deepened at the same time. Based on macroscopic identification accomplished via the human panel, ASA samples with varying degrees of rancidness were divided into four groups. The result of colorimeter analysis was in agreement with that of the human panel, as well as the determination of the amygdalin content and peroxide value. Moreover, there were obvious differences in the amygdalin content and peroxide value among ASA samples with different rancidness degrees. With a higher degree of rancidness, the content of amygdalin decreased, while the peroxide value increased significantly. The rancidness degree of ASA has a negative correlation with the amygdalin content and a positive correlation with the peroxide value. The newly discovered nonanal and 2-bromopropiophenone in rancid ASA samples may be the key components of “rancidity smell,” and these two components would be the exclusive components that trigger “quantitative change” to “qualitative change” in the process of rancidness of ASA. This study sheds light on studying the internal mechanism of “rancidness” of CMMs and provides an important basis for the effective storage and safe medication of easy-to-get rancid herbs, and it also plays an important foundation for the establishment of a stable and controllable quality system for CMMs.
... An existing systematic review shows that TCM herbs can improve the vascular endothelial function of patients with hypertension, inhibit inflammatory reactions, regulate blood lipids, and improve mood. Adjuvant TCM therapy more easily achieves the targeted blood pressure and improves the comfort of patients, protecting target organs and reducing cardiovascular events [7][8][9]. ...
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Hypertension and coronary heart disease are the most common cardiovascular diseases, and traditional Chinese medicine is applied as an auxiliary treatment for common cardiovascular diseases. This study is based on 3 years of electronic medical record data from the Affiliated Hospital of Shandong University of Traditional Chinese Medicine. A complex network and machine learning algorithm were used to establish a screening model of coupled herbs for the treatment of hypertension complicated with coronary heart disease. A total of 5688 electronic medical records were collected to establish the prescription network and symptom database. The hierarchical network extraction algorithm was used to obtain core herbs. Biological features of herbs were collected from public databases. At the same time, five supervised machine learning models were established based on the biological features of the coupled herbs. Finally, the K-nearest neighbor model was established as a screening model with an AUROC of 91.0%. Seventy coupled herbs for adjuvant treatment of hypertension complicated with coronary heart disease were obtained. It was found that the coupled herbs achieved the purpose of adjuvant therapy mainly by interfering with cytokines and regulating inflammatory and metabolic pathways. These results show that this model can integrate the molecular biological characteristics of herbs, preliminarily screen combinations of herbs, and provide ideas for explaining the value in clinical applications.
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Background : Depression is one of the most debilitating and severe psychiatric disorders and a serious public health concern. Currently, many treatments are indicated for depression, including traditional Chinese medicinal formulae such as Xiao-Yao-San (XYS), which has effective antidepressant effects in clinical and animal studies. Purpose : To summarize current evidence of XYS in terms of the preclinical and clinical studies and to identify the multi-level, multi-approach, and multi-target potential antidepressant mechanisms of XYS and active components of XYS by a comprehensive search of the related electronic databases. Methods : The following electronic databases were searched from the beginning to April 2022: PubMed, MEDLINE, Web of Science, Google Scholar, and China National Knowledge Infrastructure. Results : This review summarizes the antidepressant mechanisms of XYS and its active ingredients, which are reportedly correlated with monoamine neurotransmitter regulation, synaptic plasticity, and hypothalamic–pituitary–adrenal axis, etc. Conclusion : XYS plays a critical role in the treatment of depression by the regulation of several factors, including the monoaminergic systems, hypothalamic–pituitary–adrenal axis, synaptic plasticity, inflammation, brain-derived neurotrophic factor levels, brain-gut axis, and other pathways. However, more clinical and animal studies should be conducted to further investigate the antidepressant function of XYS and provide more evidence and recommendations for its clinical application. Our review provides an overview of XYS and guidance for future research direction.
Article
Background Hypertension is one of the most significant public health challenges worldwide. An increasing number of patients prefer to incorporate traditional Chinese medicine into their hypertensive care. The Songling Xuemaikang capsule (SXC), a Chinese herbal formula, is widely used in China for essential hypertension. Purpose To assess the efficacy and safety of SXC for essential hypertension. Study design Systematic review and meta-analysis of randomized controlled trials. Methods We conducted a systematic literature search of seven databases to identify randomized controlled trials (RCTs) of SXC for hypertension. The outcome measures included blood pressure parameters and patient-reported outcomes. Potential heterogeneity between the studies was resolved by subgroup and sensitivity analyses. The quality of the results was evaluated using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach. Results A total of 34 trials with 4306 patients were included. The results showed that SXC plus antihypertensive drugs produced a greater effect on reducing systolic blood pressure (SBP) (MD: -7.54 mmHg; 95% CI: -8.92, -6.17; P < 0.00001), diastolic blood pressure (DBP) (MD: -6.42 mmHg; 95% CI: -7.54, -5.29; P < 0.00001), 24-hour SBP (MD: -6.88 mmHg; 95% CI: -8.36, -5.39; P < 0.00001), and 24-hour DBP (MD: -4.31 mmHg; 95% CI: -6.55, -2.07; P = 0.0002) and improving hypertensive symptoms (SMD: -1.09; 95% CI: -1.34, -0.84; P < 0.00001) than antihypertensive drugs alone. SXC monotherapy was less effective than antihypertensive drugs for 24-hour SBP reduction (MD: 2.07 mmHg; 95% CI: 0.19, 3.96; P = 0.03). No significant difference was observed in the incidence of adverse events between the SXC and control groups. Conclusion SXC is beneficial for essential hypertension; it can lower BP, improve hypertensive symptoms and is well tolerated.
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Ethnopharmacological relevance Integrated Chinese herbal medicine (CHM) and Western Medicine (WM) treatments have been used for primary hypertension (PHTN) patients in China. Currently, there are many randomized control trials (RCTs) published regarding the effect of CHM and WM on PHTN, which indicated that combining Chinese with WM was effective and safe for PHTN when compared with WM alone, but the quality of evidence was insufficient, and there is no clear information and summary are available for these RCTs assessing the effectiveness of CHM with WM versus WM in patients with PHTN. Objectives This systematic study and meta-analysis aimed to evaluate the effectiveness and safety of CHM combined with WM in comparison with WM in reducing systolic and diastolic blood pressure for patients with PHTN. Methods The information of this study was searched from electronic databases (PubMed, COCHRANE, EMBASE, Ovid, CNKI, VIP, Wanfang, and CBM). The markedly effective and effective terms were according to Guiding Principles for Clinical Research of New Chinese Medicines. Two investigators independently reviewed each trial. The Cochrane risk of bias assessment tool was used for quality assessment, and RevMan 5.4 was used for meta-analysis. Results In this study, a total of 29 studies that included 2623 patients were recorded. The study results displayed that the clinical effectiveness in the treatment of hypertension patients from the integrated medicines was considerably higher than that with WM alone, clinical effective (RR 1.23, 95% CI [1.17, 1.30], P < 0.00001), and markedly effective (ME) in the patients (RR 1.66, 95% CI [1.52, 1.80], and P < 0.00001). Random effect in SBP (MD 7.91 mmHg,[6.00, 983], P < 0.00001) and DBP (MD 5.46 mmHg, [3.88, 6.43], P < 0.00001), a subgroup analysis was carried out based on the type of intervention, duration of treatment, and CHM formulas that showed significance. Furthermore, no severe side effects were reported, and no patients stopped treatment or withdrawal due to any severe adverse events. Conclusion Compared to WM alone, the therapeutic effectiveness of CHM combined with WM is significantly improved in the treatment of hypertension. Additionally, CHM with WM may safely and efficiently lower systolic blood pressure (SBP) and diastolic blood pressure (DBP) in individuals with PHTN. However, rigorous randomized controlled trials with a large sample, high quality, long duration of treatment, and follow-up are recommended to strengthen this clinical evidence.
Article
Introduction Irritable bowel syndrome (IBS) is a prevalent functional gastrointestinal disorder, and xiaoyao-san (XYS) has been prescribed for gastroenterological and neurological diseases in TCM. This meta-analysis evaluated the efficacy and safety of XYS on IBS. Methods RCTs were searched from nine electronic databases to April 30, 2021. RCTs that applied XYS or modified XYS as an experimental intervention and adopted Rome Criteria for IBS diagnosis were included. There were no limits for IBS-subtypes, patient information and publication language, and trials with improper randomization were excluded. The following indices were extracted from each identified trial: efficacy rate, symptom scores, IBS symptom severity score (IBS-SSS), IBS quality of life (IBS-QoL), Short Form Health Survey (SF-36), and adverse effects. Data analysis was conducted using RevMan 5.3, and Cochrane's risk of bias tool was used to assess the risk of bias in each trial. Results Twenty-one RCTs with 1858 patients were included in this review. XYS appeared to be better than conventional therapies in improving the clinical efficacy. Furthermore, XYS significantly reduced abdominal pain, abdominal distention, diarrhea, and IBS-SSS. XYS was also effective on five of the IBS-QoL subscales; dysphoria, interference with activity, body image, food avoidance, and social reaction. In addition, XYS was effective on four of the SF-36 subscales: physical functioning, bodily pain, physical role functioning, and emotional role functioning. Conclusion XYS may have a potential benefit for managing IBS. Moreover, it also needs to be recommended large-scale RCTs having more sufficient global IBS symptom scales in the future.
Article
Introduction Studies have suggested that different administration times may lead to different antihypertensive effects. This systematic review was designed to evaluate the effectiveness of evening versus morning drug administration for hypertension. Methods Eight databases were searched to identify randomized controlled trials (RCTs) from database inception to August 2021. The RCTs compared the effects of evening and morning dosing on cardiovascular disease events, adverse events and reduction of blood pressure (BP) in hypertensive. Two reviewers independently extracted data and assessed trial quality. Meta-analysis was performed using Stata 12.0 software. Results A total of 36 RCTs were included and analysed. The results showed that, compared with the morning administration, evening administration of hypertensives could decrease cardiovascular disease events (risk ratio=0.39, 95% confidence interval (CI)=0.25 to 0.60), 24h/48h mean systolic BP (SBP) (mean differences (MD) =-3.39, 95% CI=-4.57 to -2.22), 24h/48h mean diastolic BP (DBP) (MD=-1.12, 95% CI=-1.70 to -0.53), nocturnal mean SBP (MD=-6.70, 95% CI=-8.35 to -5.05) and nocturnal mean DBP (MD=-3.54, 95% CI= -4.46 to -2.63), while diurnal mean SBP (MD=-0.53, 95% CI=-1.72 to 0.65) and diurnal mean DBP (MD=-0.31, 95% CI=-1.04– 0.42) showed no difference between two groups. Conclusion This meta-analysis indicated that evening administration was superior to morning administration in reducing asleep BP and the risk of cardiovascular disease events, especially for patients with essential hypertension, patients with renal hypertension and the non-dipper hypertensive patients. More evidence is needed to support this conclusion.
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Systematic reviews and meta-analyses are often considered the highest level of evidence, with high impact on clinical practice guidelines. The methodological literature on systematic reviews and meta-analyses is extensive and covers most aspects relevant to the design and interpretation of meta-analysis findings in general. Analyzing the effect of blood pressure–lowering on clinical outcomes poses several challenges over and above what is covered in the general literature, including how to combine placebo-controlled trials, target-trials, and comparative studies depending on the research question, how to handle the potential interaction between baseline blood pressure level, common comorbidities, and the estimated treatment effect, and how to consider different magnitudes of blood pressure reduction across trials. This review aims to address the most important methodological considerations, to guide the general reader of systematic reviews and meta-analyses within our field, and to help inform the design of future studies. Furthermore, we highlight issues where published meta-analyses have applied different analytical strategies and discuss pros and cons with different strategies.
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Background: Hypertension is one of the main comorbidities associated with dyslipidemia. This study aimed to examine the extent to which dyslipidemia increases the risk of developing hypertension in a Japanese working-age male population. Methods and results: We analyzed data from 14 215 nonhypertensive male workers (age 38±9 years) who underwent annual medical checkups. Subjects were followed up for a median of 4 years to determine new-onset hypertension, defined as blood pressure (BP) ≥140/90 mm Hg or use of antihypertensive medication. The associations between serum lipid levels and development of hypertension were examined. During the follow-up period, 1483 subjects developed hypertension. After adjusting for age, body mass index, impaired fasting glucose/diabetes, baseline BP category, alcohol intake, smoking, exercise, and parental history of hypertension, subjects with a total cholesterol (TC) level ≥222 mg/dL were at a significantly increased risk of developing hypertension (hazard ratio: 1.28; 95% CI: 1.06-1.56) compared to subjects with a TC level ≤167 mg/dL. Similar results were observed for subjects with high low-density lipoprotein cholesterol (LDLC) and non-high-density lipoprotein cholesterol (HDLC) levels. A U-shaped relationship was found between HDLC level and risk of hypertension; compared to the third quintile, the multiadjusted hazard ratio was 1.22 (95% CI: 1.03-1.43) in the lowest quintile and 1.34 (95% CI: 1.12-1.60) in the highest quintile. Conclusions: Elevated serum levels of TC, LDLC, and non-HDLC were associated with an increased risk of hypertension in working-age Japanese men. For HDLC, risk of hypertension was increased at both low and high levels.
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Background: The benefits of blood pressure lowering treatment for prevention of cardiovascular disease are well established. However, the extent to which these effects differ by baseline blood pressure, presence of comorbidities, or drug class is less clear. We therefore performed a systematic review and meta-analysis to clarify these differences. Method: For this systematic review and meta-analysis, we searched MEDLINE for large-scale blood pressure lowering trials, published between Jan 1, 1966, and July 7, 2015, and we searched the medical literature to identify trials up to Nov 9, 2015. All randomised controlled trials of blood pressure lowering treatment were eligible for inclusion if they included a minimum of 1000 patient-years of follow-up in each study arm. No trials were excluded because of presence of baseline comorbidities, and trials of antihypertensive drugs for indications other than hypertension were eligible. We extracted summary-level data about study characteristics and the outcomes of major cardiovascular disease events, coronary heart disease, stroke, heart failure, renal failure, and all-cause mortality. We used inverse variance weighted fixed-effects meta-analyses to pool the estimates. Results: We identified 123 studies with 613 815 participants for the tabular meta-analysis. Meta-regression analyses showed relative risk reductions proportional to the magnitude of the blood pressure reductions achieved. Every 10 mm Hg reduction in systolic blood pressure significantly reduced the risk of major cardiovascular disease events (relative risk [RR] 0·80, 95% CI 0·77-0·83), coronary heart disease (0·83, 0·78-0·88), stroke (0·73, 0·68-0·77), and heart failure (0·72, 0·67-0·78), which, in the populations studied, led to a significant 13% reduction in all-cause mortality (0·87, 0·84-0·91). However, the effect on renal failure was not significant (0·95, 0·84-1·07). Similar proportional risk reductions (per 10 mm Hg lower systolic blood pressure) were noted in trials with higher mean baseline systolic blood pressure and trials with lower mean baseline systolic blood pressure (all ptrend>0·05). There was no clear evidence that proportional risk reductions in major cardiovascular disease differed by baseline disease history, except for diabetes and chronic kidney disease, for which smaller, but significant, risk reductions were detected. β blockers were inferior to other drugs for the prevention of major cardiovascular disease events, stroke, and renal failure. Calcium channel blockers were superior to other drugs for the prevention of stroke. For the prevention of heart failure, calcium channel blockers were inferior and diuretics were superior to other drug classes. Risk of bias was judged to be low for 113 trials and unclear for 10 trials. Heterogeneity for outcomes was low to moderate; the I(2) statistic for heterogeneity for major cardiovascular disease events was 41%, for coronary heart disease 25%, for stroke 26%, for heart failure 37%, for renal failure 28%, and for all-cause mortality 35%. Interpretation: Blood pressure lowering significantly reduces vascular risk across various baseline blood pressure levels and comorbidities. Our results provide strong support for lowering blood pressure to systolic blood pressures less than 130 mm Hg and providing blood pressure lowering treatment to individuals with a history of cardiovascular disease, coronary heart disease, stroke, diabetes, heart failure, and chronic kidney disease. Funding: National Institute for Health Research and Oxford Martin School.
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Systematic reviews should build on a protocol that describes the rationale, hypothesis, and planned methods of the review; few reviews report whether a protocol exists. Detailed, well-described protocols can facilitate the understanding and appraisal of the review methods, as well as the detection of modifications to methods and selective reporting in completed reviews. We describe the development of a reporting guideline, the Preferred Reporting Items for Systematic reviews and Meta-Analyses for Protocols 2015 (PRISMA-P 2015). PRISMA-P consists of a 17-item checklist intended to facilitate the preparation and reporting of a robust protocol for the systematic review. Funders and those commissioning reviews might consider mandating the use of the checklist to facilitate the submission of relevant protocol information in funding applications. Similarly, peer reviewers and editors can use the guidance to gauge the completeness and transparency of a systematic review protocol submitted for publication in a journal or other medium.
Article
Objectives: Several studies have suggested a positive association between serum lipid levels and blood pressure (BP). This study investigated this association in a large population from 12 European countries. Methods: Data were taken from the European Study on Cardiovascular Risk Prevention and Management in Usual Daily Practice (ClinicalTrials.gov identifier: NCT00882336). Associations between BP and lipid levels in patients free from cardiovascular disease and with at least one major cardiovascular disease risk factor (N = 7641) were assessed using linear regression analyses. Results: Overall, 72.8 and 64.8% of patients had hypertension and dyslipidaemia, respectively; 47.0% had both conditions. Regression coefficients (95% confidence interval) for the associations of LDL cholesterol, non-HDL cholesterol, total cholesterol and apolipoprotein B levels with SBP, adjusted for age, sex and BMI, were 0.93 mmHg/mmol per l (0.54-1.31), 1.07 mmHg/mmol per l (0.73-1.40), 1.02 mmHg/mmol per l (0.69-1.35) and 4.94 mmHg/g per l (3.43-6.46), respectively. The corresponding values (95% confidence interval) for the associations with DBP were 0.96 mmHg/mmol per l (0.73-1.19), 0.95 mmHg/mmol per l (0.75-1.15), 0.87 mmHg/mmol per l (0.67-1.07) and 4.33 mmHg/g per l (3.42-5.23), respectively. Most of these associations remained significant whether patients were treated with statins or not. Conclusion: Small but statistically significant associations between lipid levels and BP were observed in a large, multinational European population. Further research is warranted to assess the causality of this association and its implications on the management of patients with both hypertension and dyslipidaemia.
Article
Objective: The aim of the study was to assess the association of hypertension and symptoms of depression and generalized anxiety in a large cohort of elderly people. Methods: Data were derived from the 8-year follow-up (2008-2010) of the epidemiological ESTHER-cohort study. A total of 3124 randomly chosen participants aged 57-84 were visited at their homes by trained study doctors. General practitioner based diagnosis, self-reported status of hypertension, medication, and blood pressure measurement were considered to define the existence of hypertension. Depression and general anxiety severity were assessed using validated questionnaires. Logistic regression analyses were performed to determine cross-sectional associations between hypertension and clinically significant symptoms of depression (CSD) and generalized anxiety. Well known lifestyle risk factors for hypertension such as obesity were included in multivariate cross-sectional analyses. Results: Hypertension was prevalent in 1659 participants [53.1%; 95% confidence interval (CI) = (51.3; 54.9)]. CSD was detected in 163 participants [5.2%; 95%-CI = (4.4; 6.0)]. Symptoms of generalized anxiety were found in 434 participants [13.9%; 95%-CI = (12.7; 15.1)]. Patients with CSD showed significantly higher odds of being hypertensive [odds ratio (OR) = 1.76; 95%-CI = (1.14; 2.74)]. Participants with symptoms of generalized anxiety were found to have no higher odds for a hypertension diagnosis [OR = 1.1; 95%-CI = (0.85; 1.44)]. Overweight [OR = 1.86; 95%-CI = (1.53; 2.25)] as well as obesity [OR = 3.58; 95%-CI = (2.84; 4.52)] was significantly associated with hypertension. Conclusion: CSD appear to be related to hypertension in elderly adults. No association was found between symptoms of generalized anxiety and hypertension.
Article
The objective of this study was to evaluate the estrogenic effects and mechanisms of three flavonoid components in Xiaoyao powder: quercetin, kaempferol, and isorhamnetin. The drugs were used to treat estrogen receptor (ER)-positive human breast cancer MCF-7 cells, and proliferation was measured using the MTT method. The expression of proteins and mRNA of the ER subtype were measured using western blotting and real time polymerase chain reaction. The quercetin (10-2 μM, 10-3 μM), kaempferol (100 μM, 10-2 μM), and isorhamnetin (10-3 μM) promoted the proliferation of MCF-7 cells, and the expression of ERα and ERβ proteins and mRNA were all increased significantly (P < 0.05). These effects were reversed by treatment with 0.1 μM estrogen antagonist ICI182780. Three flavonoid components in Xiaoyao powder increased the expression of proteins and mRNA of ERα and ERβ and promoted the proliferation of MCF-7 cells. These estrogenic effects were mediated by the ER.