Traditional chinese interventions for stable angina
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the effect (harms and benefits) of Traditional Chinese Medicine for stable angina. Specific comparisons will be made between Traditional Chinese Medicine and current standard treatment regime.
Background
ANGINA PECTORIS
Angina pectoris is the result of myocardial ischaemia caused by an imbalance between myocardial blood supply and oxygen demand. Angina is a common presenting symptom (typically chest pain) among patients with coronary artery disease (Bernard 1979; Kau 1996). 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. Angina is a sign that someone is at increased risk of heart attack, cardiac arrest and sudden cardiac death (Bernard 1979; Kau 1996).
STABLE ANGINA
Stable angina is defined as: more than 4 months typical effort angina occuring more than 5 times a week. Effort angina is characterized by transient episodes of chest pain precipitated by exercise or by other situations resulting in an increased myocardial oxygen demand. The pain usually disappears rapidly with rest or with sublingual nitroglycerin (Bernard 1979). People with stable angina (or chronic stable angina) have episodes of chest discomfort, pressure, or squeezing sensation that are usually predictable. Less commonly sensations of burning, sticking, or sharp pain may occur (Pope 2000).
As a symptom of cardiac ischaemia, stable angina occurs because the flow of blood is being restricted by any of the following:
(1) Clogged arteries, which are often a sign of coronary artery disease;
(2) Problems in the aortic valve (one of the four heart valves), such as regurgitation (leaking) or stenosis (narrowing);
(3) Problems in the heart muscle (e.g., hypertrophic subaortic stenosis) (Hamby 2001).
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 there has been an increasing tendency for ischaemic heart disease incidence to rise in developing countries, in conjunction with their economic development e.g. in Beijing China, the mortality of this disease has increased from 21.7/100,000 in 1970 to 62.0/100,000 in 1980 (Chen 2000).
Although angina attacks usually pass with little long‐term damage to the heart, the episodes of cardiac ischaemia that trigger the angina attacks can lead to dangerous problems if left untreated:
(1) They can cause abnormal heart rhythms (arrhythmias), which can lead to either syncope (fainting) or sudden cardiac death;
(2) Heart disease patients whose episodes are triggered by stress (e.g., frustration) are more likely to die from their heart condition;
(3) Severe or lengthy episodes can trigger a heart attack;
(4) The small effects of minor episodes can eventually add up and lead to permanent weakening of the heart muscle (cardiomyopathy). So people with new,worsening or persistent chest discomfort should be monitored carefully (Hamby 2001).
ANTIPLATELET AGENTS
These type of agents consist of aspirin, ticlopidine, clopidogrel and dipyridamole (ACC/AHA 1999). These agents prevent thrombus formation by inhibition of platelet aggregation (Alaeddini 2002). The Swedish Angina Pectoris Trial (SAPAT 1992) randomised 2,935 patients with a history of at least one month of exertional angina to receive 75 mg aspirin daily in addition to beta‐blockers. It resulted in a 34% reduction in primary outcomes (non‐fatal myocardial infarction (MI), fatal MI or sudden death) and a 32% decrease in secondary vascular events after 72 months. Absolute risk reduction was 4% (95% confidence intervals 1‐7%) (SAPAT 1992).
BETA BLOCKERS
These agents inhibit the activation of beta‐receptors associated with a reduction in inotropic state and sinus rate and slowing of atrioventricular (AV) conduction. The decrease in resting and exercise heart rate, contractility and arterial pressure with beta‐blockers is associated with decreased myocardial oxygen demand. A reduction in heart rate also increases diastolic perfusion time, which may enhance left ventricular (LV) perfusion (Narahara 1990; Frishman 1991). Patients who require regular symptomatic treatment should be treated initially with a beta‐blocker (unless specifically contraindicated) (SIGN 2001). The Beta‐Blocker Pooling Project reported a highly significant reduction in mortality in this sub‐group, and it seems reasonable to assume that beta blockers have the potential to prevent death, especially sudden death, and the development of myocardial infarction even when there has been no prior infarction (ESC 1997).
CALCIUM ANTAGONISTS
These agents reduce the transmembrane flux of calcium via the calcium channels. They can reduce smooth muscle tension in the peripheral vascular bed. This is associated with vasodilation, and can decrease coronary vascular resistance and increase coronary blood flow. All of these agents cause dilation of the epicardial conduit vessels and the arteriolar resistance vessels. Calcium antagonists improve exercise time to onset of angina or ischaemia (ACC/AHA 1999). Long‐acting and slow‐release calcium antagonists are effective in relieving symptoms in patients with chronic stable angina (ACC/AHA 1999) and are specifically indicated for vasospastic angina (ESC 1997).
NITROGLYCERIN AND NITRATES
Nitrates can reduce the myocardial oxygen requirement by reducing LV volume and preload and also by improved nitroglycerin‐induced central arterial compliance. Nitrates can improve myocardial perfusion by dilating large epicardial coronary arteries and collateral vessels. Nitroglycerin also exerts antithrombotic and antiplatelet effects in patients with stable angina (ACC/AHA 1999). Sublingual (under the tongue) nitroglycerin tablets or nitroglycerin spray are used for the immediate relief of angina However these have not been shown to decrease death or the incidence of heart attacks (Caremark 2003). Both isosorbide dinitrate and mononitrate have been shown in controlled trials to be superior to placebo in controlling symptomatic angina (Thadani 1992; Chrysant 1993).
ACE INHIBITORS
Angiotensin converting enzyme (ACE) inhibitors, which lower blood pressure and have other effects on blood vessels, could save lives and prevent heart attacks and strokes among certain patients with chronic stable angina (ACC 2002). The Heart Outcomes Prevention Evaluation (HOPE) trial, which compared the ACE inhibitor ramipril against placebo in more than 9,000 patients with vascular disease, including more than 3,500 patients with diabetes, suggests that the use of an ACE inhibitor reduces rates of death, MI, heart attack, stroke, and revascularization procedures (ACC 2002).
LIPID LOWERING AGENTS
These agents including statins help lower lipid levels in blood. Recent clinical trials have documented that low density lipoprotein (LDL) lowering agents can decrease the risk of adverse ischaemic events in patients with established coronary artery disease (CAD) (ACC/AHA 1999). The Scandinavian Simvastatin Survival Study showed that a statin, given to patients with angina pectoris and a total cholesterol level between 5.5 and 8.0 mmol/L (212 and 308 mg/dL), substantially reduces the risk of myocardial infarction, death, and the need for coronary bypass surgery by 30% to 35% (4S 1994). In patients with established CAD, including chronic stable angina, lipid‐lowering therapy should be recommended even in the presence of mild to moderate elevations of LDL cholesterol (ACC/AHA 1999).
CHINESE HERBAL MEDICINE IN THE TREATMENT OF STABLE ANGINA
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 treatment and prevention of disease (Fulder 1996). TCM has its 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).
It has been proved that Chinese herbal medicine has following effects:
(1) Relieving myocardial ischaemia: Some Chinese herbal medicine can dilate coronary arteries and increase coronary blood flow, e.g. Flos carthami , Radix puerariae, Rhizoma ligustici chuanxiong, Radix astragali seu hedysari, Radix notoginseng and Radix salviae miltiorrhizae (Ou 1992);
(2) Reduce myocardial oxygen consumption: Some Chinese herbal medicine can reduce myocardial oxygen consumption, e.g. Radix augelicae sinensis, Radix notoginseng (Ou 1992);
(3) Antiplatelet and anticoagulant action: Some Chinese herbal medicine act on various blood‐clotting factors, increase the level of cAMP in thrombocytes, inhibiting the rheological state of blood, so impeding the formation of thrombus e.g.Radix salviae miltiorrhizae, Hirudo. Some can lower the level of blood lipids and counter the development of atheroma, e.g. Radix augelicae sinensis (Ou 1992);
(4) Relieve pain: Some Chinese herbal medicine can relieve the symptom of chest pain and radiation pain, e.g. Radix augelicae sinensis, Radix notoginseng, Radix astragali seu hedysari (Ou 1992).
In addition, when using Chinese treatments two or more drugs are always used together in one prescription. In this way drugs used as a correct prescription will give rise to interactions. They may coordinate each other to increase their effects or counteract each other to reduce or remove toxicity or side effects (Ou 1992).
However some adverse effects have also been reported. These include minor gastrointestinal tract reactions, dry mouth and partial thromboplastin time lincreased to longer than normal.
The effectiveness 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 Traditional Chinese Medicine for stable angina. Specific comparisons will be made between Traditional Chinese Medicine and current standard treatment regime.
Methods
Criteria for considering studies for this review
Types of studies
We are particularly interested in randomised and quasi‐randomised controlled trials, but in their absence, any controlled study will be included.
Types of participants
Participants will be male or female of any age or ethnic origin with stable angina. Participants will be excluded if they have acute myocardial infarction, heart failure, hepatic failure and renal failure.
Types of interventions
Traditional Chinese Herbs will be compared with other anti‐angina pectoris drugs, placebo or no intervention, as well as comparisons between different doses or routes of administrations of traditional Chinese herbs. If participants suffer an attach of angina pectoris during trials, nitroglycerin may be used. Dosage should be recorded as an outcome measure.
Types of outcome measures
We will consider the following outcome measures:
PRIMARY OUTCOME MEASURES
Death and/or acute myocardial infarction.
SECONDARY OUTCOME MEASURES
(1) Resolution of anginal symptoms;
(2) Frequency of anginal symptoms;
(3) Use of nitroglycerine;
(4) Quality of life.
Readmission to hospital or use of revascularisation might also be useful secondary outcomes.
ADVERSE EVENT OUTCOME MEASURES
Any adverse events as a result of treatment that are
(1) mortality;
(2) life threatening;
(3) toxic response, for example, gastrointestinal reaction;
(4) 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 specialized trials register and the Cochrane Central Register of Controlled Trials (CENTRAL) will be searched for relevant trials.
The following electronic databases will also be searched:
(1) MEDLINE (1995 to 2002);
(2) EMBASE (1995 to 2002);
(3) CBM (Chinese biomedical database, 1995 to 2002);
(4) Chinese Cochrane Centre Controlled Trials Register (to 2002);
(5) Cochrane Library (to 2002).
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)
The following MEDLINE search strategy will be used and adapted for the different databases:
#1 ANGINA‐PECTORIS*:ME
#2 ANGINA
#3 CORONARY‐DISEASE*:ME
#4 (CORONARY near DISEASE*)
#5 (((#1 or #2) or #3) or #4)
#6 MEDICINE‐ORIENTAL‐TRADITIONAL*:ME
#7 DRUGS‐CHINESE‐HERBAL*:ME
#8 (CHINESE near MEDICINE*)
#9 (TRADITIONAL near CHINESE)
#10 (TRADITIONAL near MEDICINE*)
#11 (CHINESE next DRUG*)
#12 KAMPO
#13 ((((((#6 or #7) or #8) or #9) or #10) or #11) or #12)
#14 Composite Dansheng droplet pills
#15 Tong xin tang
#16 Yi Qi Tong Bi Tang
#17 Svate
#18 Ci Wu Jia injection
#19 Yi Qi Huo Xue Hua Yu Fa
#20 Puerarin
#21 Ligustrazine
#22 Mai Luo Ning
#23 Sheng Mai
#24 Huang Dan Xin Le pills
#25 Xin ta hua capsule
#26 Yi Qi Huo Xue Tang
#27 Bao Xin Yao Zhen
#28 ((((((((((((((#13 or #14) or #15) or #16) or #17) or #18) or #19 ) or #20) or #21) or #22) or #23) or #24) or #25) or #26) or #27)
#29 (#5 and #28)
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
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 Journal 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
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 known published and unpublished work.
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 additional references if needed, 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
TRIALS SELECTION:
To determine the studies to be assessed further, we 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 stable angina;
(2) Compares Traditional Chinese Medicine 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 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 quality of reporting each trial will be assessed based largely on the quality criteria specified by Schulz and by Jadad (Schulz 1995; Jadad 1996). In particular, the following factors will be studied:
(1) Minimization of selection bias ‐ a) was the randomisation procedure adequate? b) Was the allocation concealment adequate?
(2) Minimization of performance bias ‐ were the patients and people administering the treatment blind to the intervention?
(3) Minimization of attrition bias ‐ a) were withdrawals and dropouts completely described? b) Was analysis by intention‐to‐treat?
(4) Minimization 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 (Zheng, Li). Interrater agreement will be calculated using the kappa statistic, and disagreements will be resolved, where necessary, by recourse to a third reviewer (Liu). In cases of disagreement, the rest of the group will be consulted and a judgment will be made based on consensus. 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 (Zheng, Li) 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 Zheng and Li. Disagreement will be resolved by discussion and, where necessary, in consultation with a third reviewer (Liu). 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). These 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 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 ones 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 are any);
(2) Repeating the analysis taking account of study quality, as specified above;
(3) Repeating 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).
