Chinese Herbal Medicine for Vascular Dementia: A Systematic Review and Meta-Analysis of High-Quality Randomized Controlled Trials

Abstract

Background:

Vascular dementia (VaD) is the second common form of dementia and Chinese herbal medicine (CHM) has been used for aging-related disorders for thousands of years. However, there is still a lack of scientific evidence using CHM for VaD.

Objective:

To conduct a systematic review to assess the current evidence available for the effectiveness and safety of CHM for VaD.

Methods:

Six databases were searched for high-quality randomized-controlled clinical trials that met the requirements of at least 4 of the 7 domains of the Cochrane risk of bias tool from their inception to February 2017. RevMan 5.3 was applied for data analysis.

Results:

Forty studies with 42 comparisons and 3,572 individuals were included. The studies investigated the CHM versus placebo (n = 4), CHM versus western conventional treatment (WCT) (n = 36), and CHM plus WCT versus WCT (n = 2). Meta-analysis showed that CHM for VaD could improve Mini-Mental State Examination (MMSE), the Activities of Daily Living, Hasegawa’s dementia scale, and clinical effective rate but had statistically similar effect based on Blessed Behavior Scale (BBS) outcome when compared with WCTs. When compared with placebo, CHMs were more beneficial in improving MMSE but showed no significant difference in BBS scores. CHM as adjuvant therapy exerted an additive anti-VaD benefit on MMSE scores. The participants of CHM group had fewer adverse events than that of the placebo group or WCT group.

Conclusion:

The findings of the present study support, at least to an extent, that CHM can be recommended for routine use for treatment of VaD.

Keywords

Chinese herbal meta-analysis systematic review traditional Chinese medicine vascular dementia

INTRODUCTION

Vascular dementia (VaD) is the second common form of dementia after Alzheimer’s disease (AD), accounting for more than 20% of all dementia cases worldwide [1]. In particular, VaD constitutes about 30% of the dementia prevalence in developing countries due to poorer control of cardiovascular risk factors [2]. The incidence of VaD increases with age steeply, rising from 1.5% at the age of 70–75 years old to 15% at the age of 80 years old and above [3]. VaD is caused by a reduced cerebral blood flow supplying the brain that may be associated with a stroke or its risk factors [4]. The main risk factors include hypertension, cardiac diseases, diabetes, hyperlipidemia, genetic disposition, physical inactivity, and obesity [5]. Currently, cerebrovascular diseases (CVDs) contribute to cognitive impairment that is receiving heightened attention because they are potentially modifiable factors for both VaD and AD [6, 7]. However, definition of the term vascular dementia is still controversial and ongoing. In 1906, Dr. Alois Alzheimer and colleagues first described “arteriosclerosis of the small cerebral vessels” as a potential cause of dementia [8]. In 1968, Blessed et al. [9] raised that VaD was associated with multiple brain infarctions exceeding a certain threshold and distinct from AD based on neuropathological studies. In 1974, Hachinski et al. [10] proposed that the dementia is related to the occurrence of multiple small or large cerebral infarcts. In 1993, the term vascular cognitive impairment (VCI) was introduced to better reflect the full range of cognitive alterations resulting from vascular diseases [11]. This definition of VaD does not require evidence of memory impairment(s) in more than one cognitive domain. Subsequently, the concept of VCI was widely accepted and updated its definition as “a syndrome with evidence of clinical stroke or subclinical vascular brain injury and cognitive impairment affecting at least one cognitive domain” [12]. Many different subtypes of VCI was introduced, including multi-infarct dementia (cortical vascular dementia), small vessel dementia (subcortical vascular dementia), strategic infarct dementia, hypoperfusion dementia, hemorrhagic dementia, hereditary vascular dementia (CADASIL), and AD with CVD [6]. In 2014, the categories under the term vascular cognitive disorders were divided into the mild vascular cognitive disorder, and vascular dementia or major vascular cognitive disorder [13].

The pathophysiology of VaD incorporates interactions between vascular etiologies such as cerebrovascular disorders and vascular factors, changes in the brain such as infarcts, white matter lesions, and atrophy, and host factors such as age and education [14]. The final common etiopathogenic pathway is mostly ascribed to a hypoxic, hypoperfusion, or vascular occlusive process, leading to ischemic damage in various areas of the brain with subsequently cognitive and memory function impairments [15]. AD, amyloid deposition, aging, and atherosclerosis also make a contribution to VaD development through inflammation and oxidative stress [5]. Both AD and VaD can occur in one patient, known as mixed type dementia [16]. VaD frequently coexists along with AD pathology in persons with dementia and they share multiple etiology, especially vascular factors. Currently, vascular risk factors and vascular mechanisms have emerged as an area of key importance for AD [17]. There is abundant and converging evidence showing that CVDs and relative factors play an important role in the etiology of AD [18]. Based on the recent epidemiological and clinico-pathological data, considerable overlap between CVD and AD, such as cerebral amyloid angiopathy and small vessel disease, indicated additive or synergistic effects of both pathologies on cognitive decline [19]. Mutually, AD pathology in the form of cerebral amyloidosis has an impact on vascular and endothelial function, further impairing vascular mechanisms that potentially eliminate abnormal proteins such as amyloid-β protein from the brain [20]. Thus, the study of mechanisms and intervention of VaD may provide an idea and novel therapeutic strategy for benefit of both VaD and AD.

VaD patients generally suffer from not only cognitive impairment but also a progressive disturbance in memory, mood, and behavior [21]. Currently, there is still no effective treatment available for VaD. Standard treatment mostly focuses on symptomatic management and prevention of additional brain damage [6]. Anti-AD pharmaceutical agents, known as cholinesterase inhibitors, glutamate receptor antagonists, and N-methyl-D-aspartate (NMDA) receptor antagonists, have been used off-label for the symptomatic relief in people with VaD, exerting modest short-term (5-6 months) clinical benefits in improving cognitive function [22]. However, the safety and the long-term therapeutic benefits of these interventions in VaD have not been validated.

Given the absence of modified therapies, more and more VaD patients resorted to Traditional Chinese medicine (TCM). Chinese herbal medicine (CHM), as a pharmacological form of TCM, has been used for the treatment of aging-related disorders to improve memory function and increase longevity thousands of years ago in ancient China [23]. Two previous systematic reviews addressing the efficacy and safety of CHM for VaD has been published in 2013 by Qin et al. [24] and in 2015 by Zeng et al. [25], respectively, and they reached similar conclusions that CHM for VaD appears to be effective and generally safe. However, there are still lack of evidence to recommend the routine use CHM for VaD because of low methodological quality in the included studies. In addition, there have been a number of new controlled studies after these two systematic reviews were published. Thus, it is worth conducting an updated systematic review of high-quality randomized controlled trials (RCTs) using CHM for VaD after the strict exclusion of “not-so-good” studies as indicated by the Cochrane group guidelines for clinical reviews [26].

METHODS

Types of studies

All RCTs evaluate the efficacy and safety of CHM for VaD were selected in the qualitative analyses, regardless of blinding, language, or publication status. We included only high-quality studies that met the requirements of at least 4 of the 7 domains of the Cochrane risk of bias (RoB) tool [27, 28] based on our previous meta-analysis study design [29].

Types of participants

Patients with a diagnosis of VaD were included, irrespective of ethnicity, gender, age, or duration of the disease. The following eligibility criteria of VaD were accepted: the National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et l’Enseignementen Neurosciences scale (NINDS-AIREN) [30]; NINDS-AIREN clinical criteria for the diagnosis of vascular dementia (CCDVD); Diagnostic and Statistical Manual of Mental Disorders (DSM-III [31], DSM-IV [32], DSM-IV-R [33]); the International Classification of Diseases, 10th Revision (ICD-10) [34]. Other diagnostic criteria with comparable definitions were also used such as the Criteria for Diagnosis, TCM Differentiation and Clinical Effectiveness Assessment in Treating VaD [35], Clinical Research Guidelines of New Chinese Medicine For Curing Dementia [36], or the scale differentiation of syndromes of vascular dementia (SDSVD) [37]. Participants with mild cognitive impairment (MCI), other forms of dementia (e.g., AD, frontotemporal dementia, and Lewy body disease), or mixed dementia were excluded.

Types of interventions

The studies met one of the following criteria: 1) Comparing CHM with western conventional treatments (WCTs); 2) Comparing CHM with Placebo; 3) Comparing CHM plus WCTs with WCTs alone. The CHM interventions were defined as a prescription containing multiple herbs, extracts from an herb, a single herb, or patent herbal products, regardless of dosage, modes of administration, and duration of treatment. Any non-herbal TCM therapies such as acupuncture, moxibustion, and massage in the intervention group or any TCM therapies in control group were excluded.

Types of outcome measures

The primary outcome measures were the Mini-Mental State Examination (MMSE), the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog), and the Vascular Dementia Assessment Scale cognitive subscale (VADAS-cog). The secondary outcome measures were the Activities of Daily Living (ADL), Blessed Behavior Schedule (BBS), Hasegawa’s dementia scale (HDS), the effective rate of VaD and adverse events.

Information sources and search strategy

A comprehensive search strategy was conducted in six databases, including PubMed, Embase, CENTRAL (The Cochrane Library), Chinese National Knowledge Infrastructure (CNKI), VIP Journals Database, and Wangfang Database from inception to February 2017. The search terms were “(vascular dementia OR acute onset vascular dementia OR subcortical vascular dementia OR arteriosclerotic dementia) AND (herbal medicine OR Chinese herbal medicine OR Chinese traditional medicine OR Chinese medicine OR CHM OR TCM)”. No restrictions were placed on date, country, or language of publication.

Study selection and data collection process

Endnote X8 and Excel software were applied to manage the articles and data. Two independent reviewers assessed the articles for the eligibility. The inclusion of trials was confirmed upon consensus of reviewers. Disagreements were settled through discussion with the corresponding author. The data extracted from the eligible articles consists of study characters (title, author, publication date, publication language, and study designs), eligibility criteria, participants’ characters (number of participants, age, gender, duration of the disease, and course of treatment), interventions, outcomes, follow-ups, and adverse events. If the data were unavailable, an attempt was made to contact the corresponding author(s) to request missing data.

Assessment of study quality and risk of bias

The RoB assessment was conducted by two independent researchers by using Cochrane Handbook tool [38]. The RCTs that met the requirements of at least 4 of the 7 domains of the Cochrane RoB tool were selected in further analysis [29, 39].

Data analysis and statistical methods

RevMan 5.3 from the Cochrane Collaboration was applied for Data Analysis. Cochrane’s χ² test and I² were used to assess heterogeneity. A model of random-effect (RE) was applied to estimate pooled effect if statistical heterogeneity was found (p < 0.1, I² > 50%), while a model of fixed-effect (FE) was set if no statistical evidence of heterogeneity existed (p≥0.1, I²≤50%). The mean difference (MD) or standardized mean differences (SMD) with a 95% confidence intervals (CI) was calculated for continuous outcomes, whereas risk ratio (RR) with a 95% CI was used for dichotomous outcomes. Sensitivity analyses were performed by omitting every one or two study at a time from the included studies. Publication bias was detected by funnel plot analyses. Two tailed P values less than 0.05 were considered statistically significant.

RESULT

Study selection

After primary search from six databases, 3,638 articles were identified potentially relevant, in which 1,453 records were excluded because of duplication. After removal of duplicates, 2,185 articles were screened by reading titles and abstracts, and 1,651 of them were excluded for at least one of following reasons: 1) The study was a protocol, case report, review, or comment; 2) Not a clinical trial; 3) The targeting disease was not VaD; 4) The intervention group did not use Chinese herbs for VaD. Of 534 full-text articles assessed for eligibility, 102 records were removed for at least one of following reasons: 1) Quasi-RCT or not a RCT; 2) Non-herbal TCM therapies such as acupuncture, moxibustion, and massage used in the intervention group; 3) CHM therapies used in control group. The remaining 432 clinical trials were included for qualitative analysis, and 40 studies [40 –79] that met the requirements of at least 4 of the 7 domains of the Cochrane RoB tool were finally selected for quantitative analysis. The flow diagram is shown in Fig. 1.

Fig.1

Flow diagram of the search process. A total of 3,638 potentially relevant citations were retrieved, in which 1,453 records were excluded because of duplication. After removal of duplicates, 2,185 articles were screened by reading titles and abstracts and 1,651 of them were excluded. Of the remaining 534 articles subjected to full-text reading, 102 were excluded. Ultimately, 432 articles were included in the final systematic review and 40 (Cochrane risk of bias score≥4) were included in meta-analysis.

Study characteristics

Forty studies with 42 comparisons (two studies [61, 73] were three-arm clinical designs) involving 3,572 VaD patients were included. Among them, 1,919 were male and 1,308 were female, whereas the gender of the rest 345 participates cannot be confirmed from the primary data. One study [56] was carried out in Japan and others were conducted in China. Among all the studies, three studies [55, 56, 76] were published in English while the other 37 studies were published in Chinese. The duration of treatment lasted from 21 days to 3 months and sample sizes varied from 48 to 469. Of the all comparisons, 36 compared CHM with WCT, 2 [47, 77] compared CHM plus WCT with WCT alone, and 4 [56 , 76] compared CHM with placebo. Only 3 studies [59 , 73] reported follow-up, which ranged from 1 month to 6 months. Adverse events were found in 12 studies [40 , 76]. More details about the characteristics of the included studies were shown in Table 1.

Table 1

Characteristics of included studies

Included trials	Publication language	Osserman Classification	Study designs	Eligibility criteria	Sample and characteristics (male/female; mean age)		Duration of disease		Interventions		Course of treatment	Follow up	Outcome index	Intergroup differences	Adverse events
					Trial	Control	Trial	Control	Trial	Control
Cai J [40]	Chinese	NR	RCT, single-center, single-blind	1. DSM-IV-R2. CMTDDG	33 (21/12)	30 (15/15)	53.66±36.89 m	48.75±45.59 m	Kangxin Capsule (0.9 g, tid, po)	Hydergine Tablet (2 mg, tid, po)	3 m	NR	1. MMSE2. ADL3. Clinical effective rate4. HCY changes5. β-Ap changes6. ET changes7. NO changes8. Peripheral blood sex hormone level	1. p > 0.052. p > 0.053. p > 0.054. NR 5. p < 0.056. NR7. NR8. p > 0.05	1. Insomnia2. Constipation3. Thirst
					70.3±5.73	71.5±6.34
Liao XL [41]	Chinese	Mild to severe (MMSE, HDS)	RCT, single-center	1. DSM-IV2. CDDCEATVD	32(17/15)	28 (15/13)	3.8±0.6 y	4.6±1.0 y	Shouling-jiannao Capsule (0.9 g, tid, po)	Hydergine Tablet (1 mg, tid, po)	2 m	NR	1. MMSE2. HDS3. Clinical effective rate4. SASDTCM	1. p < 0.052. p < 0.053. p > 0.054. p < 0.05	NO
					72.0±1.0	72.6±1.1
Liu T [42]	Chinses	NR	RCT, single-center	1. DSM-III2. CCMD-2-R	37(21/16)	31 (19/12)	2.9±1.5 y	2.8±1.3 y	Modified Sanjiasan Decoction (1 dose/d, bid, po)	Piracetam Tablet (0.8 g, tid, po)	3 m	NR	1. HDS2. MMSE3. IQ4. MQ	1. p > 0.052. p > 0.053. p > 0.054. p > 0.05	NO
					65.6±13.7 y	65.3±13.4 y
Xia X [43]	Chinese	NR	RCT, single- center	1. DSM-IV2. CDDCEATVD	37 (28/9)	28 (21/7)	2.76±1.89 y	2.28±1.45 y	Baisuifang Oral Liquid (2 0 ml, bid, po)	Piracetam Tablet (1.2 g, tid, po)	3 m	NR	1. MMSE2. ADL3. Therapeutic rate of MMSE4. Therapeutic rate of ADL5. SASDTCM6. Hemorheological characters (TG, TC, HDL, LDL)	1. p < 0.052. p < 0.013. p < 0.054. p < 0.055. p < 0.056. p < 0.01	NR
					67.59±8.22 y	68.50±8.16y
Zhang Y [44]	Chinese	Mild to moderate (MMSE)	RCT, single-center	1. DSM-IV2. GPCSNTCM	25 (9/16)	25 (15/10)	NR	NR	BushenYizhi Decoction (1 dose/d, bid, po)	Hydergine Tablet (2 mg, tid, po)	2 m	NO	1. Velocity of middle cerebral artery2. Hemorheological characters	1. p < 0.052. p < 0.05	NR
					68.7 y	72.3 y
Peng W [45]	Chinese	NR	RCT, single-center	DSM-IV	28 (18/10)	28 (19/9)	1.685±0.64 m	1.547±0.58 m	Huayuyizhi mixture Decoction (40 ml, bid, po)	Hydergine Tablet (1 pill, tid, po)	2 m	NO	1. MMSE2. HDS3. FAQ	1. p < 0.052. p > 0.053. p > 0.05	NO
					68.50±7.85 y	64.30±8.14y
Xu XC [46]	Chinese	NR	RCT, single-center	DSM-IV	36 (20/16)	34 (24/10)	1.79±0.61 y	1.87±0.52 y	QingxinHuatan Decoction (1 dose/d, bid, po)	Huperzine A Tablet (2 pills, bid, po)	3 m	NR	1. MMSE2. HDS3. ADL4. NFDS	1. p > 0.052. p > 0.053. p < 0.014. p < 0.01	1. Nausea2. Dizziness3. Insomnia4. Tinnitus
					68.34±9.65 y	70.64±8.39y
Xu ZH [47]	Chinese	Mild to moderate (CDR)	RCT, single-center	1.DSM-IV2. SDSVD3. GPCSNTCM	30 (18/12)	30 (16/14)	2.34±1.25 m	2.25±1.36 m	1. Naokang granule (1 package, tid, po)2. Nimodipine Tablet (20 mg, tid, po)	Nimodipine Tablet (20 mg, tid, po)	30 d	NR	1. MMSE2. Clinical effective rate3. Mo-CA scale4. SDSVD5. Hemorheological characters (TG, TC, HDL, LDL)	1. p < 0.052. p < 0.053. p < 0.054. p < 0.015. p < 0.01 (HDL, LDL); p < 0.05 (TG, TC)	NO
					67.7±4.0 y	69.3±5.0 y
Li JY [48]	Chinese	NR	RCT, single-center	NINDS-AIREN	30 (15/15)	30 (17/13)	NR	NR	Ruanmailing oral liquid (10 ml, tid, po)	Donepezil Hydrochloride Tablet (5 mg, qd, po)	3 m	NR	1. MMSE2. ADL3. Clinical effective rate4. TXB₂5. PGI₂6. HCY7. ET8. TXA₂/PGI₂	1. p < 0.012. p > 0.053. p > 0.054. p > 0.055. p > 0.056. p > 0.057. p < 0.058. p < 0.05	NR
					72.0±6.7 y	73.9±6.3 y
Yang YQ [49]	Chinese	Mild to moderate (CDR)	RCT, single-center	1. CCDVD 2. SDSVD	43 (19/24)	43 (20/23)	NR	NR	Dingzhiyi-conggranule (1 dose/d, bid, po)	Piracetam Tablet (0.8 g, tid, po)	40 d	NO	1. MMSE2. ADAS-cog3. BI index4. CIBIC-Plus5. CDT6. SASDTCM	1. p < 0.012. p < 0.013. p < 0.014. p < 0.055. p < 0.016. p < 0.01	NR
					66.76±8.00 y	66.22±8.05y
Pu ZP [50]	Chinese	NR	RCT, single-center	CCMD-3	35(20/15)	35 (22/13)	4.55±2.48 y	4.51±2.63 y	Tongqiao-huoxue Decoction (1 dose/d, bid, po)	Oxcarbazepine Tablet (300-600 mg/d, po)	8 w	NR	1. MMSE2. ADL3. BEHAVE-AD	1. p < 0.052. p < 0.053. p < 0.05	1. Excessive sedation2. Cognitive function decreasing3. Constipation4. Dizziness
					68.79±7.99 y	71.34±8.25y
Wang JS [51]	Chinese	NR	RCT, single-center	CDDCE-ATVD	40 (23/17)	40 (24/16)	NR	NR	Shengmai Capsule (2 pills, tid, po)	Donepezil Tablet (5 mg, qd, po)	60 d	NR	1. MMSE2. BBS3. SDSVD	1. p > 0.052. p > 0.053. p < 0.05	1. Hypertension2. Diarrhea3. Insomnia4. Bradycardia
					70.2±8.4 y	71.8±9.3 y
Tian JB [52]	Chinese	Mild to moderate (DSM-IV)	RCT, single-center	1. DSM-IV2. GPCSNTCM	48(28/20)	24 (15/9)	1.35±0.31 y	1.42±0.38 y	QiangliZengzhiling (1 dose/d, bid, po)	Nimodipine Tablet (30 mg, tid, po)	4 w	NR	1. MMSE2. HDS3. ADL4. Clinical effective rate	1. p < 0.012. p < 0.013. p < 0.014. p > 0.05	NR
					69.83±9.72 y	67.85±8.69y
Chen T [53]	Chinese	Mild to moderate (CDR)	RCT, single-center	1. NINDS-AIREN2. CDDCEATVD	30 (18/12)	30 (14/16)	4.93±1.93 m	5.17±2.36 m	Jiannao-Yifang (1 dose/d, qd, po)	Nimodipine Tablet (20 mg, tid, po)	6 w	NR	1. MMSE2. ADL3. Therapeutic rate of MMSE4. Therapeutic rate of ADL5. NPI6.SASDTCM	1. p > 0.052. p > 0.053. p < 0.054. p > 0.055. p > 0.056. p < 0.01	1. Diarrhea2. Dizziness3. Headache4. Insomnia5. Anxiety
					68.63±4.28 y	66.33±6.81y
Cheng WP [54]	Chinese	NR	RCT, single-center, single blind	1. DSM-IV2. SDSVD	26 (12/14)	26 (18/8)	NR	NR	Naozhitong Capsule (7.9 g, tid, po)	Naofuhuo Tablet (4 pills, tid, po)	60 d	NR	1. Caleitonin gene related peptide2. Clinical effective rate	1. p < 0.052. p > 0.05	1. Thirst
					68.5 y	66.8 y
Liu XF [55]	English	NR	RCT, single-center, double-blind	1. DSM-IV2. CRGNCMCD3. CSDD	29 (12/17)	27 (12/15)	NR	NR	Kangxin Capsule (0.9 g, tid, po)	Piracetam Tablet (0.8 g, tid, po)	1 m	NR	1. MMSE2. ADL3. HIS4. GDS5. SASDTCM6. ASBSD7. ET8. Sex hormone	1. p < 0.012. p > 0.053. p < 0.014. p < 0.015. p < 0.016. p < 0.017. p < 0.018. p < 0.01	NR
					61.0±7.7 y	62.4±6.6 y
K Terasawa [56]	English	NR	RCT, multi-center, double-blind, placebo-controlled	1. DSM-III-R2. Carlo Loeb modified ischemic scores	69 (28/41)	70 (22/48)	23.7±20.0	23.5±17.6	Choto-san extract (2.5 g, tid, po)	Placebo (2.5 g, tid, po)	12 w	NR	1. HDS-R	1. p > 0.05	1. Urticaria2. Diarrhea3. Appetite loss4. Heartburn5. Hypertension6. Oral bitterness7. Liver dysfunction
					75.7±8.9 y	77.6±7.9 y
Wu BB [57]	Chinese	NR	RCT, single-center, double-blind	1. NINDS-AIREN2. GPCSNTCM	31 (16/15)	31 (18/13)	NR	NR	Jianghuang-Yizhi Capsule (1.4 g, tid, po)	Nicergoline Tablet (10 mg, tid, po)	3 m	NR	1. MMSE2. NIHSS3. rCBF	1. p < 0.052. p < 0.013. p < 0.05	NO
					70.78 y	73.07 y
Tang N [58]	Chinese	Mild to moderate (CDR, HDS)	RCT, multi-center, double-blind	1. DSM-IV2. GPCSNTCM	107 (68/39)	102 (62/40)	2.2±1.4 y	2.5±1.8 y	YifeiXuan-feiJiangzhuo Capsule (1.7 5 g, tid, po)	Piracetam Tablet (0.8 g, tid. Po)	2 m	NO	1. ADL2. SASDTCM3. SOD4. MDA	1. p < 0.052. p < 0.053. p < 0.054. p < 0.05	NR
					70.5±6.1 y	68.6±6.7 y
Yao JS [59]	Chinese	Mild to moderate (MMSE)	RCT, single-center, double-blind, double dummy	DSM-IV	24 (15/9)	24 (14/10)	10.65±16.79 m	9.89±13.93 m	1. Congzhi granule (6 g, tid, po)2. Placebo Tablet (1 mg, tid, po)	1. Hydergine Tablet (1 mg, tid, po)2. Placebo granule (6 g, tid, po)	12 w	3 m	1. MMSE2. BBS3. Clinical effective rate	1. p > 0.052. p > 0.053. p > 0.05	NO
					64.24±8.82 y	64.38±10.24 y
Song XX [60]	Chinese	Mild to moderate (DSM-III)	RCT, single-center, double-blind, placebo-controlled	1. DSM-IV2. DSM-III3. GPCSNTCM	30 (21/9)	25 (13/12)	4.12±2.09 m	4.66±1.75 m	Congsheng Capsule (4 pills, tid, po)	Hydergine Tablet (4 pills, tid, po)	60 d	6 m	1. MMSE2. BBS3. Clinical effective rate3. Hemorheological characters (TG, TC)4. Blood glucose	1. p > 0.052. p < 0.053. p > 0.054. p > 0.05	NR
					66.63±8.38 y	67.72±8.21y
Zhang BL [61]	Chinese	Mild to moderate (CDR)	RCT, multi-center, double-blind	1. DSM-IV2. CDR3. HIS	89 (64/25)	106 (76/30)	11.51±9.12 m	12.50±8.33 m	Jiannaoyi-zhiGranule (10 g, bid, po)	Hydergine Tablet (2 mg, bid, po)	60 d	NO	1. MMSE2. BBS3. Clinical effective rate	1. p > 0.052. p > 0.053. p > 0.05	NO
					74.35±7.12 y	76.21±6.67y
					89 (64/25)	47 (34/13)	11.51±9.12 m	11.84±10.55 m	Jiannaoyi-zhiGranule (10 g, bid, po)	Placebo (10 g, bid, po)	60 d	NO	1. MMSE2. BBS3. Clinical effective rate	1. p < 0.052. p < 0.013. p < 0.05	NO
					74.35±7.12 y	73.59±8.74y
Zhu AH [62]	Chinese	Mild to moderate (CDR)	RCT, single-center, double-blind, double dummy	1. NINDS-AIREN2. DSM-IV3. CDR4. HIS	70 (44/26)	50 (31/19)	NR	NR	1. Tianzhi Granule (1 package, tid, po)2. Placebo (1 pill, bid, po)	1. Duxil (1 pill, bid, po)2. Placebo (1 package, tid, po)	60 d	NO	1. MMSE2. BBS3. Clinical effective rate	1. p > 0.052. p < 0.053. p > 0.05	NR
					65.93±8.64 y	68.68±7.53y
Du GY [63]	Chinese	Mild to moderate (CDR)	RCT, multi-center, double-blind, double dummy	1. DSM-IV-R2. CDR3. NINDS-AIREN4. GPCSNTCM5. HIS6. CSDD	100 NR	100 NR	NR	NR	1. Tianzhi Granule (5 g, tid, po)2. Placebo (1 pill, bid, po)	1. Duxil (1 pill, bid, po)2. Placebo (5 g, tid, po)	60 d	NR	1. MMSE2. BBS3. Clinical effective rate	1. p > 0.052. p > 0.053. p > 0.05	NO
Niu QY [64]	Chinese	Mild to moderate (CDR)	RCT, multi-center, double-blind, double dummy	1. GPCSNTCM2. DSM-IV3. CDR4. NINDS-AIREN5. HIS	42 (27/15)	25 (15/10)	13.22±7.76 m	12.57±8.32 m	Tianzhi Granule (1 package, tid, po)	Aniracetam Capsule (0.5 g, tid. Po)	60 d	NR	1. MMSE2. BBS3. Clinical effective rate	1. p > 0.052. p > 0.053. p > 0.05	NR
					65.52±8.12 y	66.23±7.76 y
Wang J [65]	Chinese	Mild to moderate (CDR)	RCT, single-center, double-blind, double dummy	1. GPCSNTCM2. DSM-IV-R3. CDR4. HIS	42 (29/13)	40 (23/17)	5.52±6.09 m	5.85±6.20 m	1. Bushenjiannao Capsule (4 pills, tid, po)2. Placebo Tablet (2 mg, tid, po)	1. Hydergine Tablet (2 mg, tid, po)2. Placebo Capsule (4 pills, tid, po)	60 d	NO	1. MMSE2. BBS3. Clinical effective rate	1. p > 0.052. p > 0.053. p < 0.05	1. Nausea2. Stomach disorder
					62.69±7.39 y	62.83±7.68 y
Wang X [66]	Chinese	Mild to moderate (CDR)	RCT, multi-center, double-blind, double dummy	1. DSM-IV-R2. CDR3. NINDS-AIREN4. HIS5. MMSE	352 (201/151)	117 (69/48)	NR	NR	1. Naomaitai Capsule (1 g, tid, po)2. Placebo Tablet (1 mg, tid, po)	1. Hydergine Tablet (1 mg, tid, po)2. Placebo Capsule (1 g, tid, po)	12 w	NR	1. SASDTCM2. Therapeutic rate of MMSE3. Therapeutic rate of BBS	1. p > 0.052. p > 0.053. p > 0.05	1. Bradycardia2. Liver dysfunction3. Oral bitterness4. Hyperglycemia
					66.691±9.061 y	66.178±9.468 y
Wang JP [67]	Chinese	Mild to moderate (HDS)	RCT, single-center, double-blind	1. DSM-IV2. GPCSNTCM3. HDS4. HIS	40 (23/17)	40 (21/19)	2.2±1.4 y	2.7±1.7 y	YifeiXuan-feiJiangzhuo Capsule (1.75 g, tid, po)	Piracetam Tablet (0.8 g, tid. Po)	2 m	NO	1. SDSVD2. MMSE3. ADL	1. p < 0.052. p < 0.053. p < 0.05	1. Nausea2. Appetite loss3. Insomnia4. Constipation5. Abdominal distension
					70.5±6.1 y	68.6±6.7 y
Wang Q [68]	Chinese	Mild to moderate (MMSE)	RCT, single-center, double-blind, double dummy	1. DSM-IV-R2. MMSE-R3. CCDVD4. HIS5. CSDD6. NINDS-AIREN	30 (19/11)	30 (18/12)	NR	NR	1. Congzhi Granule (6 g, tid, po)2. Placebo Tablet (1 mg, tid, po)	1. Co-dergocrine Mesylate Tablet (1 mg, tid, po)2. Placebo Granule (6 g, tid, po)	12 w	NR	1. MMSE2. BBS3. Clinical effective rate	1. p > 0.052. p > 0.053. p > 0.05	NO
					63.24±7.82 y	63.38±9.23 y
Wang YL [69]	Chinese	Mild to moderate (CDR)	RCT, single-center, double-blind, double dummy	1. NINDS-AIREN2. DSM-IV3. CCDVD4. CDR5. MMSE-R6. ADL7. GPCSNTCM8. HIS9. CSDD	30 (19/11)	30 (18/12)	NR	NR	1. Jiannaoning Capsule (3 pills, tid, po)2. Placebo Tablet (4 pills, bid, po)	1. Huperzine A Tablet (4 pills, bid, po)2. Placebo Capsule (3 pills, tid, po)	12 w	NR	1. MMSE-R2. ADL3. Clinical effective rate	1. p > 0.052. p > 0.053. p > 0.05	NO
					64.22±8.72 y	64.33±10.14 y
Cheng Y [70]	Chinese	Mild to moderate (CDR)	RCT, single-center, double-blind, double dummy	1. DSM-IV-R2. CDR3. GPCSNTCM4. HIS5. CSDD6. NINDS-AIREN	40 (28/12)	40 (23/17)	5.80±6.11 m	5.85±6.20 m	1. TianmacuzhiGranule (1 package, tid, po)2. Placebo Tablet (1 pill, qd, po)	1. Duxil Tablet (1 pill, qd, po)2. Placebo Granule (1 package, tid, po)	60 d	NR	1. MMSE2. BBS3. Clinical effective rate	1. p > 0.052. p > 0.053. p > 0.05	NO
					62.68±7.55 y	62.83±7.68 y
Tong L [71]	Chinese	Mild to moderate (MMSE)	RCT, single-center, double-blind, double dummy	1. DSM-IV2. GPCSNTCM3. MMSE4. HIS5. ADL6. BBS	24 (14/10)	24 (16/8)	3.12±2.57 y	2.17±2.27 y	1. Congsheng Capsule (4 pills, tid, po)2. Placebo Tablet (2 pills, tid, po)	1. Hydergine Tablet (2 pills, tid, po)2. Placebo Capsule (4 pills, tid, po)	12 w	NR	1. MMSE2. BBS3. ADL4. SASDTCM	1. p > 0.052. p > 0.053. p > 0.054. p < 0.05	1. Diarrhea2. Premature beat3. Death due to cerebral infarction
					69.29±7.41 y	69.29±8.39 y
Luo ZG [72]	Chinese	NR	RCT, single-center, double-blind, double dummy	1. DSM-IV2. ICD-103. HIS	35 (22/13)	33 (23/10)	1.47±0.48 y	1.73±0.34 y	1. Shenmayizhi Capsule (1 g, tid, po)2. Placebo Tablet (1 mg, tid, po)	1. Hydergine Tablet (1 mg, tid, po)2. Placebo Capsule (1 g, tid, po)	75 d	NR	1. MMSE2.Clinical effective rate	1. p < 0.052. p > 0.05	NR
					68.2±8.26y	68.09±8.25 y
Zou HY [73]	Chinese	Mild to moderate (DSM-IV)	RCT, single-center, double-blind, double dummy	1. DSM-IV2. HIS	30 NR	30 NR	NR	NR	Congsheng Capsule (4 pills, tid, po)	Hydergine Tablet (4 pills, tid, po)	60 d	NR	1. MMSE2. BBS	1. p > 0.052. p > 0.05	NR
					30 NR	17 NR	NR	NR	Congsheng Capsule (4 pills, tid, po)	Placebo (4 pills, tid, po)	60 d	NR	1. MMSE2. BBS	1. p > 0.052. p < 0.05	NR
Guo DM [74]	Chinese	Mild (CDR, MMSE)	RCT, single-center, double-blind, double	1. DSM-IV2. NINDS-AIREN3. MMSE4. HIS5. HAMD6. CDR7. CDDCEATVD8. GPCSNTCM	50 (32/18)	20 (14/6)	10.86±8.415 m	11.30±7.248 m	Shenxiong invigorating the kidney Capsule (1.75 g, tid, po)	Piracetam Tablet (2 g, tid, po)	2 m	1 m (1/3 patients)	1. MMSE2. ADL3. NFDS4. SASDTCM5. Ach6. NE	1. p < 0.052. p > 0.053. p > 0.054. p < 0.055. p < 0.056. p < 0.05	NO
					70.1±5.504 y	70.2±4.841 y
Chen LP [75]	Chinese	NR	RCT, single-center, double-blind	1. DSM-IV2. HDS3. MMSE4. BBS	36 NR	32 NR	NR	NR	Shenlong Decoction (1 dose/d, po)	Piracetam Tablet (1.6 g, tid, po)	3 m	NR	1. MMSE2. BBS3. Clinical effective rate	1. p > 0.052. p > 0.053. p > 0.05	NR
Wei QM [76]	English	Mild to moderate (MMSE)	RCT, single-center, double-blind, placebo-controlled	1. DSM-IV2. NINDS-AIREN3. HIS4. MMSE5. HAMD	24 (16/8)	24 (16/8)	NR	NR	Chinese medicine composed of Danshen and Sanqi (3 dose/d, po)	Placebo (3 dose/d, tid, po)	12 w	NR	1. ADAS-cog2. ADL3. MMSE	1. p = 0.0272. p > 0.053. p > 0.05	1. Upper respiratory infection2. Stomach pain3. Urinary system infection
					66.9±7.0 y	62.5±8.5 y
Fang X [77]	Chinese	Mild to moderate (SASVD)	RCT, single-center	1. DSM-IV2. CDDCEATVD3. HDS4. MMSE5. HIS	30 (18/12)	30 (17/13)	2.86±0.81 y	3.02±0.92 y	1. Shuxue Tong Injection (6 ml added in 0.9% N.S. 250 ml, qd, iv)2. Edaravone Injection (30 mg added in 0.9% N.S. 100 ml, bid, iv)	Edaravone Injection (30 mg added in 0.9% N.S. 100 ml, bid, iv)	21 d	NR	1. MMSE2. ADL3. Quality of Life Scale4. SASDTCM5. P300	1. p > 0.052. p > 0.053. p < 0.014. p < 0.055. p < 0.01	NO
					68±5.81 y	69±6.18 y
Zhao ZK [78]	Chinese	Mild to moderate	RCT, single-center, double blind	1. DSM-IV2. GPCSNTCM	51 (28/23)	52 (30/22)	3.58±0.79 y	3.21±0.78 y	Yizhicon-gming Decoction (1 dose/d, bid, po)	Piracetam Tablet (0.8 g, tid, po)	3 m	NR	1. MMSE2. NFDS3. ADL4. SDSVD5. ET6. NO7. Clinical effective rate	1. p > 0.052. p > 0.053. p < 0.054. p < 0.055. p < 0.056. p < 0.057. p > 0.05	NR
					62.15±11.38 y	61.98±11.33 y
Song MY [79]	Chinese	Mild to moderate (MMSE)	RCT, single-center, double-blind, double dummy	1. DSM-IV2. GPCSNTCM3. MMSE4. HIS	28 (17/11)	27 (20/7)	2.66±2.9 3 y	2.12±1.75 y	1. Congzhi Granule (1 package, tid, po)2. Placebo Tablet (1 pill, tid, po)	1. Hydergine Tablet (1 pill, tid, po)2. Placebo Granule (1 package, tid, po)	12 w	NO	1. MMSE2. BBS3. SASDTCM	1. p > 0.052. p > 0.053. p > 0.05	NR
					67.11±9.92 y	66.00±7.00y

DSM-IV, the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; DSM-IV-R, the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text revision; DSM-III, the Diagnostic and Statistical Manual of Mental Disorders, Third edition; NINDS-AIREN, the National Institute of Neurological Disorders and Stroke and the Association International pour la Recherche et l’Enseignementen Neurosciences; RCT, randomized Controlled Trial; ADAS-cog, the Alzheimer’s Disease Assessment Scale-cognitive subscale; ADL, the Activities of Daily Living; MMSE, the Mini-Mental State Examination; TCM, traditional Chinese medicine; SDSVD, the scale differentiation of syndromes of vascular dementia; HDS, Hasegawa’s dementia scale; HDS-R, the revised version of Hasegawa’s dementia scale; BBS, Bless Behavior Schedule; CRGNCMCD, Clinical Research Guidelines of New Chinese Medicine For Curing Dementia; HIS, Hachinski Ischemia Scale; GPCSNTCM, The Guiding Principles of Clinical Studies of New Traditional Chinese Medicine; CDR, Clinical dementia rating; CSDD, Cornell Scale for Depression in Dementia; HDS, Hasegma dementia scale; HCY, homocysteine; β-Ap, β-amyloid protein; IQ, intelligence quotient; MQ, memory quotient; CIBIC-plus, Clinician’s Interview Based Impression of Change-plus Caregiver Input scores; HAMD, Hamilton Depression Scale; TXA₂, thromboxame A₂; TXB₂, thromboxame B₂; PGI₂, prostaglandin I₂; CCDVD, NINDS-AIREN clinical criteria for the diagnosis of vascular dementia; CCMD-3, Chinese Classification and Diagnosis of Mental Diseases-3rd edition; BEHAVE-AD, the Rating Scale of Behavioral Pathology in Alzheimer’s Disease; NFDS, Neural Function Defect Score; Ach, acetylcholine; ICD-10, International Classification of Disease 10th Revision; FAQ, Functional activities questionnaire; SASDTCM, Symptom Accumulation Scores of Dementia in Traditional Chinses Medicine; ASBSD, Accumulation Scores of Blood Stagnation Disease; NIHSS, National Institute of Health Stroke Scale; rCBF, the regional cerebral blood flow; SOD, the superoxide dismutase; MDA, malondialdehyde; CDDCEATVD, the Criteria for Diagnosis, TCM Differentiation and Clinical Effectiveness Assessment in Treating VaD.

Risk of bias in included studied

The RoB Scores ranged from 4/7 to 6/7. Thirty-three studies reported ‘randomized’ and their sequence generation, whereas the other 7 studies [56 , 79] just mentioned the word ‘randomization’ without any description of the random allocation process. Among these 33 studies, 26 studies used a random number table in allocation of participants; 2 studies [40, 77] mentioned randomization by computer random number generator; 4 studies [66 , 79] applied Statistical Analysis System (SAS) software, while 1 study [58] employed PMS statistic software to generate the random numbers. Four studies [47 , 77] applied sealed envelopes to conceal allocation. Twenty-four studies [55–76 , 79] blinded both participants and personnel. Two studies [57, 61] described blinding procedure of outcome assessment. One study [63] did not report the balance in the baseline of participants. The Cochrane RoB scores for the included clinical studies showed in Table 2.

Table 2

The methodological quality of included studies based on Cochrane handbook

Study	A	B	C	D	E	F	G	Total
Cai J, [40]	+	–	–	–	+	+	+	4
Chen LP, [75]	+	–	+	–	+	+	+	5
Chen T, [53]	+	–	–	–	+	+	+	4
Cheng WP, [54]	+	–	–	–	+	+	+	4
Cheng Y, [70]	+	–	+	–	+	–	+	4
Du GY, [62]	+	–	+	+	+	+	–	5
Guo MD, [74]	+	–	+	–	+	+	+	5
Li JY, [48]	+	–	–	–	+	+	+	4
Liao XL, [41]	+	–	–	–	+	+	+	4
Liu T, [42]	+	–	–	–	+	+	+	4
Liu XF, [55]	+	–	+	–	+	+	+	5
Luo ZG, [72]	?	–	+	–	+	+	+	4
Peng W, [45]	+	–	–	–	+	+	+	4
Pu ZP, [75]	+	–	–	–	+	+	+	4
Song XX, [60]	+	–	+	–	+	–	+	4
Tang N, [58]	+	–	+	–	+	–	+	4
Terasawa K, [56]	?	–	+	–	+	+	+	4
Tian JB, [52]	+	–	–	–	+	+	+	4
Tong L, [71]	+	–	+	–	+	–	+	4
Wang J, [65]	+	–	+	+	+	–	+	5
Wang JP, [67]	+	–	+	–	+	+	+	5
Wang Q, [68]	+	–	+	–	+	–	+	4
Wang X, [66]	+	–	+	–	+	–	+	4
Wang YL, [69]	+	–	+	–	+	–	+	4
Wei QM, [76]	+	–	+	+	+	+	+	6
Wu BB, [57]	?	–	+	+	+	+	+	5
Xia X, [42]	+	–	–	–	+	+	+	4
Xu XC, [46]	+	–	–	–	+	+	+	4
Xu ZH, [47]	+	+	–	–	+	–	+	4
Yang YQ, [49]	+	–	–	–	+	+	+	4
Yao JS, [59]	+	–	+	–	+	–	+	4
Zhang BL, [61]	?	–	+	+	+	+	+	5
Zhang Y, [44]	+	–	–	–	+	+	+	4
Zhu AH, [62]	?	+	+	–	+	+	+	5
Zou YH, [73]	?	–	+	–	+	+	+	4
Fang X, [77]	+	+	–	–	+	–	+	4
Niu QY, [64]	+	–	+	–	+	–	+	4
Song MY, [79]	+	–	+	–	+	–	+	4
Wang JS, [51]	+	–	–	–	+	+	+	4
Zhao ZK, [78]	?	–	+	+	+	+	+	5

A to G, the 7-Item criteria. A, Random sequence generation; B, Allocation concealment; C, Blinding of participants and personnel; D, Blinding of outcome assessment; E, Incomplete outcome data; F, Selective reporting; G, Other bias; +: low risk of bias, – : high risk of bias; ?: uncertain risk of bias.

Description of the herbs and prescriptions in the treatment of VaD

Thirty-four Chinese herbal prescriptions were used for treating VaD, including 7 patent herbal prescriptions. The top 5 Chinese herbal prescriptions used were as follows: 1) Congsheng Capsule (7.50%) that consists of Radix Polygoni Multiflori, Herba Cistanches, Radix Rhapontici, Lumbricus and Folium Nelumbinis; 22) Tianzhi Granule (7.50%) that consists of Rhizoma Gastrodiae, Ramulus Uncariae Cum Unci, Concha Haliotidis, Cortex Eucommiae, Herba Leonuri, Caulis Polygoni Multiflori, Flos Sophorae and Fructus Gardeniae; 3) Kangxin Capsule (5.00%) that consists of Fructus Ligustri Lucidi, Semen Cuscutae, Fructus Lycii, Radix Polygoni Multiflori, Radix Astragali seu Hedysari and Rhizoma Polygonatum; 4) Yifei Xuanfei Jiangzhuo Capsule (5.00%) that consists of Radix Astragali seu Hedysari, Radix Ginseng, Radix Platycodnis, Radix Ophiopogonis, Rhizoma Acori Tatarinowii, Semen Armeniacae Amarum and Fructus Cannabis; 5) Congzhi Granule (5.00%) that consists of Radix Polygoni Multiflori, Radix Astragali seu Hedysari, Radix Angelicaesinensis, Rhizoma Ligustici Chuanxiong, Fructus Ligustri Lucidi, Herba Cynomorii, Radix Puerariae, Radix Polygalae and Rhizoma Acori Tatarinowii.

The number of Chinese herbs in the formulas varied from 3 to 13. A total of 98 single herbs were used in the included articles. Heshouwu (Radix Polygoni Multiflori) was the most frequently used herb in 19 out of the 40 studies (47.50%), followed by Shichangpu (Rhizoma Acori Tatarinowii, 42.50%), Chuanxiong (Rhizoma Ligustici Chuanxiong, 27.50%), Huangqi (Radix Astragali seu Hedysari, 27.50%), Danggui (Radix Angelicae Sinensis, 25.00%), Renshen (Radix Ginseng, 25.00%), Danshen (Radix Salviae Miltiorrhizae, 20.00%), Yuanzhi (Radix Polygalae, 17.50%), Dilong (Lumbricus, 17.50%), and Nvzhenzi (Fructus Ligustri Lucidi, 17.50%). More details about the top 10 single herbs are shown in Table 3.

Table 3

The most commonly used herbs for vascular dementia

Chinese name	English name	Latin name	Family	N/40 (%)
He Shou Wu	Fleece flower root	Radix Plygoni Multiflori	Poygonum multiflorum Thunb	19 (47.50)
Shi Chang Pu	Grassleaf sweetflag rhizoma	Rhizoma Acori Tatarinowii	Acorus tatarinowii Schoot	17 (42.50)
Chuan Xiong	Sichuan lovage rhizoma	Rhizoma Ligustici Chuanxiong	Ligusticum chuanxiong Hort	11 (27.50)
Huang Qi	Milkvetch root	Radix Astragali seu Hedysari	Astragalus membranace (Fisch) Bge	11 (27.50)
Dang Gui	Chinese angelica	Radix Angelicase Sinensis	Angelica sinensis (Oliv) Diels	10 (25.00)
Ren Shen	Ginseng	Radix Ginseng	Panax ginseng C. A. Mey.	10 (25.00)
Dan Shen	Danshen root	Radix Salviae Miltiorrhizae	Salvia miltiorrhiza Bge	8 (20.00)
Yuan Zhi	Milkwort root	Radix Polygalae	Polygala tenuifolia Willd	7 (17.50)
Di Long	Earthworm	Lumbricus	Pheretima aspergillum (E Perrier)	7 (17.50)
Nv Zhen Zi	Glossy privet fruit	Fructus Ligustri Lucidi	Ligustrum lucidum Ait.	7 (17.50)

Effectiveness assessment

MMSE

CHM versus placebo: Two studies [61, 73] showed a statistically significant difference in improving MMSE scores when CHM was compared with placebo [n_Treatment/n_Control (n_T/n_C) = 119/64, SMD 0.44, 95% CI: 0.13 to 0.75, p = 0.005, heterogeneity χ² = 0.01, df = 1, p = 0.94, I² = 0% ]. (Fig. 2a).

Fig.2

The forest plots of MMSE. (a) CHM versus Placebo: Meta-analysis of two studies showed a statistically significant difference in improving MMSE scores when CHM was compared with placebo (n_T/n_C = 119/64, SMD 0.44, 95% CI: 0.13 to 0.75, p = 0.005, heterogeneity χ² = 0.01, df = 1, p = 0.94, I² = 0%). (b) CHM versus WCT: Meta-analysis of thirty-two studies showed a significant increase in MMSE scores for CHM-treated groups relative to WCT-treated groups (n_T/n_C = 1274/1163, SMD 0.27, 95% CI: 0.19 to 0.35, p < 0.00001, heterogeneity χ² = 62.32, df = 31, p = 0.0007, I2 = 50%). (c) CHM plus WCT versus WCT alone: Meta-analysis showed a significant increase in MMSE scores for the combination therapy relative to WCT alone (n_T/n_C = 60/60, SMD 0.42, 95% CI: 0.06 to 0.79, p = 0.02; heterogeneity χ² = 0.75, df = 1, p = 0.39, I² = 0%).

CHM versus WCT: Meta-analysis of thirty-two studies showed a significant increase in MMSE scores for CHM-treated groups relative to WCT-treated groups (n_T/n_C = 1274/1163, SMD 0.27, 95% CI: 0.19 to 0.35, p < 0.00001, heterogeneity χ² = 62.32, df = 31, p = 0.0007, I² = 50%) (Fig. 2b).

CHM plus WCT versus WCT alone: CHM plus WCT was compared to WCT alone in 2 trials [45, 75]. Meta-analysis showed a significant increase in MMSE scores for the combination therapy relative to WCT alone (n_T/n_C = 60/60, SMD 0.42, 95% CI: 0.06 to 0.79, p = 0.02; heterogeneity χ² = 0.75, df = 1, p = 0.39, I² = 0%) (Fig. 2c).

ADAS-cog

CHM versus placebo: One study [76] applied ADAS-cog as outcome measure. Wei et al. [76] compared administration of CHM composed of Danshen and Sanqi (3 dose/d, p.o.) with placebo (3 dose/d, p.o.) for 12 weeks and reported no significant difference in ADAS-cog between the CHM group and placebo group (n_T/n_C = 23/24).

CHM versus WCT: One study [49] reported ADAS-cog scores of VaD patients. Using Dingzhiyicong Granule (1 dose/d, bid, p.o.) for 12 weeks as an experimental administration (n_T/n_C = 43/43), Yang et al. [49] found that this CHM was more effective than Piracetam tablet (0.8 g, tid, p.o.).

VADAS-cog

Among the all included studies, none of them applied VADAS-cog as primary outcome measure to assess the efficacy of CHM in the treatment of VaD patients.

ADL

CHM versus placebo: One study [76] applied ADL scores as outcome between CHM and placebo. When compared Chinese medicine composed of Danshen and Sanqi (3 dose/d p.o.) with placebo (3 dose/d p.o.) for 12 weeks, Wei et al. [76] found no significant difference between two groups (n_T/n_C = 23/24).

CHM versus WCT: When CHM was compared with WCT alone, ADL scores were used as one of the outcomes in fourteen studies. Meta-analysis showed a significant difference with substantial heterogeneity between the CHM group and the WCT group (n_T/n_C = 574/502, SMD –0.58, 95% CI: –1.02 to –0.13, p = 0.01, heterogeneity χ² = 151.96, df = 13, p < 0.00001, I² = 91%). Sensitivity analyses conducted to explore potential sources of heterogeneity after the omissions of each individual study from the original analysis. Sensitivity analyses pointed to two studies [46, 52] as a likely source of heterogeneity. After removal of the two studies, the ADL outcomes between the two groups remained similar and the heterogeneity was reduced (n_T/n_C = 490/444, SMD –0.40, 95% CI: –0.53 to –0.27, p < 0.00001, heterogeneity χ² = 20.81, df = 11, p = 0.04, I² = 47%) (Fig. 3).

Fig.3

The forest plots of ADL (CHM versus WCT). Meta-analysis of twelve studies showed a significant difference in ADL score between the CHM group and the WCT group (n_T/n_C = 490/444, SMD –0.40, 95% CI: –0.53 to –0.27, p < 0.00001, heterogeneity χ² = 20.81, df = 11, p = 0.04, I2 = 47%).

CHM plus WCT versus WCT alone: Fang et al. [77] compared the combinational administration of Shuxue Tong Injection (6 ml added in 0.9% N.S. 250 ml, qd, iv) and Edaravone Injection (30 mg added in 0.9% N.S. 100 ml, bid, iv) with Edaravone Injection alone (30 mg added in 0.9% N.S. 100 ml, bid, iv) for 21 days, finding no significant difference (n_T/n_C = 30/30, SMD 0.02, 95% CI: –0.48 to 0.53, p = 0.93).

BBS

CHM versus placebo: Two studies [61, 73] showed no significant difference in improving BBS when CHM was compared with placebo but with substantial heterogeneity (n_T/n_C = 119/64, SMD –0.40, 95% CI: –1.09 to 0.29, p = 0.25, heterogeneity χ² = 3.93, df = 1, p = 0.05, I² = 75%). Zhang et al. [61] compared administration of Jiannao Yizhi Granule (10 g, bid, p.o.) with placebo (10 g, bid, p.o.) for 60 days and found a significant difference in BBS between the CHM group and placebo group (n_T/n_C = 89/47). Zou et al. [73] reported that an experimental group given Congsheng Capsule (4 pills, tid, p.o., for 60 d) had no significant difference relative to the placebo group (n_T/n_C = 30/17).

CHM versus WCT: Fourteen studies [51 , 79] based on BBS outcome were qualified for inclusion in our meta-analysis (n_T/n_C = 622/590, SMD –0.06, 95% CI: –0.18 to 0.05, p = 0.27, heterogeneity χ² = 24.53, df = 13, p = 0.03, I² = 47%) (Fig. 4); the BBS scores were statistically similar between the CHM-treated and WCT-treated groups.

Fig.4

The forest plots of BBS (CHM versus WCT). Meta-analysis of fourteen studies showed no significant difference in BBS scores for CHM-treated groups relative to WCT-treated groups (n_T/n_C = 622/590, SMD –0.06, 95% CI: –0.18 to 0.05, p = 0.27, heterogeneity χ² = 24.53, df = 13, p = 0.03, I² = 47%).

HDS

CHM versus placebo: Tersawa et al. [56] found that, relative to a placebo group (n_T/n_C = 69/70), an experimental group given Choto-san extract (2.5 g, tid, p.o.) had a statistically significant effect to improve HDS scores.

CHM versus WCT: Meta-analysis of five studies [41 , 52] showed that participants in the CHM-treated group had statistically significant higher HDS scores than the WCT-treat group with substantial heterogeneity (n_T/n_C = 181/145, SMD 0.79, 95% CI: 0.05 to 1.52, p = 0.04, heterogeneity χ² = 39.25, df = 4, p < 0.00001, I² = 90%). Sensitivity analyses was conducted and one studies [46] was likely the source of heterogeneity. After removing this study, the HDS outcomes between the two groups remained similar and the heterogeneity turned out to decrease (n_T/n_C = 145/11, SMD 0.38, 95% CI: 0.12 to 0.63, p = 0.003, heterogeneity χ² = 3.54, df = 3, p = 0.32, I² = 15%) (Fig. 5).

Fig.5

The forest plots of HDS (CHM versus WCT). Meta-analysis of four studies showed that participants in the CHM-treated group had statistically significant higher HDS scores than the WCT-treat group (n_T/n_C = 145/111, SMD 0.38, 95% CI: 0.12 to 0.63, p = 0.003, heterogeneity χ² = 3.54, df = 3, p = 0.32, I² = 15%).

Clinical effective rate

CHM versus placebo: The clinical effective rate was assessed in one study [61] that reported a significantly better clinical effective rate of CHM relative to placebo.

CHM versus WCT: Meta-analysis of 19 studies showed a significant difference in the clinical effective rate in favor of the CHM treatment (n_T/n_C =839/769, RR 1.16, 95% CI: 1.07 to 1.27, p = 0.0004, heterogeneity χ² = 22.36, df = 28, p = 0.23, I² = 19%) (Fig. 6).

Fig.6

The forest plots of clinical effective rate (CHM versus WCT). Meta-analysis of 19 studies showed that participants in the CHM-treated group had statistically significant higher clinical effective rate than the WCT-treat group (n_T/n_C = 839/769, RR 1.16, 95% CI: 1.07 to 1.27, p = 0.0004, heterogeneity χ² = 22.36, df = 28, p = 0.23, I² = 19%).

CHM plus WCT versus WCT alone: One study [47] indicated that the clinically effective rate of CHM plus WCT group was significantly higher than that of the WCT group.

Adverse events

Twelve studies [40 , 76] reported adverse events. In the 12 studies with adequate information about adverse events, patients in the treatment group (40/751, 5.33%) had apparently fewer adverse events than the control group (77/509, 15.13%).

Gastrointestinal discomfort symptoms (nausea, diarrhea, thirst, poor appetite, stomach pain, and constipation) were the most frequently occurring adverse events, affecting 22/40 (55.00%) patients in the treatment groups and 16/77 (20.77%) patients in control group. Insomnia, dizziness, excessive sedation, bradycardia, and cognitive function decreasing also occurred frequently, affecting 20/40 (50.00%) patients in the treatment groups and 21/74 (28.37%) of patients in the control groups. No severe adverse events were reported. All adverse events were resolved without any interventions or relieved by symptomatic treatments.

Publication bias

There were four comparisons between CHM and WCT in the meta-analysis of MMSE, ADL, BBS, and clinical effective rate that included more than 10 studies. Publication bias is presented as funnel plots (Fig. 7). The funnel plots were roughly symmetric, leading to no obvious publication bias.

Fig.7

The funnel plots of the efficacy of CHM for vascular dementia. (a) The funnel plot of MMSE score (CHM versus WCT) were roughly symmetric. (b) The funnel plot of ADL score (CHM versus WCT) were roughly symmetric. (c) The funnel plot of BBS score (CHM versus WCT) were roughly symmetric. (d) The funnel plot of clinical effective rate (CHM versus WCT) were roughly symmetric.

DISCUSSION

Summary of evidence

A systematic review addressing the efficacy and safety of CHM on VaD was undertaken in 2013 by identifying 31 RCTs from 2004 to 2011, and it concluded that CHM for VaD appears to be safer and more effective than controls [24]. However, there was still insufficient evidence to support routine use of CHM for VaD because the conclusion of this systematic review was not scientifically sound due to the low methodological quality in the included primary studies [24]. Another systematic review [25] was conducted in 2015, which demonstrated that CHM as an adjunctive therapy can improve cognitive impairment and enhance immediate response and quality of life in senile VaD patients. Despite the positive findings, the conclusion cannot be made that there is sufficient efficacy and safety of CHM for senile VaD due to the limitations of methodological quality in the included studies. In the present study, we conducted an updated systematic review of CHMs for VaD according to high-quality RCTs. In this updated systematic review, 432 studies claimed to be RCTs, of which 40 high-quality RCTs with 3,572 participants were selected. The pooled data suggested that the CHM group was superior to the WCT group for MMSE, ADL, HDS, and clinical effective rate but had statistically similar effect based on BBS outcome; when compared with placebo, CHM was more beneficial in improving MMSE but showed no significant difference in BBS scores; compared with WCT, CHM as adjuvant therapy exerted an additive anti-VaD benefit on MMSE scores. In addition, CHMs were generally safe.

Limitations

Firstly, the databases were in English or Chinese, so studies published in other languages may be left out. Second, although all the RCTs included met the requirements of at least 4 of the 7 domains of the Cochrane RoB tool, some methodological limitations did exist in the primary studies. Most included studies had not been formally registered, which may lead to a certain degree of selective reporting bias [80]. Only two studies described a proper method of allocation concealment; 7 out of 40 studies did not detail the randomization method. It is no doubt that unclear descriptions of the randomization method, allocation concealment, and dropouts would further hamper the ability to assess the validity of the evidence reported by these studies. Third, most clinical trials did not estimate a sample size formally. Trials without adequate sample sizes usually have the risk of overestimating intervention benefits [81]. Fourth, a large variety of CHMs were applied as interventions in the included studies, with a great deal of variation in the composition, dosage, and the duration of treatment. Fifth, although it was suggested that the duration of follow-up should be 6–12 months [82], few studies (3/40) reported follow-ups, which only ranged from 1 month to 6 months. Sixth, some of outcome measures such as HDS and BBS have limited number of eligible studies used and some even in one single study is available for assessment.

Implications for practice

In the present study, the current evidence from this systematic review revealed that applying CHM as monotherapy or adjuvant therapy may be additionally beneficial for VaD patients and be generally safe. Radix Polygoni Multiflori, Rhizoma Acori Tatarinowii, Rhizoma Ligustici Chuanxiong, Radix Astragali seu Hedysari, Radix Angelicae Sinensis, Radix Ginseng, and Radix Salviae Miltiorrhizae have been identified as the most commonly used herbs in prescriptions for VaD and should be considered further in the development of Chinese herbal prescriptions for VaD.

TCM is characterized by syndrome differentiation and prescription corresponding to syndrome [83]. Diagnosis methodology of TCM is different from the conventional medicine that is used in orthodox medical practice, including inspection, palpation, percussion, and auscultation. The former consists of a series of diagnostic procedures, i.e., syndrome differentiation, which is the process of comprehensive analysis of clinical information obtained by the four main diagnostic TCM procedures: observation, listening, questioning, and pulse analyses. Observation means that the doctors observe the physical conditions of the patients, the complexion and tongue coating included. Listening is the doctors listening to the words, coughing, and breathing of a patient. Questioning involves the inquiry into the patient’s symptoms, medical history, and so on. Pulse analyses means that doctors note the pulse condition of patients on the radial artery to deduce the disorder. Through the combined use of the four methods of diagnosis, the symptoms and physical signs of the disease manifested in various facets are diagnosed with a view to understanding the causes or nature of the disease as well as their connections with the internal organs, which provide a solid basis for the diagnosis of the illnesses. A high-quality study published in JAMA [84] revealed that individualized CHM for irritable bowel syndrome is more effective than a common hypnotic prescription. Therefore, syndrome differentiation should be combined with western medical diagnosis. Based on each individual syndrome, a precisely tailored Chinese herbal prescription for individuals is commonly considered to achieve better clinical efficacy. The frequently used single herbs selected in the present study, which exerted the function of invigorating kidney, promoting blood circulation, and eliminating phlegm for resuscitation. Thus, the present prescription can be specifically used the syndrome of kidney deficiency, phlegm, and blood stasis obstructing in VaD patients.

Implication for research

Although the current included studies were high-quality, they had some methodological limitations. It is necessary for further RCTs of CHM for VaD to take a rigor standard design into consideration. First, registration for clinical trials and requirement for Clinical Trial Data Sharing [85] by The International Committee of Medical Journal Editors was needed. Second, the CONSORT 2010 statement [86], CONSORT for TCM [87], and RCTs investigating CHM [88] are recommend as guidelines for the design, registration, and reporting of future RCTs examining CHMs for VaD treatment. Third, it was found that outcome measures varied in the included studies. Many studies used TCM symptom scores or home-made scales as second outcome measures; however, these outcome measures are not internationally recognized, and the validity and reliability of that were uncertain in assessing the outcome. A very small part of (5.0%) studies used the ADAS-cog, the internationally recognized cognitive assessment tool. None of the included studies applied VADAS-cog as the primary outcome measure. VADAS-cog highlights attention and executive function and can be more sensitive to impairments, especially in characteristic deficits, than standard screening tests for VaD [21]. Therefore, it is essential for further clinical trials of CHM for VaD to choose more appropriate outcome measures such as the VADAS-cog. Fourth, adequate sample size is of great importance in methodologic quality, intervention effects, and publication bias [81]. Trials without sample sizes estimation generally have the risk of overestimating intervention benefits [29]. Thus, it is necessary to estimate sample size through a pre-study power analysis. Fifth, VaD patients are suggested to be followed for 6–12 months to guarantee the long-term safety after the treatment [82]. Furthermore, trials with short duration of follow-up cannot scientifically assess the long-term therapeutic effect of CHM for VaD. Therefore, the optimum duration of follow-up is apparently important.

Conclusion

The current evidence from this review demonstrated that CHM could, at least to an extent, improve cognitive function and activities of daily life. In addition, CHMs were generally safe and well tolerated in VaD patients. Thus, the findings of the present systematic review support, at least to an extent, that CHM can be recommended for routine use for treatment of VaD.

Footnotes

ACKNOWLEDGMENTS

This project was supported by the grant of National Natural Science Foundation of China (81573750/81473491/81173395/H2902); the Young and Middle-Aged University Discipline Leaders of Zhejiang Province, China (2013277); Zhejiang Provincial Program for the Cultivation of High-level Health talents (2015).

Authors’ disclosures available online ().

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