The effect of chinese herbal medicine Banxia Baizhu Tianma Decoction for the treatment of vertebrobasilar insufficiency vertigo: A systematic review and meta-analysis of randomized controlled trials

Complementary Therapies in Medicine 31 (2017) 27–38

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Review

The effect of chinese herbal medicine Banxia Baizhu Tianma Decoction for the treatment of vertebrobasilar insufficiency vertigo: A systematic review and meta-analysis of randomized controlled trials夽 ZhenLang Guo a , ZhenNing Su b , ZhengFei Wang c , XiaoMu Luo c , RenKui Lai d,∗ a

The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou 510405, China DaAn Gene Co., Ltd. of Sun Yat-Sen University, Guangzhou 510665, China c School of Medical Information Engineering, Guangzhou University of Chinese Medicine, Guangzhou 510006, China d Department of Cardiovasology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou 510120, China b

a r t i c l e

i n f o

Article history: Received 15 April 2016 Received in revised form 9 August 2016 Accepted 16 January 2017 Available online 20 January 2017 Keywords: Banxia Baizhu Tianma Decoction Vertebrobasilar Insufficiency Vertigo Systematic review Meta-analysis

a b s t r a c t Objectives: Banxia Baizhu Tianma Decoction (BBTD) is widely used to treat vertebrobasilar insufficiency vertigo (VBIV) in China, but its efficacy remains largely unexplored. We systemically summarized relevant evidence from randomized controlled trials (RCTs) to assess the therapeutic effect of BBTD. Methods: Seven electronic databases were searched for relevant electronic studies published before July 2016. We evaluated RCTs that compared BBTD, anti-vertigo drugs and a combination of BBTD and antivertigo drugs. We performed a meta-analysis in accordance with the Cochrane Collaboration criteria. The outcomes were clinical efficacy (CE), blood flow velocity of the vertebrobasilar artery by transcranial Doppler (TCD), and adverse effects. Results: Twenty-seven studies with a total of 2796 patients were identified. Compared with anti-vertigo drugs, BBTD showed slight effects on CE (n = 350; RR, 1.09; 95% CI, 1.01–1.18; p = 0.03; I2 = 0%); however, BBTD plus anti-vertigo drugs (BPAD) significantly improved the clinical efficacy (n = 2446; RR, 1.20; 95% CI, 1.16–1.24; p < 0.00001; I2 = 0%) and accelerated the blood flow velocity of the left vertebral artery (LVA) (n = 1444; WMD, 5.21 cm/s; 95% CI, 3.72–6.70 cm/s; p < 0.00001; I2 = 91%), the blood flow velocity of the right vertebral artery (RVA) (n = 1444; WMD, 5.45 cm/s; 95% CI, 4.02–6.88 cm/s; p < 0.00001; I2 = 89%), and the blood flow velocity of the basilar artery (BA) (n = 1872; WMD, 5.20 cm/s; 95% CI, 3.86–6.54 cm/s; p < 0.00001; I2 = 90%). Adverse effects were mentioned in six studies. Conclusions: The current evidence indicates that BPAD is effective for the treatment of VBIV, but the efficacy and safety of BBTD is uncertain because of the limited number of trials and low methodological quality. Hence, high-quality and adequately powered RCTs are warranted. © 2017 Elsevier Ltd. All rights reserved.

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 2.1. Search strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 2.2. Study selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 2.2.1. Types of studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 2.2.2. Types of participants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 2.2.3. Types of interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 2.2.4. Types of controls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 2.2.5. Types of outcome measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

夽 Trial registration number: PROSPERO 2016: CRD42016034094. ∗ Corresponding author. E-mail address: [email protected] (R. Lai). http://dx.doi.org/10.1016/j.ctim.2017.01.004 0965-2299/© 2017 Elsevier Ltd. All rights reserved.

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2.3. Data extraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 2.4. Methodological quality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 2.5. Data synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 2.6. Subgroup synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 2.7. Grading quality of evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 3. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 3.1. Study characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 3.2. Treatment groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 3.3. Control groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 3.4. Treatment duration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 3.5. Methodological quality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 3.6. Outcome measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 3.6.1. Clinical efficacy (CE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 3.7. Adverse effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 3.8. Evaluation of publication bias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 3.9. Grade profile evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 4.1. Main findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 4.2. Comparison with other meta-analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 4.3. Implications for clinical practice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 4.4. Limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 4.5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 Contributors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .37 Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 Competing interests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 Provenance and peer view . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 Appendix A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ?? A. Search Strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 A. 1 Pubmed database . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37

1. Introduction Vertebrobasilar insufficiency (VBI) is a rare hemodynamic posterior circulation transient ischaemic attack (TIA); it is induced by head rotation or extension that impairs the flow through the vertebral or basilar arteries, resulting in ischaemia of the brain-stem, cerebellum, thalamus and occipital lobes.1–3 In general, posterior circulation strokes represent 20–30% of all intracranial stokes.4,5 As VBI is a clinical syndrome, it can develop into vertigo, syncope, sudden sensorineural hearing loss, and cerebral or brain stem ischaemia, leading to severe morbidity or even death.6–8 However, vertigo caused by VBI is usually accompanied by other neurological disturbances that inconvenience a patient’s life and work.9 To rule out other diseases that can cause vertigo similar to VBIV, such as multiple sclerosis, brain tumors and Meniere’s disease, a doctor may order a magnetic resonance imaging (MRI) scan or a computerized tomography (CT) scan to assess possible problems of the brain or inner ear.10,11 The highest incidence of VBIV occurs among the middle and older-aged persons who have suffered from severe vertigo and dizziness that affects their quality of daily life, particularly among females older than 60 years old.12–14 Treatment options include medical therapy such as antithrombotic agents, intracranial and extracranial angioplasty and stenting, and surgical revascularization.15,16 Unfortunately, many medications for the treatment of VBIV have direct vestibulotoxicity, especially caffeine and nicotine, which can have wide rang of autonomic effects that may exacerbate vestibular symptoms. However, complications of vascular surgery, such as plaque disruption, may result in distal emboli and arterial vasospasm and have limited the utility of this practice; moreover, drugs, such as antithrombotic agents, could lead to a high risk of fatal or disabling strokes.17–20 In contrast, complementary and alternative medicine (CAM), such as traditional Chinese medicine (TCM), can effectively alleviate the symptoms of dizziness and reduce adverse reactions and compli-

cations. Currently, many clinicians do not hesitate to recommend herbs or herbal products to their patients for the effective treatment of vertigo diseases. BBTD is widely used in clinical settings and is a famous prescription of TCM that contains Pinellia ternata, Atractylodes macrocephala, Gastrodia elata, tangerine peel, Poria cocos, Glycyrrhiza, ginger, and red jujube as recorded in Medical Insights during the Qing dynasty.21 It has been generally used to treat VBI-related symptoms in clinical practice for centuries in China.22,23 This prescription primarily treats symptoms of dizziness, headaches and abnormal sensations, which are cause by blood deficiency and stagnation and turbid phlegm, leading to a loss in brain nourishment.24–26 In addition, according to TCM theory, this prescription utilizes mechanisms that maybe strengthen the spleen, supplement Qi and promote blood circulation to remove obstructions; furthermore, in accordance with the Treatise on Cold Pathogenic Diseases, BBTD utilizes mechanisms that treat the six climatic conditions in excess as pathogenic factors for a lesser yang disease pattern.25 Recently, modern pharmacological studies and long-term clinical observations have shown that BBTD dilates cerebral vessels, increases vertebrobasilar artery volume, reduces blood viscosity, and improves microcirculation and haemodynamics.27,28 Zoopery results confirmed that BBTD caused the positive effect of contraction on cerebral vasospasm and promoted the reduction of cerebral vascular resistance, achieving anti-platelet aggregation and anti-vertigo effects. Biochemically, BBTD could improve the ability of scavenging, oxygen-derived free radicals and reduce the damage of free radicals to the human body; thus, it could effectively improve the haemodynamic stability of the vertebrobasilar artery and play a role in the prevention of vertigo and sedation.29–31 However, individual studies have yielded inconsistent or conflicting findings, possibly caused by limitation associated with an individual study.32 Therefore, we performed a meta-analysis of published studies to shed light on these contradictory results,

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to more precisely evaluate the relationship between BBTD and VBIV, and to help health-care professionals make clinical decisions. This study was in compliance with the recommendations of the Cochrane Collaboration, and our study protocol was registered with PROSPERO. 2. Methods This study complied with the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) statement.33 2.1. Search strategies To identify eligible studies, the main search was conducted in the following electronic databases from inception to July 2016: CENTRAL (1996–2016), EMBASE (1980–2016), PubMed (1959–2016), the Chinese National Knowledge Infrastructure (CNKI, 1980–2016), the Chinese Scientific Journal Database (VIP, 1989–2016), the Chinese Biomedical Literature Database (CBM, 1978–2016) and the Wanfang Database (1998–2016). Each database was searched using a combinations of Medical Subject Headings (MeSH) and non-MeSH terms without restrictions to the regions and publication status. The searches were restricted to papers that were published in English or Chinese. The procedure was concluded by performing the following: (1) perusing the reference sections of all relevant studies, (2) manually searching key journals and abstracts from the major annual meetings in the field of VBIV and (3) contacting experts. The manual searching techniques were also used to identify appropriate studies (manual searches of reference lists were also performed). The main search was completed independently by the investigators. Any discrepancy was solved by consulting an investigator who was not involved in the initial procedure. More details regarding the search strategy are described in the Appendix A, and those strategies were modified for use with other databases. 2.2. Study selection 2.2.1. Types of studies RCTs on the use of BBTD for the treatment of VBIV were included without limitations on the region or publication status. The searches were restricted to papers that were published in English or Chinese. Trials were excluded if any of the following factors were identified: (1) trial that failed to provide detailed results, (2) animal trials, and (3) quasi-randomized trials. 2.2.2. Types of participants The patients were diagnosed in accordance with at least one of the current or past internationally accepted diagnostic criteria for VBI with vertigo as the main symptoms. The diagnosis procedure was as follows. (1) The patient felt a sense of vertigo as he or she spun or shook their head and/or changed their posture. (2) The patient felt vertigo along with at least one sign or symptom of nerve ischaemia in the vertebrobasilar artery blood supply region, including eye disease (e.g., amaurosis, flash, deformation, diplopia), ear pain, numbness or weakness, cataplexy, and syncope. (3) The patients had some of the following minor signs of brain stem injury: the corneal reflex was diminished or disappeared, the vertebral artery was constricted by spontaneity or neck rotation (which could result in nystagmus), and a positive pathologic reflex. (4) The cause of the VBIV was clear, including cervical spondylosis, cervical vertebra trauma, cerebral arteriosclerosis, diabetes, heart disease, and low blood pressure. (5) Other causes of vertigo, such as severe hypertension, Meniere’s disease, intracranial space-occupying lesions, or other cerebrovascular diseases, were eliminated. (6) Transcranial Doppler (TCD) ultrasound was used in

29

all cases to detect that the mean blood flow velocity of the vertebrobasilar artery was lower than normal.34,35 No limitations on the gender, age, or ethnic origin of the patients were set. 2.2.3. Types of interventions Only studies that compared BBTD used alone with antivertigo drugs, or that compared BPAD with anti-vertigo drugs were included. Studies that included other co-interventions (e.g., another herbal formula, moxibustion, massage, acupuncture, yoga, cupping, qigong, Tai Chi, and aromatherapy) were excluded as the intervention effect of BBTD could not be distinguished. According to the basic theory of Traditional Chinese Medicine (TCM), BBTD can contain a few extra herbs, but the resulting prescription should contain the following six key drugs: Pinelliae, Atractylodes Macrocephala, Gastrodiae, Aurantii nobilis Pericarpium, Hoelen, and Glycyrrhiza uralensis. 2.2.4. Types of controls The control group included conventional anti-vertigo drugs use, placebo use, no treatment and usual or standard care. The treatment cycle lasted for at least two weeks. 2.2.5. Types of outcome measures The primary outcome of this systematic review was clinical efficacy. This specifically refers to the following three categories. Recovery indicated that the clinical symptoms disappeared completely, that the signs improved, and that the physical index of the TCD examination of the blood flow in the vertebrobasilar arteries was completely normal. Validity indicated that the clinical symptoms were alleviated significantly, that the main signs significantly improved, and that the physical index of the Transcranial Doppler (TCD) examination of the blood flow in the vertebrobasilar arteries was significantly improved. Invalidity indicated that the clinical symptoms, the main signs, and the physical index of Transcranial Doppler (TCD) examination of vertebrobasilar arteries blood are not improved. The secondary outcome was the velocity of the blood flow in the vertebrobasilar artery by TCD, including the blood flow velocity of the left vertebral artery (LVA), the right vertebral artery (RVA), and the basilar artery (BA). In addition, adverse reactions were also taken into account. 2.3. Data extraction Two reviewers extracted the data independently using a predefined data extraction form. Disagreements were resolved by discussion or consensus with a third reviewer. The following data were extracted: the first author, study characteristics (i.e., year, duration, setting, and design), participant characteristics (i.e., mean age, sample size, and systemic therapy), intervention details, and measured outcomes. For studies with insufficient information, the reviewers contacted the primary authors, when possible, to acquire and verify the data. 2.4. Methodological quality The assessment was conducted by two independent reviewers according to the methodology of the Cochrane handbook.36 All disparities between them were resolved by consensus. The following domains were used to evaluate the methodological quality of the RCTs: random sequence generation, allocation concealment, blinding of participants and outcome assessors, incomplete outcome data, selective reporting, and other bias. Across studies, the risk of bias was categorized into one of three groups: ‘high’, ‘low’ and ‘unclear’.

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Z. Guo et al. / Complementary Therapies in Medicine 31 (2017) 27–38

2.5. Data synthesis

3. Results

The pooled analysis was conducted using Review Manager to assess the differences between the BBTD and control groups. Dichotomous data were analyzed by using the risk ratio (RR) computed with the Mantel-Haenszel method (fixed or random models). Continuous outcomes were measured on the same scale and were analyzed by using weighted mean differences (WMD); they are expressed as the mean and standard deviation. The I-square (I2 ) test was performed to assess the impact of study heterogeneity on the results of the meta-analysis. According to the Cochrane review guidelines, if severe heterogeneity is present (I2 > 50%), then a random-effect models should be chosen. Otherwise, a fixed-effect model should be used. Visual inspection of the funnel plot was performed to assess publication bias if a sufficient number of studies (n ≥ 10) was found. Statistical significance was set to p < 0.05.35

3.1. Study characteristics

2.6. Subgroup synthesis

A flow chart depicts the search process and study selection (as shown in Fig. 1). A total of 346 studies were identified through our search of 7 electronic databases. After removing 201 duplicates, only 145 studies were retrieved. After reading the titles and abstracts, only 39 studies remained. There were 12 articles that were excluded for the following reasons: did not use internationally recognized criteria for VBIV (n = 4), did not have a control group (n = 3), included other herbal formulas (n = 3) and did not have sufficient data for extraction (n = 2). In total, 27 RCTs were included,32,37–62 and all trials had been conducted and published in China. The basic characteristics of the included studies are described in Table 1. 3.2. Treatment groups

We conducted a subgroup analysis on the treatment duration and risk of bias of BA in this systematic review. 2.7. Grading quality of evidence Two authors (R. Lai and Z. Guo.) evaluated the quality of evidence of the primary and secondary outcomes according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE)28 methodology independently, which evaluate the risk of bias, inconsistency, indirectness, imprecision, and publication bias. These components are classified as very low, low, moderate, or high. Grade evidence profile (EP) were constructed using the GRADE Profiler (version 3.6, GRADEpro).

Among the included clinical trials, four37,40,52,56 compared BBTD use alone with conventional anti-vertigo medicine, and twenty-three32,38,39,41–51,52–55,57–62 compared BPAD with conventional anti-vertigo medicine. 3.3. Control groups All of the patients in the control group received conventional anti-vertigo medicine treatment, such as nimodipine, a puerarin injection, betahistine hydrochloride, flunarizine hydrochloride capsules, difenidol hydrochloride tablets, a cinepazide maleate injection, aspirin enteric-coated tablets.

Fig. 1. PRISMA 2009 flow diagram of study selection and identification.

Table 1 Basic characteristics of the included studies. Sample size (T/C)

Age

Diagnosis standard

Intervention

Wang, 200137

90(50/40)

T:64.54 ± 9.43C:64.67 ± 11.43

PN-1994

Wang and, Hua 201238

128(64/64)

T:53.42 ± 12.24C:52.64 ± 11.98

NDIM-2003

Xia and, Song 201039

100(52/48)

T:46-72C:45–70

Yu, 200740

116(60/56)

T:46-78C:45–76

Wu et al., 201541

122(59/63)

Zhang, 201542

140(70/70)

Zhang and Yang, 201343 Ding and Wu, 201232 Jiang and Liao, 201144

Control

Treatment duration

Followup

Main assessment

Course of disease

Modified BBTD(1 dose/day)

Nimodipine(20 mg,tid)

28 d

NR

CE

NR

Modified BBTD(1 dose/day) + controll

Puerarin injection(0.4 g,qd)

15 d

NR

CE;LVA;RVA;BA;AE

NR

PN-1994

Modified BBTD(1 dose/day) + controll

Betahistine(6 mg,bid)

15 d

NR

CE

T:6 d–7 y (M:3.8 y)C:10 d–8 y(M:4.5 y)

CN(unclear)

Modified BBTD(1 dose/day)

Flunarizine hydrochloride capsules(5 mg,qd) and nimodipine(20 mg,tid)

15 d

6 months

CE

T:3 d–10 y C:1d–8 y

T:60.7 ± 5.0C:61.4 ± 5.2

M(unclear)

Modified BBTD(1 dose/day) + controll

Betahistine hydrochloride(12 mg,tid)

4w

NR

CE;LVA;RVA;BA

T:3.8 ± 0.7 y C:4.0 ± 0.8 y

T:61.62 ± 5.38C:62.48 ± 5.32

DIMTCM-2003

Modified BBTD(1 dose/day) + controll

flunarizine(10 mg,qd)

28 d

6 months

CE;AE

NR

65(35/30)

T:43-72C:41–70

DIMDDD-1995

Modified BBTD(1 dose/day) + controll

Betahistine hydrochloride(12 mg,tid)

2w

NR

CE;LVA;RVA;BA

T:2–9y (M:8 y )C:1–7y(M:6.8 y)

54(27/27)

T:51 ± 2.1C:49 ± 3.5

N-1996

Modified BBTD(1 dose/day) + controll

Betahistine and flunarizine(NR)

14 d

NR

CE

T: M:1.5 y C:M:1.3 y

90(46/44)

T:62.5 ± 6.5C:63.5 ± 7.5

PN-2004

Modified BBTD(1 dose/day) + controll

Betahistine hydrochloride(8 mg,tid) and nimodipine(20–40 mg,tid)

2w

NR

CE

T:3 m–7 y C:4 m–6 y

Lai, 200945

80(40/40)

T:50-75C:45–75

SDCETCMS-1994

Modified BBTD(1 dose/day) + controll

Aspirin enteric-coated tablets(100 mg,qd) and nimodipine(20 mg,tid)

15 d

NR

CE;LVA;RVA;BA

NR

Lin and Li, 201246

78(40/38)

40–75

DIMTCM-2002

Modified BBTD(1 dose/day) + controll

Betahistine(6 mg,tid) and flunarizine(5 mg,qd)

15 d

NR

CE;LVA;RVA;BA;AE

2 h–1 w

Song, 201347

312(158/154)

49–79

WHO; SDCETCMS-2004

Modified BBTD(1 dose/day) + controll

Betahistine hydrochloride(10–30 mg,qd) and flunarizine(5–10 mg,qd) and nimodipine(20 mg,tid)

4w

1 month

CE;LVA;RVA;BA;AE

6 m–7 y (M:5.1 ± 1.4)

Song

et al., 201248

90(45/45)

T:45-73C:42–76

PN-1994

Modified BBTD(1 dose/day) + controll

Betahistine mesilate tablets(6 mg,tid)

15 d

NR

CE

NR

Tan et al., 200349

110(57/53)

T:48-68C:46–69

PN-1994

Modified BBTD(1 dose/day) + controll

Difenidol hydrochloride tablets(50 mg,tid)

15 d

NR

CE;LVA;RVA;BA

NR

Tian and Yan, 201250

70(35/35)

T:46-72C:48–69

PN-1994

Modified BBTD(1 dose/day) + controll

Cinepazide maleate injection(320 mg,qd) and flunarizine(5 mg,qd)

2w

NR

CE

T:6 d–4 y C:9 d–6 y

Wang, 201151

50(26/24)

T:51-72C:50–73

SDCETCMS-1994

Modified BBTD(1 dose/day) + controll

Puerarin injection(NR,qd)

14 d

NR

CE;LVA;RVA;BA

NR

94(50/44)

T:40-66C:42–64

CN-2003

Modified BBTD(1 dose/day)

Nimodipine injection(8 mg,qd)

14 d

NR

CE

T:2–5 y (M:3 y)C:26 y(M:4.8 y)

120(60/60)

T:43-76C:44–77

CN-1995

Modified BBTD(1 dose/day) + controll

Betahistine tablets(6 mg,tid)

28 d

NR

CE;BA

T:3.5 h–3 d(M:1.6 ± 1.1) C:4 h–3 d5. (M:1.5 ± 1.2)

60(30/30)

T:39-68C:36–67

CN-2003

Modified BBTD(1 dose/day) + controll

Aspirin (100 mg,qd) and diphenidol (25 mg,tid)

4w

NR

CE;LVA;RVA;BA

NR

Betahistine Hydrochloride (10 mg,tid)

2w

NR

CE;LVA;RVA;BA

T:6–29 w C:8–27 w

Liu Kong

et al., 200852 et al., 201353

Luo, 201354

Chen

et al., 201255

208(128/80)

T:45.2C:43.5

N-2003

Modified BBTD(1 dose/day) + controll

Chen, 201156

50(26/24)

T:49-70C:46–78

PN-2005

Modified BBTD(1 dose/day)

flunarizine tablets (5 mg,qn)

4w

NR

CE;BA

NR

Fang, 201257

113(57/56)

T:64.9 ± 10.68C:63.2 ± 10.8

CN-2003

Modified BBTD(1 dose/day) + controll

Nimodipine tablets (40 mg,tid) and Prostaglandin E (250 ml,qd)

20 d

NR

CE;LVA;RVA;BA

T:M:27.7 m C:M:27.3 m

Jia, 201058

80(40/40)

T:45-76C:43–74

CN-2003

Modified BBTD(1 dose/day)

flunarizine tablets (5 mg,qn)

28 d

NR

CE

>5 y

Li, 201259

120(60/60)

T:41-72C:40–75

ECPCI-2006

Modified BBTD(1 dose/day) + controll

Betahistine tablets (6 mg,tid)

15 d

NR

CE;LVA;RVA;BA

NR

Luo, 200860

94(48/46)

T:33-56C:34–57

DIMDDD-1998

Modified BBTD(1 dose/day) + controll

flunarizine tablets (10 mg,qn) and diphenidol tablets (50 mg,tid)

15 d

NR

CE;LVA;RVA;BA

T:0.5–7.4 y(M:4.16 ± 1.37 y) C:0.5–7.4 y(M:4.23 ± 1.32 y)

50(25/25)

T:53 ± 9.54C:52.56 ± 9.54

ECPCI-2006

Modified BBTD(1 dose/day) + controll

flunarizine tablets (10 mg,qn)

14 d

NR

CE;BA

T:6.47 ± 1.71 y) C:7.58 ± 1.08 y)

112(56/56)

45–70

WHO-1989; PN-1996

Modified BBTD(1 dose/day) + controll

Nimodipine tablets (20 mg,tid) and puerarin (400 mg,qd)

2w

NR

CE;LVA;RVA;BA

NR

Wang

et al., 201461

Wen and Liu, 200762

31

Note: AE, adverse effect; BA, basilar artery; Bid, twice daily; BBTD, Banxia Baizhu Tianma Decoction; C, control group; CE, clinical efficacy; CN, Clinical Neurology; d, day; DIMTCM, Department of Internal Medicine of Traditional Chinese Medicine; DIMDDD, Department of Internal Medicine Disease Differential Diagnosis; ECPCI, Expert consensus on posterior circulation ischaemia in China; h, hour; LVA, left vertebral artery; m, month; M, Medicine; N, Neurology; NDIM, Neural Department of Internal Medicine; NR, no reported; PN, Practical Neurology; RVA, right vertebral artery; SDCETCMS, Standard of Diagnosis and Curative Effect of TCM Syndrome; T, treament group; Tid, three times a day; w, week; WHO, World Health Organization; y, year.

Z. Guo et al. / Complementary Therapies in Medicine 31 (2017) 27–38

Study ID

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Z. Guo et al. / Complementary Therapies in Medicine 31 (2017) 27–38

Fig. 2. Risk of bias graph of included studies.

Table 2 Subgroup Analyses of BPAD Compared With Anti-vertigo Drugs for BA. Subgroup

No. patients

No. Trials

Mean Difference (95% CI)

P Value

I2 (%)

Total Risk of bias Low38,53,54,61 Unclear/high41,43,45–47,49,51,55–57,59,60,62

1872

17

5.20 (3.86−6.54)

0.42

90

358 1514

4 13

4.37 (2.49−6.42) 5.38 (3.77−7.00)

<0.00001 <0.00001

56 92

Treatment duration 28 days41,47,53,54,56 20 days 57 15 days38,45,46,49,59,60 14 days43,51,55,61,62

664 113 610 485

5 1 6 5

6.16 (3.91, 8.42) 5.01 (2.86, 7.16) 6.20 (3.10, 9.30) 3.05 (2.33, 3.76)

<0.00001 <0.00001 <0.0001 <0.00001

88 NA 92 0

The control group Flunarizine41,47,46,56,60,61 Nimodipine45,57 Betahistine43,46,47,53,55,59 Diphenidol49,54,60 Puerarin38,51,62 Aspirin45,54

706 305 903 264 290 140

6 3 6 3 3 2

6.89 (3.90, 9.87) 4.39 (2.86, 5.92) 4.27 (2.21, 6.34) 9.98 (2.97, 16.9) 3.26 (2.28, 4.24) 6.63 (4.04, 9.21)

<0.00001 <0.00001 <0.0001 =0.05 <0.00001 <0.00001

92 52 94 94 0 28

NA: not applicable.

3.4. Treatment duration The total duration of treatment ranged from 2 to 4 weeks. In addition, the duration of follow-up was mentioned in three trials,40,42,47 ranging from 1 to 6 months. 3.5. Methodological quality The methodological quality of the included trials is described in Figs. 2 and 3. Although randomization was declared in all of the trials, only five trials38,42,53,54,61 used a random number table. However, all of the trials did not report concrete details on allocation concealment and the blinding of participants and outcome assessors. It was difficult to determine the blinding of patients and researchers; therefore, we indicated that these studies were at a high risk of bias. There was a low risk of incomplete outcome data in twenty-six32,37,39–62 studies. Selective reporting could not be judged for all of the trials because of insufficient information. There was an unclear risk of other bias in all of the trials because the included studies appeared free of other problems that could put them at a high risk of bias. 3.6. Outcome measures 3.6.1. Clinical efficacy (CE) 3.6.1.1. BBTD versus anti-vertigo drugs (4 studies). There were 4 studies37,40,52,56 that compared the effect of BBTD used alone with the effect of anti-vertigo drugs. CE was measured in four studies. The trials showed a slight effect on the results (chi-square = 1.25,

df = 3, p = 0.03, I2 = 0%). Thus, a fixed-effect model was used for pooled analysis. The meta-analysis showed that there was a slight difference between the BBTD group and the anti-vertigo group (n = 350; RR, 1.09; 95% CI, 1.01–1.18), showing that the BBTD used alone could improve the CE (Fig. 4). 3.6.1.2. BPAD versus anti-vertigo drugs (23 studies). There were 23 studies32,38,39,41–51,52–55,57–62 that compared the effect of BPAD with the effect of anti-vertigo drugs in patients with VBIV. The trials showed a significant effect on the results (chi-square = 14.43, df = 22, p < 0.00001, I2 = 0%). Thus, a fixed-effect models was used for the pooled analysis. The meta-analysis showed that there was a significant difference between the BPAD group and the anti-vertigo group (n = 2446; RR, 1.20; 95% CI, 1.16–1.24). The results showed that the effect of BBTD on the CE was better than that of anti-vertigo drugs on the CE (Fig. 5). 3.6.1.3. The blood flow velocity of the left vertebral artery (LVA). There were 13 studies38,41,43,45–47,49,51,54,57,59,60,62 that compared the effect of BPAD with the effect of anti-vertigo drugs by measuring the blood flow velocity of the LVA in patients with VBIV. The trials showed a significant effect on the results (chi-square = 128.68, df = 12, p < 0.00001, I2 = 91%). Thus, a random-effect model was used for the pooled analysis. The meta-analysis showed that there was a significant difference between the two groups (n = 1444; WMD, 5.21 cm/s; 95% CI, 3.72–6.70 cm/s). The results showed that BPAD sped up the blood flow velocity of the LVA more than the antivertigo drugs did (Fig. 6).

IMPORTANT ⊕⊕OO LOW

c

All of the trials did not report concrete details on allocation concealment and the blinding of participants and outcome assessors. There may be negative results that were not published in the literature. Two or more than two studies’ evidence showed that RR > 2 or RR<0.5, and there were almost no confounding factors. a

b

IMPORTANT ⊕⊕ OO LOW

⊕⊕ OO LOW

MD 5.20 higher (3.86–6.54 higher) –

154 more per 1000 (from 123 more to 185 more) RR 1.20 (1.16–1.24) 916/1188 (77.1%)

the blood flow velocity of the basilar artery (follow-up 2–4 weeks; measured with: Transcranial Doppler examination; Better indicated by lower values) randomized very seriousa no serious no serious no serious reporting biasb 969 903 17 strong trials inconsistency indirectness imprecision associationc

Risk of bias

MD 5.45 higher (4.02–6.88 higher)

GRADE evidence profiles (EP) for the primary and secondary outcomes are shown in Table 3. The GRADE Working Group grades level of evidence is very low for CE (BPAD vs AD), and low for LVA, RVA, BA (BPAD vs AD). Therefore, in order to stabilize the results, high-quality and adequately powered RCTs are warranted.

the blood flow velocity of the right vertebral artery (follow-up 2–4 weeks; measured with: Transcranial Doppler examination; Better indicated by lower values) randomized very seriousa no serious no serious no serious reporting biasb 730 714 – 13 strong trials inconsistency indirectness imprecision associationc

3.9. Grade profile evidence

Design

As shown in Fig. 9, the funnel plot contains the CE outcomes for trials that compared BPAD use with anti-vertigo drug use. The results showed asymmetry, suggesting the existence of potential publication bias, and there may be negative results that were not published in the literature.

Table 3 Grade evidence profile (EP) of included studies.

3.8. Evaluation of publication bias

MD 5.21 higher (3.72–6.7 higher)

Other considerations Inconsistency

Indirectness

Imprecision

Adverse effects were reported in six studies42,46,47,55–57 and were not mentioned in the others. One trial42 reported that the control group had three cases of nausea and vomiting and two cases of headache on the fifth day of observation, while the experimental group did not have any of the aforementioned symptoms. These symptoms disappeared after drug withdrawal, but they were not significantly different (p > 0.05) between the two groups. One trial46 reported that both groups had two cases of nausea and vomiting and two cases of headache that disappeared after the routine medicine was taken. Three trials47,56,57 noted that there were no adverse effects in the two groups. One trial55 reported that the control group had twelve cases of thirst and palpitation and five cases of itching, while the experimental group did not have any of the aforementioned symptoms, and they were significantly different (p < 0.05) between the two groups.

the blood flow velocity of the left vertebral artery (follow-up 2–4 weeks; measured with: Transcranial Doppler examination; Better indicated by lower values) very seriousa 13 randomized no serious no serious no serious reporting biasb 730 714 – trials strong inconsistency indirectness imprecision associationc

Banxia Baizhu Tianma Decoction No of studies

3.7. Adverse effects

clinical efficacy (follow-up 2–4 weeks; assessed with: Transcranial Doppler examination and the clinical symptoms evaluation) very seriousa 23 randomized no serious no serious no serious reporting biasb 1159/1258 trials inconsistency indirectness imprecision (92.1%)

No of patients Quality assessment

Control

Effect

3.6.1.5. The blood flow velocity of the basila artery (BA). There were 17 studies38,41,43,45–47,49,51,53–57,59,60–62 that compared the effect of BPAD with the effect of anti-vertigo drugs by measuring the blood flow velocity of the BA in patients with VBIV. The trials showed a significant effect on the results (chi-square = 160.25, df = 16, p < 0.00001, I2 = 90%). Thus, a random-effect model was used for the pooled analysis. The meta-analysis showed that there was a significant difference between the two groups (n = 1872; WMD, 5.20 cm/s; 95% CI, 3.86–6.54 cm/s). The results showed that BPAD sped up the blood flow velocity of the BA more than the anti-vertigo drugs did (Fig. 8). The results of subgroup analyses are shown in Table 2. The findings of speeding up the blood flow velocity of the RVA were consistent in all subgroup analyses.

Relative (95% CI)

Absolute

Quality

⊕⊕ OO VERY LOW

CRITICAL

Importance

3.6.1.4. The blood flow velocity of the right vertebral artery (RVA). There were 13 studies38,41,43,45–47,49,51,54,57,59,60,62 that compared the effect of BPAD with the effect of anti-vertigo drugs by measuring the blood flow velocity of the RVA in patients with VBIV. The trials showed a significant effect on the results (chi-square = 110.91, df = 12, p < 0.00001, I2 = 89%). Thus, a random-effect model was used for the pooled analysis. The meta-analysis showed that there was a significant difference between the two groups (n = 1444; WMD, 5.45 cm/s; 95% CI, 4.02–6.88 cm/s). The results showed that BPAD sped up the blood flow velocity of the RVA more than the antivertigo drugs did (Fig. 7).

33

IMPORTANT

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could be obviously improved by receiving BPAD therapy (duration ranging 2–4 weeks) and slight improvements were observed for the BBTD alone group compared with the anti-vertigo drugs group and (2) BPAD was more effective in speeding up the blood flow velocity of the LVA, RVA, and BA than conventional anti-vertigo drugs. However, as there was a lack of studies that evaluated the doseresponse relationship, the optimal dosage for active treatment with BBTD was difficult to precisely confirm. 4.2. Comparison with other meta-analyses Two meta-analyses63,64 that evaluated a similar topic have been recently published in Chinese. We have noted the differences between our meta-analysis and these previous ones, although our major findings agreed with their findings (Table 4). First, the previous meta-analyses included no more than eighteen trials and 1606 patients. In contrast, our meta-analysis included 27 trials, totalling 2796 patients. As expected, with the added evidence of at least 346 cases, our current meta-analysis was the most comprehensive and recent, and it further reinforced the results of the previous metaanalyses. Second, we also conducted a subgroup analysis based on several factors to analyze the heterogeneity and to provide a more conservative estimate. Finally, we evaluated the quality of evidence of the outcomes using the GRADE system to help health-care professionals make clinical decisions. 4.3. Implications for clinical practice Our meta-analysis showed the obvious benefit of BPAD but not BBTD compared with conventional anti-vertigo drugs. Furthermore, there were more cases that received BPAD for the treatment of VBIV than cases that received BBTD. Therefore, BPAD might be the better treatment for VBIV and is worthwhile in a clinical context. Our subgroup analysis found that the high heterogeneity across studies was potentially due to the treatment duration. Furthermore, the experience level of the clinician and the learning curve are generally factors of heterogeneity. The experience level of clinicians varied from inexperienced to briefly trained and fairly experienced, which not only contributed to heterogeneity but also influenced the prescription composition, further impacting the effect of BBTD on the CE. Moreover, the information on the safety of BBTD or comprehensive therapies including BBTD was insufficient in the included studies. As there was limited data, whether BBTD alone or the combination of BBTD with conventional therapy caused adverse effects is not known, but the most common gastrointestinal symptoms (including nausea and vomiting) and headaches were found in six trials.42,46,47,55–57 4.4. Limitations Before accepting the results of this study, the following limitations should be taken into account comprehensively.

Fig. 3. Risk of bias summary of included studies.

4. Discussion 4.1. Main findings Our meta-analysis systematically and comprehensively evaluated the available evidence. It found the following results: (1) the CE

(1) (The methodological quality was estimated to be commonly poor for the overwhelming majority of the included trials, and the primary causes are as follows: First, although all trials described randomization, only five38,42,53,54,61 described random sequence generation (random number table). Additionally, no trials demonstrated the implementation of allocation concealment; therefore, selection bias may exist. Second, none of the trials reported the blinding of participants and outcome assessors; thus, both selection bias and detection bias might affect these studies. Third, only three trials reported a follow-up,40,42,47 and none of the trials presented dropout or withdrawal statistics, suggesting that attrition bias may exist. Fourth, all of the included studies

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Fig. 4. Forest plot of the effect of Banxia Banzhu Tianma Decoction (BBTD) versus anti-vertigo drugs (AD) in clinical efficacy (CE).

Fig. 5. Forest plot of the effect of Banxia Banzhu Tianma Decoction plus anti-vertigo drugs (BPAD) versus AD in CE.

Fig. 6. Forest plot of the effect of BPAD versus AD in the blood flow velocity (cm/s) of the left vertebral artery (LVA).

Fig. 7. Forest plot of the effect of BPAD versus AD in the blood flow velocity (cm/s) of the right vertebral artery (RVA).

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Fig. 8. Forest plot of the effect of BPAD versus AD in the blood flow velocity (cm/s) of the basila artery (BA).

Table 4 Comparison With Other Meta-analyses. Author/Year

Jie/2015

Gan et al./2016

Current Meta-analysis

No. of randomized controlled trials No. of participants Search strategy until, year Type of interventions

9 897 May 2014 BBTD, BPAD

27 2796 July 2016 BBTD, BPAD

Primary outcome

CE (OR, 3.50; 95% CI, 2.36–5.19)

18 1606 Not Reported BBTD, BPAD, and other TCM co-interventions CE (OR, 3.85; 95% CI, 2.83-5.27)

Secondary outcome

V- BA: SMD, 1.16; 95% CI, 0.87-1.45

Evidence of effect

LVA: WMD, −4.21; 95% CI, −7.00- −1.41 RVA: WMD, −4.40; 95% CI, −6.62- −2.17 BA: WMD, −3.28; 95% CI, −5.25- −1.31 Sufficiently effect

Subgroup analysis

Not applied

Not applied

GRADE

Not applied

Not applied

Sufficiently effect

CE (BBTD vs anti-vertigo drugs: RR, 1.09; 95% CI, 1.01–1.18; BPAD vs anti-vertigo drugs: RR, 1.20; 95% CI, 1.16–1.24) LVA: WMD, 5.21 cm/s; 95% CI, 3.72–6.70 RVA: WMD, 5.45 cm/s; 95% CI, 4.02–6.88 BA: WMD, 5.20 cm/s; 95% CI, 3.86–6.54

Slightly effect in CE of BBTD vs anti-vertigo drugs; Sufficiently effect in CE of BPAD vs anti-vertigo drugs; Sufficiently effect in LVA, RVA and BA Treatment duration; Risk of bias Low

Note: BBTD, Banxia Baizhu Tianma Decoction; BPAD, BBTD plus anti-vertigo drugs; GRADE, Grading of Recommendations Assessment, Development, and Evaluation; RCT, randomized controlled trial; RR, Relative risk; OR, odds risk; SMD, Standardized mean difference; WMD, Weighted mean difference; V- BA, the blood flow velocity of the vertebrobasilar artery. See Table 1 legend for expansion of other abbreviation.

did not mention an intention-to-treat (ITT) analysis, which may lead to some other biases. Fifth, no trials reported a preestimation of the sample size or placebo control, which might decrease their quality of evidence. (2) As shown in Figs. 6–8, heterogeneity is another critical issue that should be given great attention as it may be associated with variations in study quality, participants, the BBTD composition and anti-vertigo drugs. (3) The effect of publication bias should be considered. In this meta-analysis, all of the included trials were conducted in China and published in Chinese. Almost all studies claimed that BBTD had a similar beneficial effect or a better effect than anti-vertigo drugs alone and negative conclusions were not reported. Moreover, the funnel plot showed asymmetry, suggesting the existence of potential publication bias. (4) Patients frequently apply auxiliary products in various healthcare settings; hence, the safety of BBTD has become a focus. This meta-analysis suggested that BBTD may be safe for the treatment of VBIV. However, parallel, double-blind, random-

ized, placebo-controlled trials indicated that adverse effects of BBTD for VBIV could not be found. As there is insufficient clinical evidence, it is difficult to draw a definitive conclusion regarding the safety of BBTD for VBIV. We therefore suggest that the adverse effects of BBTD need to be strictly supervised in future studies. (5) Not only were the sample sizes of the included trials relatively small but the trials did not specify the basis for their sample size estimation, which may lead to a low test effectiveness.

4.5. Conclusions BBTD combined with conventional anti-vertigo drugs appears to improve the CE and significantly speed up the blood flow velocity of the vertebrobasilar artery, but the confidence in the effect estimates may be reduced due to the limited number of included trials and the methodological limitations. Future RCTs with larger sample sizes and longer follow-ups that report their results according

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Fig. 9. Funnel plot of the effect of BPAD versus AD in CE.

to the Consolidated Standards of Reporting Trials (CONSORT)65,66 are needed to verify the effectiveness and safety of BBTD for the treatment of VBIV. Contributors All of the authors approved the final version of the paper. R. Lai conceived the idea for the study. Z. Guo, Z. Su, and Z. Wang performed the literature search. Z. Wang and X. Luo performed the data collection and extraction. Z. Guo and Z. Guo assessed the methodological quality. Z. Guo, Z. Su, and R. Lai performed the meta-analysis and wrote the article. Funding This work was supported by National Nature Science Foundation Youth Project of China (Grant No. 61301294) and the College Students’ Innovative Entrepreneurial Training Program of China (Grant No. 201510572007). Competing interests None declared. Provenance and peer view Not commissioned; externally peer reviewed. Acknowledgment The authors would like to thank American Journal Experts (AJE) for English language editing.

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Insufficiencies OR Vertebrobasilar Dolichoectasia OR Dolichoectasia, Vertebrobasilar OR Dolichoectasias, Vertebrobasilar OR Vertebrobasilar Dolichoectasias OR Vertebral Artery Insufficiency OR Artery Insufficiencies, Vertebral OR Artery Insufficiency, Vertebral OR Insufficiencies, Vertebral Artery OR Insufficiency, Vertebral Artery OR Vertebral Artery Insufficiencies OR Vertebral Artery Ischemia OR Artery Ischemia, Vertebral OR Artery Ischemias, Vertebral OR Ischemia, Vertebral Artery OR Ischemias, Vertebral Artery OR Vertebral Artery Ischemias OR Vertebral Artery Stenosis OR Artery Stenoses, Vertebral OR Artery Stenosis, Vertebral OR Stenoses, Vertebral Artery OR Stenosis, Vertebral Artery OR Vertebral Artery Stenoses OR Basilar Artery Insufficiency OR Artery Insufficiencies, Basilar OR Artery Insufficiency, Basilar OR Basilar Artery Insufficiencies OR Insufficiencies, Basilar Artery OR Insufficiency, Basilar Artery OR Basilar Insufficiency OR Basilar Insufficiencies OR Insufficiencies, Basilar OR Insufficiency, Basilar OR Basilar Artery Ischemia OR Artery Ischemia, Basilar OR Artery Ischemias, Basilar OR Basilar Artery Ischemias OR Ischemia, Basilar Artery OR Ischemias, Basilar Artery OR Basilar Artery Stenosis OR Artery Stenoses, Basilar OR Artery Stenosis, Basilar OR Basilar Artery Stenoses OR Stenoses, Basilar Artery OR Stenosis, Basilar Artery #2 Vertigo[Mesh] OR Vertigos OR Vertigo, Subjective OR Subjective Vertigo OR Subjective Vertigos OR Vertigos, Subjective OR Spinning Sensation OR Sensation, Spinning OR Sensations, Spinning OR Spinning Sensations OR Positional Vertigo OR Vertigo, Positional OR Vertigo, Brain Stem OR Brain Stem Vertigo OR Brain Stem Vertigos OR Vertigos, Brain Stem OR Vertigo, Brainstem OR Brainstem Vertigo OR Brainstem Vertigos OR Vertigos, Brainstem OR Vertigo, Peripheral OR Peripheral Vertigo OR Peripheral Vertigos OR Vertigos, Peripheral OR Vertigo, Essential OR Essential Vertigo OR Essential Vertigos OR Vertigos, Essential OR Vertigo, Intermittant OR Intermittant Vertigo OR Intermittant Vertigos OR Vertigos, Intermittant OR Vertigo, Paroxysmal OR Paroxysmal Vertigo OR Paroxysmal Vertigos OR Vertigos, Paroxysmal OR Central Nervous System Origin Vertigo OR Vertigo, Central Origin OR Central Origin Vertigo OR Central Origin Vertigos OR Origin Vertigo, Central OR Origin Vertigos, Central OR Vertigos, Central Origin OR CNS Origin Vertigo OR CNS Origin Vertigos OR Origin Vertigo, CNS OR Origin Vertigos, CNS OR Vertigo, CNS Origin OR Vertigos, CNS Origin OR Vertigo, Central Nervous System Origin OR Vertigo, Constant OR Constant Vertigo OR Constant Vertigos OR Vertigos, Constant #3 banxia baizhu tianma OR banxia baizhu tianma decoction OR banxia baizhu tianma tang OR banxia-baizhu tianma decoction OR banxia baizhu-tianma decoction OR banxia-baizhu tianma tang OR banxia baizhu-tianma tang OR banxia baizhu tianma* #4 Randomized controlled trial[Mesh] OR clinical study OR Clinical Trial OR Controlled study OR Controlled Trial OR Random* Control* study OR random* Control* Trial OR Meta-Analysis OR Multicenter Study OR blinding OR dummy control OR placebo control OR medical trial OR clinical research OR [Animals NOT (Animals AND Humans)] #5 #1 AND #2 AND #3 AND #4.

Appendix A. A. Search Strategies A. 1 Pubmed database #1 Vertebrobasilar Insufficiency[Mesh] OR Insufficiencies, Vertebrobasilar OR Insufficiency, Vertebrobasilar OR Vertebrobasilar Insufficiencies OR Vertebro-Basilar Ischemia OR Ischemia, Vertebro-Basilar OR Ischemias, Vertebro-Basilar OR Vertebro Basilar Ischemia OR Vertebro-Basilar Ischemias OR Vertebrobasilar Ischemia OR Ischemia, Vertebrobasilar OR Ischemias, Vertebrobasilar OR Vertebrobasilar Ischemias OR Vertebro-Basilar Insufficiency OR Insufficiencies, Vertebro-Basilar OR Insufficiency, VertebroBasilar OR Vertebro Basilar Insufficiency OR Vertebro-Basilar

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