Chinese medicinal herbs "Dan Shen" compound for acute myocardial infarction
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the effect (harms and benefits) of Dan Shen compound for acute MI. Specific comparisons will be made between Dan Shen compound and current standard treatment.
Background
EPIDEMIOLOGY AND NATURAL HISTORY
Literally, acute myocardial infarction is a focus of necrosis resulting from inadequate perfusion of the heart muscle (Sobel 1996). After approximately 3 to 6 hours the area of necrotic cardiac muscle reaches its largest size. The possible outcomes to patients following an infarction are survival, death from acute heart failure, death from heart rupture, development of heart complication as a result of replacement of infarcted tissue with fibrous scar tissue (Pathology 2001). The mortality of myocardial infarction will depends on the patient's sex and age (McIntyre 2001). Acute myocardial infarction (AMI) is the most important cause of morbidity from ischaemic heart disease (IHD) and is the leading cause of death in the western world. Each year approximately 800 000 persons in the United States experience acute MI, and about 213,000 of them die. At least one half of these persons die within 1 hour of onset of symptoms and before reaching a hospital emergency department(MVS 2002). For example every year over 1.5 million people in the USA suffer acute myocardial infarction and one third of these are hospitalised (Herlitz 1989; NHLBI 1992; MVS 2002)
DIAGNOSIS
Clinical diagnosis of acute myocardial infarction is usually based on clinical history includes severe and prolonged chest pain, ECG shows unequivocal changes and serum enzymes changes, especial Cardiac enzymes(WHO 1979). Currently myocardial infarction can be accurately diagnosed on the basis of clinical history and ECG evidence. However if the ECG evidence is unclear then cardiac enzymes such as troponin are used. However this means the patient must be admitted to hospital for monitoring to allow time for the Troponin level to rise, if it is going to. Troponin is therefore used with ECG evidence and not instead of, for the diagnosis of myocardial infarction (Anon 2001). Some complications of acute myocardial infarctions that can lead to death, such as cardiogenic shock, cardiac perforation ‐ external or interventricular, embolism, coronary heart failure, papillary muscle rupture, rhythm disturbances, pericarditis ‐ autoimmune (MVS 2002).
THERAPY
Drug therapy for AMI includes aspirin, morphine, thrombolytic therapy. In addition to the pharmacotherapy, there are some other measures such as: supplemental oxygen, continuous ECG monitoring, direct PTCA, bed rest for 24‐36 hrs and admission to cardiac care unit (MVS 2002).
DAN SHEN COMPOUND
The main ingredient of Dan Shen compound is the plant Dan Shen (Salvia miltiorrhiza). Three other plants are typically also present Crataegus laevigata (Hawthorn), Coleus forskohlii (an Indian herb) and Valeriana officinalis (Valerian).
Salvia miltiorrhiza or Dan Shen promotes blood circulation and relieves blood stasis (Bensky 1987). Dan Shen herb increases the activity of superoxide dismutase in platelets, thus providing protection against pulmonary embolism and inhibition of platelet aggregation. Other effects include cholesterol lowering, reduction of endothelial damage, inhibition of lipid peroxidation, inhibition of noradrenaline induced contraction of the aortic strips through reduction in calcium ion mobilization (Negard 1996; Wang 1996; Wu 1998).
Crataegus laevigata lowers blood pressure but can lead to arrhythmia in the ischaemic myocardium (Garjani 2000).
Valariana officinalis is used as a sedative, lowers blood pressure and relieves blood vessel spasm (BHMA 1983).
Coleus forskohlii inhibits platelet activation, increases force of contraction of heart muscle and lowers blood pressure.
Dan Shen compound can:
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dilate the coronary arteries and increase the coronary arterial blood flow (Sang 1979; Sun 1992);
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increase the deformability of white blood cell and reduce the adherence and so improve the flow of blood (Su 1991)
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protect cardiac muscle from ischaemia (Zhou 1991);
and together with its commonly included constituents (Crataegus laevigata, Coleus forskohlii andValeriana officinalis)
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can improve peripheral circulation and general well being.
The actions ofCrataegus laevigata are thought to be enhanced by Salvia miltiorrhiza (Dan Shen) and Coleus forskohlii. The relaxing and stress reducing actions of Valeriana officinalis are thought to further enhance the overall effect of this herbal compound. In addition there are other herbs which can be used with "Dan Shen compound" for example, "Dang Shen", "Huang Qi" and others.
REPORTED SIDE EFFECTS of DANSHEN
Reported side effects of Dan Shen are stomach discomfort, loss of appetite; itching; low blood pressure; increased risk of bleeding. If used in excess Dan Shen will cause bleeding for example from the skin, mucous membranes; dizziness; menorrhagia; headache and increased serum aminotransferases (Lu 1996).
Salvia miltiorrhiza may exaggerate the anticoagulant effect of warfarin (Chan 2001). Crataegus laevigata (hawthorn) may act synergistically with digitalis, cardiac glycosides and hypotensive drugs and the dose of concommitant medication may need to be modified.
Up to now, there have been some investigations about Dan Shen compound, such as the curative therapy of Wutoucishizhitang and Dan Shen compound injection for acute myocardial infarction (Xu 2001). They showed a markedly benefits and have been widely used clinically. But the quality and effects of these trials has not been systematically reviewed.
This review aims to summarise the existing evidence of comparative effectiveness and safety of Dan Shen compounds.
Objectives
To assess the effect (harms and benefits) of Dan Shen compound for acute MI. Specific comparisons will be made between Dan Shen compound and current standard treatment.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled studies with duration of intervention of at least seven days. If RCTs cannot be identified controlled trials will be considered.
Types of participants
Male or female of any age or ethnic origin with acute myocardial infarction. Diagnosis of acute myocardial infarction is the presence of unequivocal ECG changes and/or unequivocal enzyme changes; the history may be typical or atypical. Trials in which participants have complications of arrhythmia, heart failure, or shock will be included .
Types of interventions
(1) Dan Shen compound defined as drugs which contain Dan Shen;
(2) Dan Shen compound or other drugs containing Dan Shen will be compared with standard or usual care for acute myocardial infarction;
(3) Dan Shen compound or other drugs containing Dan Shen will be compared with usual pharmacotherapy;
(4) Dan Shen compound or other drugs containing Dan Shen will be compared with placebo;
(5) Dan Shen compound or other drugs containing Dan Shen will be compared with other Chinese herbal medicine.
When "Dan Shen" compound is used with other different drugs, the effective dose or route of administration of Dan Shen compound may vary. For example, if "Dan Shen" is used with "Dang Shen", "Huang Qi", the dose is 30g per recipe. But, if "Dan Shen" is used with "Chi Zhuo", "Yu Jin", the dose is 10ml or 20ml, in glycose solution.
Types of outcome measures
PRIMARY OUTCOMES MEASURES
Mortality: sudden death from acute myocardial infarction within 30 days.
SECONDARY OUTCOME MEASURES
(1) More severe degree and resolution of symptoms of angina such as chest distress, short breath, hypodynamia;
(2) Recurrent myocardial infarction;
(3) Quality of life;
(4) Readmission to hospital or use of revascularisation
ADVERSE EVENT OUTCOME MEASURES
Any adverse events as a result of treatment that are
(1) fatal;
(2) life threatening;
(3) cause a toxic response;
(4) cause anaphylaxis;
(5) result in the discontinuation of treatment.
Search methods for identification of studies
A comprehensive and exhaustive search strategy will be formulated in an attempt to identify all relevant studies regardless of language or publication status (published, unpublished, in press, and in progress).
ELECTRONIC SEARCHES:
The Cochrane Heart Review Group specialised trials register will be searched for relevant trials using the search term: 'Dan Shen'.
We will search the Cochrane Central Register of Controlled Trials (CENTRAL) using the search terms below .
We will also search other databases for completed and ongoing trials:
(1) MEDLINE (1995 to 2002);
(2) EMBASE (1995 to 2002);
(3) CBM (Chinese biomedical database, 199? to 2002);
(4) Chinese Cochrane Centre Controlled Trials Register (to 2002);
(5) Current Controlled Trials (www.controlled‐trials.com);
(6) The National Research Register (www.update‐software.com/National/nrr‐frame.html).
Search terms below will be used for CENTRAL and adapted appropriately for other databases:
#1 DANSHEN
#2 (DAN next SHEN)
#3 SALVIA*
#4 SAGE
#5 (((#1 or #2) or #3) or #4)
#6 MYOCARDIAL‐INFARCTION*:ME
#7 (MYOCARDIAL next INFARCT*)
#8 (ACUTE next CORONARY)
#9 (UNSTABLE near ANGINA)
#10 (HEART next ATTACK)
#11 (CORONARY near DISEAS)
#12 MYOCARDIAL‐ISCHEMIA*:ME
#13 AMI
#14 (((((((#6 or #7) or #8) or #9) or #10) or #11) or #12) or #13)
#15 (#5 and #14)
We will try to identify additional studies by searching the reference lists of relevant trials and reviews identified. Authors of identified studies will be sent a list of identified studies and asked to notify us of any other known published and unpublished work.
HANDSEARCHES:
We will handsearch the following Chinese traditional medicine Journals:
Acta Chinese Medicine and Pharmacology
Beijing Journal of Traditional Chinese Medicine
China Journal of Chinese Materia Medica
China Journal of Basic Medicine in Traditional Chinese Medicine
Chinese Journal of Integrated Traditional and Western Medicine
Chinese Journal of Integrated Traditional and Western Medicine in Intensive and Critical Care
Chinese Journal of Traditional Medical Science and Technology
Chinese Journal of Traditional & Western Medicine
Chinese Traditional Patent Medicine
Chinese Traditional Patent Medicine Research
Chinese Traditional Herbal Drags
Chinese Pharmaceutical Abstracts
Clinical Journal of Anhui Traditional Chinese Medicine
Forum on Traditional Chinese Medicine
Fujian Journal of Traditional Chinese Medicine
Guang Ming Zhong Yi Journal of Traditional Chinese Medicine
Gansu Journal of Traditional Chinese Medicine
Guangxi Journal of Traditional Chinese Medicine
Guangdong Journal of Traditional Chinese Medicine
Hebei Integrated Traditional and Western Medicine
Hebei Journal of Traditional Chinese Medicine
Heilongjang Journal of Traditional Chinese Medicine
Henan Journal of Traditional Chinese Medicine and Pharmacy
Henan Journal of Traditional Chinese Medicine
Hunan Journal of Traditional Chinese Medicine
Information on Traditional Chinese Medicine
Jiangxi Journal of Traditional Chinese Medicine
Jiangshu Journal of Traditional Chinese Medicine
Jilin Journal of Traditional Chinese Medicine
Journal of Anhui College of Traditional Chinese Medicine
Journal of Beijing University of Traditional Chinese Medicine
Journal of Chengdu University of Traditional Chinese Medicine
Journal of Chinese Medicinal Materials
Journal of Emergency in Traditional Chinese Medicine
Journal of Guangzhou University of Traditional Chinese Medicine
Journal of HeNan College of Traditional Chinese Medicine
Journal of Integrated Traditional and Western Medicine
Journal of Practical Traditional Chinese Medicine
Journal of Practical Chinese Traditional Internal Medicine
Journal of Sichuan of Traditional Chinese Medicine
Journal of Traditional Chinese Medicine
Journal of Emergency Syndromes in Chinese Medicine
Journal of Nanjing college of Traditional Chinese Medicine
Journal of Hubei college of Traditional Chinese Medicine
Journal of Guiyang college of Traditional Chinese Medicine
Journal of Gansu college of Traditional Chinese Medicine
Journal of Changchun college of Traditional Chinese Medicine
Journal of Yunnan college of Traditional Chinese Medicine
Journal of Tianjin college of Traditional Chinese Medicine
Journal of Liaoning college of Traditional Chinese Medicine
Journal of Hujian college of Traditional Chinese Medicine
Journal of Jiangxi college of Traditional Chinese Medicine
Journal of Shandong college of Traditional Chinese Medicine
Journal of Hebei college of Traditional Chinese Medicine
Journal of Zhejiang college of Traditional Chinese Medicine
Journal of Shanghai University of Traditional Chinese Medicine
Journal of the Traditional Chinese Medicine
Journal of University of Traditional Chinese Medicine
Liaoning Journal of Traditional Chinese Medicine
Modern Journal of Integrated Chinese Traditional and Western Medicine
Modern Traditional Chinese Medicine
Neimongol Journal of Traditional Chinese Medicine
New Jounal of Traditional Chinese Medicine
Pharmacology and Clinics of Chinese Materia Medica
Research of Traditional Chinese Medicine
Shanxi Journal of Traditional Chinese Medicine
Shanxi Journal of Traditional Chinese Medicine
Shandong Journal of Traditional Chinese Medicine
Shanghai Journal of Traditional Chinese Medicine
Shenzhen Journal of Integrated Traditional and Western Medicine
Tianjin Journal of Traditional Chinese Medicine
Traditional Chinese Medicine Research
Xinjiang Journal of Traditional Chinese Medicine
Yunnan Journal of Traditional Chinese Medicine and Materia Medica
Zhejiang Journal of Traditional Chinese Medicine
OTHER SEARCH STRATEGIES:
Organisations (including the World Health Organization), individual researchers working in the field, and medicinal herbs manufacturers will be contacted in order to obtain additional references, unpublished trials, or ongoing trials, confidential reports and raw data of published trials. Studies published in any language will be included.
Data collection and analysis
SIFTING RESULTS OF SEARCHES
The numbers of hits from all searches will be recorded and results from searching electronic databases will be stored using reference management software.
TRIALS SELECTION
To determine the studies to be assessed further, we will scan the titles, abstract sections and keywords of every record retrieved. Full articles will be retrieved for further assessment if the information given suggests that the study:
(1) Includes patients with acute MI;
(2) Compares Dan Shen compound with any other active intervention;
(3) Assesses one or more relevant clinical outcome measure;
(4) Uses random allocation to the comparison groups.
If there is any doubt regarding these criteria from the information given in the title and abstract, the full article will be retrieved for clarification. Interrater agreement for study selection will be measured using the kappa statistic (Cohen 1960). Where differences in opinion exist, they will be resolved by discussion. If resolving disagreement is not possible, the article will be added to those 'awaiting assessment' and the authors will be contacted for clarification. If no clarification is provided, the Cochrane Heart Group editorial base will be consulted.
QUALITY ASSESSMENT OF TRIALS
Each area of quality should be considered separately and sensitivity analyses conducted for each area in turn. In particular, the following factors will be studied:
(1) Minimisation of selection bias ‐ a) was the randomisation procedure adequate? b) Was the allocation concealment adequate?
(2) Minimisation of performance bias ‐ were the patients and people administering the treatment blind to the intervention?
(3) Minimisation of attrition bias ‐ a) were withdrawals and dropouts completely described? b) Was analysis by intention‐to‐treat?
(4) Minimisation of detection bias ‐ were outcome assessors blind to the intervention?
Based on these criteria, studies will be broadly subdivided into the following three categories:
A ‐ all quality criteria met: low risk of bias.
B ‐ one or more of the quality criteria only partly met: moderate risk of bias.
C ‐ one or more criteria not met: high risk of bias.
This classification will be used as the basis of a sensitivity analysis. Additionally, we will explore the influence of individual quality criteria in a sensitivity analysis.
Each trial will be assessed by two reviewers independently (Ni, Wu). Interrater agreement will be calculated using the kappa statistic, and disagreements will be resolved, where necessary, by recourse to a third reviewer (Wei). In cases of disagreement, the rest of the group will be consulted and a judgement will be made based on consensus, and we will keep a record of this using reference management software such as ProCite.
DATA EXTRACTION
Data concerning details of study population, intervention and outcomes will be extracted independently by two reviewers (Ni, Wu) using a form designed specifically for the purpose. We will collect the following information:
(1) General information: published/unpublished, title, authors, reference/source, contact address, country, urban/rural etc., language of publication, year of publication, duplicate publications, sponsor, setting;
(2) Trial characteristics: design, duration of follow up, method of randomisation, allocation concealment, blinding (patients, people administering treatment, outcome assessors);
(3) Intervention(s): intervention(s) (dose, route, timing), comparison intervention(s) (dose, route, timing), co‐medication(s) (dose, route, timing);
(4) Patients: exclusion criteria, total number and number in comparison groups, age (adults), baseline characteristics, diagnostic criteria, similarity of groups at baseline (including any co‐morbidity), assessment of compliance, withdrawals/losses to follow‐up (reasons/description), subgroups;
(5) Outcomes: outcomes specified above, any other outcomes assessed, other events, length of follow‐up, quality of reporting of outcomes;
(6) Results: for outcomes and times of assessment (including a measure of variation), if necessary converted to measures of effect specified below, intention‐to‐treat analysis.
Differences in data extraction will be resolved by consensus, referring back to the original article. When necessary, information will be sought from the authors of the primary studies.
Data from reports of trials will be transcribed by two people independently (Ni and Wu). Disagreement will be resolved by discussion and, where necessary, in consultation with a third reviewer (Wei). For binary outcomes, number of events and total number in each group will be extracted. For continuous outcomes, mean, standard deviation and sample size of each group will be abstracted or imputed.
DATA ANALYSIS
Data will be included in a meta‐analysis if they are available, of sufficient quality and sufficiently similar. Only randomised controlled trials will be included in a meta‐analysis. We expect both event (dichotomous) data and continuous data. Dichotomous data will be expressed as relative risks (RR). They may be converted to absolute measures like the number needed to treat if doses and follow‐up times are similar. Continuous data will be expressed as weighted mean differences (WMD). Overall results will be calculated based on the random effects model. Heterogeneity will be tested for using the Z score and the Chi square statistic with significance being set at p < 0.1. Possible sources of heterogeneity will be assessed by sensitivity and subgroup analyses as described below. Small study bias will be tested for using the funnel plot or other corrective analytical methods depending on the number of clinical trials included in the systematic review.
SUBGROUP ANALYSES
We will aim to perform subgroup analyses in order to explore effect size differences as follows:
(1) Duration of follow‐up ( 4 weeks versus >5 weeks);
(2) Patients with Asian ethnic origin compared with those of non‐Asian origin;
(3) Dose (low, medium, high ‐ based on data).
SENSITIVITY ANALYSES
We will perform sensitivity analyses in order to explore the influence of the following factors on effect size:
(1) Repeating the analysis excluding unpublished studies (if there were any);
(2) Repeating the analysis taking account of study quality, as specified above;
(3) Repeat the analysis excluding studies using the following filters: diagnostic criteria, language of publication, source of funding (industry versus other), country.
The robustness of the results will also be tested by repeating the analysis using different measures of effects size (risk difference, odds ratio etc.) and different statistic models (fixed and random effects models).
