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Chuanxiong type compounds for preventing cardiovascular diseases

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Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To assess the effects and safety of Chuanxiong compounds in preventing acute stroke in adults at high risk of stroke.

Background

Stroke (cerebrovascular accident) is divided into two types according to its underlying pathology. Ischaemic stroke is caused by a blocked arterial blood vessel, whereas haemorrhagic stroke is due to an arterial blood vessel rupture in, or surrounding, the brain (ASA 2005). Several risk factors are common to both types of stroke and include gender, increasing age, family history, race, hypertension, blood disorders, excessive alcohol, and drug abuse. Risk factors for ischaemic stroke are similar to those for ischaemic heart disease and include raised blood cholesterol, smoking, pre‐existing markers of atherosclerosis, and diabetes mellitus (ASA 2005). Recent studies also indicate that the risk of stroke may be higher in women during pregnancy and the 6 weeks following childbirth. For every five deaths from stroke, two occur in men and three in women (ASA 2005).

Stroke is the third leading cause of death after heart disease and cancer, and the first leading cause of serious, long‐term disability in the United States, Canada and Japan (Bonita 1990, ASA 2005). There are about 600,000 new strokes each year in the European Union (EUSI 2007), and nearly 163,000 people die from stroke each a year in USA (ASA 2005). In 2005, the economic burden of stroke‐related medical costs and disability was estimated as 56.8 billion US dollars in United States (AHA 2005). Stroke causes about 10% of all deaths and about 25% of all chronic disability in Australia (NHMRC 1996). In China, the incidence of stroke varies widely from 40 to 3300 per 100,000 in populations aged greater than 40 years, and stroke death rates were 108 to 130 per 100,000, the second highest in the world (Yan 1998). In China there are 1.5 million new strokes occurring each year and about 6 million people currently suffering with stroke (Wang 2004; Wu 1994; Wu 2001). Furthermore, there is evidence of an increasing trend in the age standardised incidence of stroke (Wu 2001).

Prevention is considered to be the best approach to reducing the burden of stroke (Goldstein 2001; Gorelick 1995; NHMRC 1996). The primary prevention strategy for stroke aims to change lifestyles among those who are at high risk of stroke through health education and control of risk factors. Relevant interventions include: regular screening and treatment for hypertension in adults; smoking cessation advice or support for all current smokers; among diabetics careful control of hypertension and glycaemia control to reduce microvascular complications; antithrombotic therapy for patients with nonvalvular atrial fibrillation based on an assessment of their risk of embolism and risk of bleeding complications; weight reduction in overweight persons on the basis of the associated increase in co‐morbid conditions that can lead to stroke; promotion of a healthy diet containing at least five daily servings of fruits and vegetables; no more than two alcoholic drinks per day for men and one drink per day for nonpregnant women. For those with a past history of ischaemic stroke or transient ischaemic attack, antithrombotic treatment with aspirin is indicated (BMJ 2002; NHMRC 1996). The role of aspirin in primary prevention among those at high risk of cardiovascular events is now established but remains controversial among people at intermediate and low risk (Ridker 2005). A Cochrane review showed that anticoagulants are beneficial and without serious adverse effects for people with nonrheumatic atrial fibrillation and recent cerebral ischaemia (Saxena 2004).

Traditional Chinese medicine Chuanxiong is the dried root of the plant Szechuan lovage, Latin botanical name Ligusticum chuanxiong Hort. The main active ingredients of Chuanxiong are ferulic acid and tetramethylpyrazine (ligustrazine) (Tang 1999; Xiao 2002). These two elements have significant effects of inhibiting platelet aggregation, reducing both blood viscosity and haematocrit (Gao 1989; Lin 1991; Tan 2003; Xiao 1994), increasing the level of superoxide dismutase (SOD), reducing malonaldehyde (MDA) and increase nitrogen monoxide (NO) concentration in both hypoxic and ischaemic damaged brain (Huang 2004) and in endothelial cells affected by both hypoxia and reduced glucose (Lin 2004). Ligustrazine also can dilate blood vessels, lower blood pressure, inhibit thrombosis, regulate lipid metabolism, and is a calcium antagonist (Chen 1999), and may prevent and reverse atherosclerosis (Mei 2004).

The available preparations of Chuanxiong compounds have different constituents, but most are based on the formulation "Bu Yang Huan Wu Tang" including Chuanxiong, Huangqi (radix astragali), Danggui (Chinese angelica), Honghua (safflower), Chishao (red paeony root), Dilong (earthworm), and Taoren (peach seed). Chuanxiong may be prepared as a capsule, a water‐based injection, or as decoction (a kind of herb soup). Although the effects of Chuanxiong may vary depending on its constituents and mode of use, some evidence suggests broadly similar effects for all preparations. For example, Nao‐an capsule, used for preventing stroke, consists of Chuanxiong, Danggui (Chinese angelica), Honghua (safflower) and Ren‐shen (ginseng), and has been shown to inhibit thrombosis induced by adenosine diphosphate (ADP) better than aspirin (Chen 1998a), and improve haemodynamic status compared with a control group in patients at high risk of stroke (Wang 2004). It also reduces brain arterial blood vessel resistance (Chen 1998b). Another preparation "Zhong Fang" powder consists of Chuanxiong, Huangqi (radix astagali), Cangzu (Chinese atractylodes rhizome), and Puhuang (cattail pollen), but appears to have similar effects to Nao‐an capsule (Zhou 1999). Chuanxiong and Danggui both contain the active element Ferulic acid (aweishuan) and are often used together in prevention of treatment of cardiovascular diseases. A companion protocol on the use of Chuanxiong compounds for treatment of stroke has been published (Jia 2006).

Although herbal medicine treatment, and its method of manufacture, is widely accepted in China, most of the constituents of the pharmacological preparations used in trials cannot be specified precisely. This is in marked contrast to industrially manufactured pharmacological agents used in Western medicine, in which the chemical constituents, their quantities, and the percentage of any impurities or contaminants, are very precisely known, and the variation between different production batches is kept within specified limits. Variation between formulations and batches of treatments is an inevitable consequence of the nature of Chinese traditional medicine (though the government also specifies the limits of variation that are acceptable). This variation is a factor that may contribute to any heterogeneity between different study results. Furthermore, one must accept that the overall treatment concept for Chinese traditional medicine is different to Western medicine.

While there is some evidence to suggest plausible biological mechanisms whereby Chuanxiong and its compounds might reduce the incidence of stroke in high risk people, the evidence relating to clinical outcomes is currently limited. There is also evidence to indicate that not all herbal medicine is free from harm. There are concerns regarding adverse events, e.g. allergic reactions and Chinese herbal nephropathy (CHN) (Lampert 2002; Lord 2001; Nortier 2000). Despite these concerns, herbal medicines are widely used. In this systematic review we wish to answer the question of whether the available clinical evidence supports the use of Chuanxiong and/or its compounds for preventing stroke.

Objectives

To assess the effects and safety of Chuanxiong compounds in preventing acute stroke in adults at high risk of stroke.

Methods

Criteria for considering studies for this review

Types of studies

All randomised controlled trials (RCTs) (published or unpublished) comparing Chuanxiong compounds with placebo or open control (no placebo) or other drugs in the prevention of acute stroke will be included.

Types of participants

Trials including participants at high risk of stroke will be eligible. High stroke risk will be defined as having one or more of the following factors: hypertension, heart disease, history of diabetes, family history of hypertension and/or stroke, smoking or raised blood cholesterol.

Types of interventions

Chinese preparations containing Chuanxiong, Danggui and Aweishuan alone or in combination. Chinese medicinal herbs Chuanxiong (Rhizoma Chuanxiong) versus placebo or control; Danggui (Radix Angelicae Sinensis) versus placebo or control; mixed herbal preparations containing ferulic acid versus placebo or control. Chuanxiong compounds compared with other Chinese herbal treatments for stroke prevention will also be included. All regimens whatever the dose or intervention duration, capsule or decoction or other forms of the Chuanxiong type compounds will be included.

Types of outcome measures

Primary outcomes
1. Fatal or non‐fatal stroke.
2. Composite clinical cardiovascular outcomes (fatal and non‐fatal stroke, myocardial infarction, revascularisation, endarterectomy).

Secondary outcomes
1. Cardiovascular risk factors: blood pressure (systolic, diastolic), lipids (cholesterol, triglycerides, LDL‐cholesterol, VLDL‐cholesterol, HDL‐cholesterol), blood glucose.
2. Cerebrovascular haemodynamic indexes (CVDI): cerebrovascular blood flow speed (Vmax, Vmin, Vmean), RV ( peripheral resistance), Zcv (specific resistance), WV (pulse wave speed), DR (dynamic resistance), CP (crisis pressure).

Adverse effects
We will define serious adverse events according to the ICH Guidelines (ICH‐GCP 1997) as any event that led to death, was life‐threatening, required in‐patient hospitalisation or prolongation of existing hospitalisation, resulted in persistent or significant disability, and any important medical event, which might have jeopardised the patient or required intervention to prevent it. All other adverse events were to be considered non‐serious. All non‐serious adverse events will be documented in detail.

Search methods for identification of studies

We will search the Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library, MEDLINE (1966 to present), EMBASE (1980 to present), AMED (the Allied and Complementary Medicine Database, 1985 to present) and the China Biological Medicine Database (CBM‐disc, 1979 to present), VIP Chinese Journals Database (1968 to present), CNKI China National Knowledge Infrastructure Whole Article Database (1994 to present). We will also search the trials registers of the Cochrane Stroke Group and the Cochrane Complementary Medicine Field as well as the Chinese Stroke Trials Register.

The following search strategy will be used for CENTRAL and will be modified to search the other databases, in combination with terms for finding RCTs on MEDLINE (Dickersin 1994) and EMBASE (Lefebvre 1996)

#1 MeSH descriptor Ligusticum explode all trees
#2 MeSH descriptor Angelica explode all trees
#3 chuanxiong
#4 chuan‐xiong
#5 tetramethylpyrazine
#6 ligustic*
#7 "ferulic acid"
#8 lovage
#9 Ligustrazin*
#10 aweishuan
#11 danggui
#12 "Dong Quai"
#13 Tang‐Kuei
#14 "sodium ferulate"
#15 Bu yang huan wu tang
#16 nao an capsule
#17 zhong fang
#18 (#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17)

We will also search relevant research databases including the Stroke Trials Directory (http://www.strokecenter.org/trials/), the National Center for Complementary and Alternative Medicine (http://www.nccam.nih.gov/clinicaltrials/), the National Institute of Health Clinical Trials Database (http://www.clinicaltrials.gov/) and HERBMED (http://www.herbmed.org). We plan to handsearch appropriate journals, and stroke and vascular surgical conference proceedings to identify further studies. All reference lists of retrieved articles will also be searched.

No language restrictions will be applied.

Data collection and analysis

Study selection
Two review authors (YCZ, ZXX) will independently select relevant articles and assess their eligibility according to the inclusion and exclusion criteria, resolving any disagreements by discussion. The third review author (WTX) will be consulted if necessary. We will obtain the full text for those articles identified as either relevant or possibly relevant from their titles and abstracts. Only those studies that meet the pre‐determined inclusion criteria will be included.

Quality assessment
Methodological quality will be assessed independently by at least two authors using the following criteria that are described in the Cochrane Handbook for Systematic Reviews of Interventions 4.2.5 (Higgins 2005) and by Wu 2007:

(1) Randomisation (true or quasi randomisation).
(2) Allocation concealment: adequate; inadequate; unclear.
(3) Blinding: blinding of investigator; blinding of participant; blinding of outcome assessor.
(4) Completeness of follow‐up.

Disagreements between authors arising at any stage will be resolved by discussion or with a third party when necessary

Data extraction
Data concerning details of patients' characteristics, study methods, interventions, and outcomes will be extracted independently by two authors using a data extraction form. Disagreement will be resolved by discussion. Where possible missing data will be obtained from the authors of the original articles.

Data synthesis
The primary analysis will be, for all adequately randomised trials, a comparison of primary outcomes in those treated with Chuanxiong preparation or compounds versus placebo or open control. Comparison of Chuanxiong preparations or compounds with other active treatments will be analysed separately.

If data are sufficiently similar, meta‐analysis will be carried out using Review Manager software (RevMan 4.2). Results will be expressed as relative risks with 95% confidence intervals (CI) for dichotomous outcomes. For continuous outcomes weighted mean difference (WMD) or the standardised mean difference (SMD) will be used. A fixed‐effect model will be used unless there is significant heterogeneity. If heterogeneity is present efforts will be made to examine the causes of this, in terms of trial design and quality, differences in intervention, or included participants, using sub‐group and sensitivity analyses where appropriate. A random‐effects model will be used if pooling is thought appropriate. Tests for homogeneity will be carried out using Chi‐square test with significance being set at P > 0.1 and I‐square (I2) will be used to estimate total variation across studies due to heterogeneity in percentage. Less than 25% will be considered as low level heterogeneity, 25% to 50% as moderate level, and higher than 50% as high level heterogeneity (Higgins 2003).

We intend to explore the following potential sources of heterogeneity using subgroup analyses or meta‐regression.
(1) Intervention (different compounds or different comparisons, for instance, Nao‐an capsule or Zhong Fang powder versus placebo or other active drugs, etc.)
(2) Dose (low, medium, high) .
(3) Duration of treatment (less than 1 year; 1 year or longer).
(4) Effects in those without previous history of cardiovascular disease compared with those with a previous history.