Tongxinluo capsule for unstable angina pectoris
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the effect (harms and benefits) of Tongxinluo capsule for unstable angina. Specific comparisons will be made between Tongxinluo capsule and current standard treatment regime.
Background
Angina is a common presenting symptom (typically chest pain) among patients with coronary artery disease (Bernard 1979; Braunwald 1994). Myocardial ischaemia develops when coronary blood flow becomes inadequate to meet myocardial oxygen demand. This will cause myocardial cells to switch from aerobic to anaerobic metabolism with a progressive impairment of metabolic, as well as mechanical and electrical, function. Angina pectoris is the most common clinical manifestation of myocardial ischaemia. It is caused by the chemical and mechanical stimulation of the sensory afferent nerve endings in the coronary vessels and myocardium. These nerve fibres extend from the first to fourth thoracic spinal nerves, ascend via the spinal cord to the thalamus and from there to the cerebral cortex. Angina often occurs when the heart needs more blood. Angina may happen during exercise, strong emotions or extreme temperatures. Some people, such as those with a coronary artery spasm, may have angina when resting. Angina is a sign that someone is at increased risk of heart attack, cardiac arrest or sudden cardiac death (Bernard 1979; Braunwald 1994).
Ischaemic heart disease is the most common cause of death in the Western countries, where it amounts to almost 33% of overall mortality (Braunwald 1992). The "first clinical sign" in over half of patients is angina pectoris. In recent years, an increasing tendency of ischaemic heart disease incidence has arisen in developing countries and this coincides with their economic development. For example in Beijing, China, the mortality of this disease increased from 21.7/100,000 in 1970 to 62.0/100,000 in 1980 (Chen 2000).
UNSTABLE ANGINA
Unstable angina is defined as new onset (within 2 months of initial presentation) angina of at least class III severity (CCS 1972), significant recent increase in frequency and severity of angina, or angina at rest (Chen 2000). De novo effort angina, worsening effort angina, and spontaneous angina are frequently referred to as "unstable angina"(Bernard 1979; Chen 2000). Most people with angina can live for many years, but the risk of acute myocardial infarction (AMI) and sudden death is increased. This is particularly true for patients with unstable angina where the risk is much higher (Chen 2000).
In people with unstable angina, chest pain is unexpected and usually occurs while at rest. The discomfort may be more severe and prolonged than typical angina, or it may be the first time a person experiences angina. The most common cause is reduced blood flow to the heart muscle due to narrowing of the coronary arteries by atherosclerosis. An artery may be abnormally constricted or partially blocked by a blood clot. Inflammation, infection and other secondary causes can also lead to unstable angina (Braunwald 1994).
Unstable angina is an acute coronary syndrome and should be treated as an emergency. People with new, worsening or persistent chest discomfort should be monitored carefully. They are at increased risk of acute myocardial infarction (heart attack) and severe cardiac arrhythmias. These may include ventricular tachycardia and fibrillation, or cardiac arrest leading to sudden death (Bernard 1979; Braunwald 1994).
PHARMACOTHERAPY
The main goals of treatment in patients with angina pectoris, including unstable angina, are relief of symptoms, slow down of progression of disease, and reduction of future events, especially myocardial infarction and death (Braunwald 1994).
Sublingual nitroglycerin has been the mainstay of treatment for angina pectoris. Sublingual nitroglycerin can be used both for acute relief of angina as well as prophylactically i.e. before activities that may precipitate angina. No evidence exists that long acting nitrates improve survival in patients with coronary artery disease(Braunwald 1994).
Beta‐blockers are also used for symptomatic relief of angina and prevention of ischaemic events. These work by reducing myocardial oxygen demand by decreasing heart rate and myocardial contractility. It has been shown that beta‐blockers reduce mortality and morbidity following acute myocardial infarction (Braunwald 1994).
Long‐acting heart‐rate slowing calcium channel blockers can be used to control anginal symptoms in patients with a contraindication to beta‐blockers as well as those in whom symptomatic relief of angina cannot be achieved with use of beta‐blockers, nitrates or their combination. However short‐acting dihydropyridine calcium channel blockers should be avoided because they have been shown to increase the risk of adverse cardiac events (Braunwald 1994).
Anginal symptoms in patients with Prinzmetal angina can be treated with calcium channel blockers with or without nitrates. In patients with syndrome X and hypertension, ACE inhibitors may normalise thallium perfusion defects and increase exercise capacity (Braunwald 1994).
TONGXINLUO CAPSULE: A CHINESE HERBAL MEDICINE IN THE TREATMENT OF HEART DISEASE
Chinese herbal medicine is part of Traditional Chinese Medicine (TCM), which is a 3000‐year‐old holistic system of medicine combining the use of medicinal herbs, acupuncture, food therapy, massage and therapeutic exercise for both the treatment and prevention of disease (Fulder 1996). TCM has unique theories for concepts of etiology, systems of diagnosis and treatment, which are vital to its practice. TCM drug treatment consists typically of complex prescriptions of a combination of several components. The combination based on the Chinese diagnostic patterns (i.e., inspection, listening, smelling, inquiry, and palpation) follows a completely different rationale than many western drug treatments (Liu 2002).
Tongxinluo capsule is a new drug (studied clinically since 1995) for cardio‐cerebral vascular diseases. It is on the national essential drug list of China, and has the second‐class award of the National Science and Technology Development of China, 2001(Anon 2002). The compositions of Tongxinluo capsule includes Radix ginseng, Scorpio, Hirudo, Eupolyphaga seu steleophage, Scolopendra, Periostracum cicadae, Radix paeoniae rubra, and Borneolum syntheticum. (Liu 1997; Wu 2001; Anon 2002). These materials are prepared as capsule (Wu 2001).
Pharmacological studies show that
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Radix ginseng strengthens cardiac contractility, increases cardiac output, has a cardiokinetic function (Jin 1983; Jiang 1985; Pei 1986), slows heart rate (Yuan 1983; Gu 1983; Pei 1986), dilates blood vessels, is an anticoagulant and inhibits platelet adhesion reaction (Xu 1988a).
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Hirudo acts as an anticoagulant (Ou 1987) is thrombolytic, reduces viscosity of whole blood (Xu 1988b), is anti‐myocardial ischaemia (Zhang 1978; Li 1989), reduces cholesterol and is anti‐atherosclerotic in action (Wu 1994).
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Periostracum cicadae is anticonvulsive and significantly slows heart rate (Anon 1960).
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Scolopendra extraction apparently strengthens cardiac contractility, decreases blood pressure, and increases blood vessel perfusion flow (Chen 1985).
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Radix paeoniae rubra has diuretic activity, is strongly anticoagulant, can prevent thrombosis, and clearly inhibit the formation of platelet and fibrin thrombi (Nu 1983; Deng 1991). It can also apparently directly dilate the coronary artery, has strong anti‐myocardial ischaemia functions, changes the compostion of lipoprotein, reduces calcium ion sediments on the arterious parietes and reduces atherosclerosis (Wang 1980; Zhang 1990).
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Eupolyphaga seu steleophage increases cardiac output and improve tolerance of hypoxia (Nong 1989; Yang 1989).
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Borneolum syntheticum are analgesia and sedation (Wu 2001).
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Scorpio is used in traditional Chinese medicine mainly for hypertension, apoplexy, arteriosclerosis, some nervous system diseases, various swellings and infections (Wang 1998). These compositions and their pharmacological action are listed in Table 1 with Latin and common names.
| Latin name | Common name | Pharma. actions |
| Radix ginseng | Ren shen | strengthens cardiac contractility, increasing cardiac output, and has cardiokinetic function, slows heart rate down, dilates blood vessel, anticoagulation, inhibits platelet adhesion reaction |
| Scorpio | Scorpion | treatment of hypertension, apoplexy, arteriosclerosis, some nervous system diseases, various tumefaction and infections |
| Hirudo | Leech | anticoagulation, thrombolysis, reduces viscosity of whole blood, antimyocardial ischemia, induces cholesterol and anti‐atherosclerosis |
| Eupolyphaga seu steleophage | Eupolyphaga sinensis walk, Ground beetle | increase cardiac output, improve tolerance of hypoxia |
| Scolopendra | Centipede | strengthens cardiac contractility, decreases blood pressure, and increases blood vessel perfusion flow |
| Periostracum cicadae | Cicada slough | anticonvulsion and slows heart rate down |
| Radix paeoniae rubra | The root of common peony | anticoagulation and prevents thrombosis functions, and obviously inhibits to form platelet and fibrin thrombus, dilate coronary artery directly, has strong anti‐myocardial ischemia function, and change the contents of lipoprotein, deduce calcium ion sediments on the arterious parietes, anti‐atherosclerosis |
| Borneolum syntheticum | Borneol | analgesia and sedation |
In experimental studies on animal models, Tongxinluo improved myocardial ischaemia, prevented the occurrence of arrhythmia and hyperlipidaemia, increased coronary arterial blood flow, dilated the coronary vessels, improved myocardial blood supply and increased left ventricular work resulting in the enhancement, readjustment of the "pump" function of heart and improvement of the intravascular stasis condition of blood circulation (Liu 1997; Shang 1997).
Tongxinluo capsule is used in the treatment of angiocardiopathy and cerebrovascular disease and is administered in capsules containing between 1.14g to 1.52g 3 to 4 capsules at a time 3 times per day, a total dose of between 3.5g to 6.0g per day. Treatment is given in a four week course (Wu 2001). Some adverse events such as slight gastrointestinal tract reaction, gingival bleeding, and partial thromboplastin time longer than normal been observed in a clinical trial (Nong 2000). The effectiveness and adverse effects of such treatment needs to be reviewed systematically and appraised critically to inform the current practice and direct the continued search for new treatment regimens.
Objectives
To assess the effect (harms and benefits) of Tongxinluo capsule for unstable angina. Specific comparisons will be made between Tongxinluo capsule and current standard treatment regime.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials will be examined, but in their absence, any controlled study will be included. To assess any harms of treatment case series or case reports will be used.
Types of participants
Participants will be male or female of any age or ethnic origin with unstable angina. Diagnostic criteria such as the Joint International Society and Federation of Cardiology/World Health Organization Task Force on Standardization of Clinical Nomenclature definition (Bernard 1979) or the Canadian Cardiovascular Society modification (CCS 1972) will be acceptable.
Participants will be excluded if they have acute myocardial infarction, heart failure, hepatic failure and renal failure.
Types of interventions
Tongxinluo capsule or other types of Tongxinluo will be compared with standard treatment, other anti‐angina pectoris drugs, placebo or no intervention. If participants suffer an attack of angina pectoris during the trial, nitroglycerin may be used. This use (and dosage) should be recorded as an outcome measure.
Types of outcome measures
We will consider the following outcome measures:
PRIMARY OUTCOME MEASURES
(1) Mortality: sudden death and/or acute myocardial infarction.
SECONDARY OUTCOME MEASURES
(1) Severity of angina pectoris;
(2) Frequency of acute attack angina;
(3) ECG improvement;
(4) Rate of dosage/frequency of use of nitroglycerine;
(5) Symptom improvement (such as chest distress, short breath, hypodynamia, etc);
(6) Levels of serum cardiac troponin T (cTnT), creatine kinase (CK) and isoenzyme MB (CK‐MB);
(7) Levels of plasma endothelin level and nitric oxide;
(8) Health‐related quality of life (ideally, using a validated instrument).
ADVERSE EVENT OUTCOME MEASURES
Any adverse events as a result of treatment that are (1) a cause of mortality, (2) life threatening, (3)a toxic response, for example, sever gastrointestinal tract reaction, gingival bleeding, and partial thromboplastin time longer than normal, (4) anaphylatic or (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). Since clinical trials of Tongxinluo have only been performed from 1995, our search will cover the duration of 1995 to 2003.
ELECTRONIC SEARCHES:
The Cochrane Heart Review Group specialised trials register will be searched for relevant trials using the search terms: 'Tongxinluo', 'TXLC' and 'TXL'.
We will search The Cochrane Central Register of Controlled Trials (CENTRAL), published in the latest issue of the Cochrane Library using the search terms: 'Tongxinluo', 'TXLC' and 'TXL'.
The following electronic databases will also be searched:
(1) MEDLINE (1995 to 2003) using the search terms: 'Tongxinluo', 'TXLC', and 'TXL';
(2) EMBASE (1995 to 2003) using the search terms: 'Tongxinluo', 'TXLC' and 'TXL';
(3) CBM (Chinese biomedical database, 1995 to 2003);
(4) Chinese Cochrane Centre Controlled Trials Register (1995 to 2003).
We will also search databases of ongoing trials:
Current Controlled Trials (www.controlled‐trials.com)
The National Research Register (www.update‐software.com/National/nrr‐frame.html)
HANDSEARCHES:
We will handsearch the following Chinese traditional medicine Journals (1995 to 2003):
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
Journal of Emergency in Traditional Chinese Medicine
Journal of Integrated Traditional and Western Medicine
Journal of Traditional Chinese Medicine
Journal of Emergency Syndromes in Chinese Medicine
Modern Journal of Integrated Chinese Traditional and Western Medicine
Modern Traditional Chinese Medicine
New Journal of Traditional Chinese Medicine
Traditional Chinese Medicine Research
We will try to identify additional studies by searching the reference lists of relevant trials and reviews identified. Authors of identified studies will be contacted.
OTHER SEARCH STRATEGIES:
Organizations (including the World Health Organization), individual researchers working in the field, and medicinal herbs manufacturers will be contacted in order to obtain any additional references to unpublished trials, ongoing trials, confidential reports or raw data of published trials. Studies published in any language will be included.
Data collection and analysis
TRIALS SELECTION:
To determine the studies to be assessed further, eight people will scan the titles, abstracts 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 unstable angina;
(2) Compares Tongxinluo with any other active or placebo intervention;
(3) Assesses one or more relevant clinical outcome measure;
(4) Uses random or pseudo 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 by 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 review group editorial base will be consulted.
QUALITY ASSESSMENT OF TRIALS:
The following three areas will be addressed, since there is some evidence that these are associated with biased estimates of treatment effect (Juni 2001):
(1) randomisation (method of generation and concealment of allocation);
(2) masking (blinding of observers / participants to the treatment allocation);
(3) loss to follow‐up (presence of dropouts and withdrawals, and the analysis of these).
The quality assessment will include an evaluation of the following components for each included study. Each component will be categorised as Adequate, Unclear, or Inadequate. The randomisation criteria will be as suggested by Juni (Juni 2001).
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Randomisation (allocation generation) ‐ adequate when the allocation sequence protects against biased allocation to the comparison groups
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Randomisation (allocation concealment) ‐ adequate when clinicians and participants are unaware of future allocations
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Masking ‐ adequate when the outcome assessor is unaware of the allocation
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Loss to follow up ‐ adequate when more than 80% of participants are followed up, then analysed in the groups to which they were originally randomised (intention to treat)
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 (WU, ZHOU). 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 (WU, ZHOU) using a data extraction form. A data abstraction form will by specifically designed for this review. Data on participants, interventions, and outcomes, as described above, will be abstracted. The data extraction form will include the following items:
(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.
Original reports of trial results will be independently abstracted by WU and ZHOU. 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, such as 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) Early outcomes (ideally <7 days) compared with late outcomes (7+ days).
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 (Chinese language papers will more likely be positive than English language ones) (Liu 2002), industry funded, 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). A funnel plot will be used to examine the possibility of publication bias.
| Latin name | Common name | Pharma. actions |
| Radix ginseng | Ren shen | strengthens cardiac contractility, increasing cardiac output, and has cardiokinetic function, slows heart rate down, dilates blood vessel, anticoagulation, inhibits platelet adhesion reaction |
| Scorpio | Scorpion | treatment of hypertension, apoplexy, arteriosclerosis, some nervous system diseases, various tumefaction and infections |
| Hirudo | Leech | anticoagulation, thrombolysis, reduces viscosity of whole blood, antimyocardial ischemia, induces cholesterol and anti‐atherosclerosis |
| Eupolyphaga seu steleophage | Eupolyphaga sinensis walk, Ground beetle | increase cardiac output, improve tolerance of hypoxia |
| Scolopendra | Centipede | strengthens cardiac contractility, decreases blood pressure, and increases blood vessel perfusion flow |
| Periostracum cicadae | Cicada slough | anticonvulsion and slows heart rate down |
| Radix paeoniae rubra | The root of common peony | anticoagulation and prevents thrombosis functions, and obviously inhibits to form platelet and fibrin thrombus, dilate coronary artery directly, has strong anti‐myocardial ischemia function, and change the contents of lipoprotein, deduce calcium ion sediments on the arterious parietes, anti‐atherosclerosis |
| Borneolum syntheticum | Borneol | analgesia and sedation |
