Three therapeutic tendencies for secondary prevention of myocardial infarction and possible role of Chinese traditional patent medicine: viewpoint of evidence-based medicine

Authors


Correspondence
Boli Zhang, Evidence-based Medicine Centre, Tianjin University of Traditional Chinese Medicine, 88 Yuquan Road, Nankai District, Tianjin, Tianjin 300193, China. Tel: 86-22-2749-3265; Fax: 86-22-2741-2619 email:zhangbolipr@126.com

Abstract

Objective The possibility of the preventive and therapeutic effects of Chinese traditional patent medicine for myocardial infarction has been reported in the literature, but there have been few studies. This paper presents three tendencies for the secondary prevention of myocardial infarction and presents a systematic evaluation of current research evidence related to the use of Chinese traditional patent medicine in secondary prevention of myocardial infarction, with a goal of making objective recommendations for patient rehabilitation.

Method Literature was retrieved from traditional Chinese medicine websites, MEDLINE, CNKI, VIP, CINAHL, The Cochrane Library, EMBASE, HealthSTAR, and Academic ASAP to locate research-based scientific evidence related to the use of Chinese traditional patent medicine for myocardial infarction.

Results Some Chinese traditional patent medicine therapies alone or in combination with routine rehabilitation therapies might be useful in patients with myocardial infarction, but we found insufficient evidence to support the use of most Chinese traditional patent medicine therapies in the secondary prevention of myocardial infarction.

Conclusion Difficulty in accessing information regarding traditional Chinese medicine has implications for health education in both myocardial infarction and patient safety. Some Chinese traditional patent medicine therapies hold promise for patients in the secondary prevention of myocardial infarction but further research is essential in all areas of traditional Chinese medicine to confirm its efficacy.

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Background

Some reports have found that 75% of patients who incurred sudden cardiac death had a previous myocardial infarction (MI) (1). As an independent risk factor, prior myocardial infarction can increase the danger of sudden cardiac death by 5% (2). With simultaneous occurrence of lower left ventricular ejection fraction and complicated ventricular premature contraction, the chance of MI is increased by 10% to 15%. Among 631 patients with myocardial infarction observed in Fuwai Hospital, China from 1980 to 1981, 74 had a subsequent infarction (11.7%), with 29 patients incurring repeat infarction in the first year (4.7%) (3). Therefore, preventing subsequent infarction is of great clinical significance for improving the survival and quality of life in patients after a myocardial infarction.

During the last 10 years, large-scale clinical trials have confirmed that antiplatelet drugs, beta-receptor blockers (4, 5), angiotensin converting enzyme inhibitors (ACEIs) (6–8), lipid regulating (9) agents, and interventional therapy (10) could greatly decrease the mortality of acute myocardial infarction (AMI) (11). However, many survivors still suffer disability, death, or other cardiovascular events (such as another infarction, serious cardiac arrhythmias, and cardiac failure). Clinical trials of the secondary prevention of myocardial infarction have confirmed that many drugs are effective to some extent (12). This raises the question of which drug should be chosen.

Recently, three evident therapeutic tendencies for secondary prevention of MI have emerged.

Tendency 1: four kinds of drugs for secondary prevention of MI

Aspirin and other antiplatelet agents

Clinical trials have proved that aspirin has a substantial beneficial effect on the secondary prevention of MI, but the dosage of aspirin is an issue. For example, high doses (>325 mg/d) have been found to increase the risk of bleeding while low doses may result in aspirin resistance. In recent years, reports of aspirin resistance have increased (13).

Statins

Patients with MI may benefit from intensive lowering of low-density lipoprotein cholesterol without an increase in noncardiovascular mortality or other serious adverse reactions (14). Statins may be the most effective drugs for the prevention and treatment of hypercholesterolemia and coronary heart disease. They are generally well-tolerated, but they have side effects with potentially severe consequences, most prominently myopathy, rhabdomyolysis, and polyneuropathy.

Beta-receptor blockers

Studies have shown that beta-blockers reduced the incidence of MI by about one quarter: relative risk of death was reduced by 23% and re-infarction by 26%. All patients after MI without adverse reactions to beta-blockers should use them for the rest of their lives. In 2001, a systematic review found no significant difference between beta-blockers and a placebo in depressive symptoms or sexual dysfunction (depressive symptoms: RR 1.12, 95% CI 0.89 to 1.41; sexual dysfunction: RR 1.10, 95% CI 0.96 to 1.25).

Angiotensin conversion enzyme inhibitors

Recently, there have been many clinical trials for application of ACEIs to MI. These studies found improvement of heart function, a reduction in mortality rate, and a lower incidence of re-infarction. Dry cough is the most frequent adverse effect of ACEIs, and is a major limiting factor for their use. The latest studies show that the incidence of cough caused by ACEIs is 10.6%, and earlier reports found it ranged 5% to 39% (15). Women and non-smokers using ACEIs were found to be particularly likely to experience this side effect (16).

Tendency 2: polypills as combination medications for secondary prevention of MI

Compared with the prescription of a drug for any single class of secondary prevention, combination therapy is thought to offer additional protection to patients with AMI (17). For example, a ‘polypill’, which is one pill containing three or more agents to prevent cardiovascular disease, can be used. The strategy was to reduce simultaneously four cardiovascular risk factors (low density lipoprotein cholesterol, blood pressure, serum homocysteine, and platelet function) regardless of pretreatment levels. It is emphasized that combined prevention therapy might reduce subsequent risk by more than 80%. Although this suggestion was met with some doubt, the idea is prescient. Many kinds of polypills are expected to be produced over the next 10 years, but considerable debate remains about issues including physician acceptability, patient compliance, registration, and cost (18).

Tendency 3: traditional Chinese medicine as holistic therapy for secondary prevention of MI

Traditional Chinese medicine (TCM) has accumulated experience in treatment of angiocardiopathy. It has been shown to have a definite therapeutic effect and can reduce the frequency of angina, lower pain levels, decrease the dosage of nitroglycerol, and prevent myocardial infarction (19). Generally, the rate of ‘very successful treatment’ with TCM has been found to be 20% to 40%, the total effective rate is 80% to 90%, and the electrocardiogram effective rate is 30% to 50% (20). The mechanism of TCM in alleviating symptoms is the expansion of the coronary artery, improving myocardial ischemia, reducing myocardial consumption of oxygen, improving the function of the blood vessel endothelium, and regulating lipid metabolism. Such multi-faceted treatment can achieve a combined therapeutic efficacy (21). Furthermore, the drug action of Chinese medicine is moderate, and they have few side effects. Therefore, they should be suitable as long-term, secondary prevention drugs.

Bensoussan and Myers conducted a critical review of clinical trials of Chinese herbal medicine in various illnesses from 1983 to 1996 (22). While no trials had been published in English concerning cardiovascular diseases, 13 articles in Chinese were found. Although there was some evidence for the efficacy of Chinese herbal medicine in treating cardiovascular diseases, Bensoussan and Myers (23) concluded that these trials did not meet a sufficiently high standard to be broadly acceptable to the western medical community. In 2001, the North Dakota Academy of Science also reported that careful scientific assessment of herbal remedies in cardiovascular treatment was lacking (23).

Methods

We searched traditional databases and TCM websites including MEDLINE, CNKI, VIP, CINAHL, The Cochrane Library databases (Database of Abstracts of Reviews of Effects, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews), EMBASE, HealthSTAR, and Academic ASAP to locate research-based scientific evidence related to the use of Chinese traditional patent medicine (CTPM) therapeutic practices in secondary prevention of MI. The key search terms were ‘myocardial infarction’ combined with ‘Chinese patent medicine’. Other search terms were ‘systematic review’, ‘meta-analysis’, ‘randomized controlled trial’, and ‘review’.

Studies reporting the most rigorous methodology and having potential value in the secondary prevention of MI were selected for research. In order to gain the most recent evidence, the search was limited to publications from September 2002 to August 2007. We expected that the very few controlled trials done before September 2002 would have been included in review papers published between 2002 and 2007.

Studies were included based on the following criteria: the therapy was examined in patients with a myocardial infarction, and the study was conducted according to clearly described methods. Most of the studies we found were excluded because they did not meet these criteria. This was primarily due to weaknesses in design, sample size, or other methodological issues. The evidence reviewed here has been rated according to the criteria outlined in Table 1 (based on the Oxford Centre for Evidence-based Medicine Levels of Evidence and Grades of Recommendation (May 2001)).

Table 1.  Rating scale for grading evidence-based recommendations
ScaleDefinition
  1. SR, systematic review; RCT, randomized controlled trial.

Grade
 AConsistent level 1 studies
 BConsistent level 2 or 3 studies or extrapolations from level 1 studies
 CLevel 4 studies or extrapolations from level 2 or 3 studies
 DLevel 5 evidence or troublingly inconsistent or inconclusive studies of any level
Level
 1SR (with homogeneity) of RCTs or individual RCT
 2SR (with homogeneity) of cohort studies or individual cohort study
 3SR (with homogeneity) of case-control studies or individual case-control study
 4Case-series (and poor-quality cohort and case-control studies)
 5Expert opinion without explicit critical appraisal, or based on physiology, bench research, or first principles

Results

We found a small number of papers on the use of Chinese patent medicine relating to MI in English-language journals (24–26). The Chinese literature describes 11 kinds of products of Chinese patent medicine, which are licensed by the State Food and Drug Administration (SFDA) of China and have been applied in the treatment of MI. Along with the spread of Good Clinical Practice, the quality of TCM clinical trials has improved recently, leading to an increased number of Chinese patent medicines being validated by research such as randomized controlled trials. From Tables 2 and 3, we consider how Chinese patent medicine plays a role in the secondary prevention of MI, although some problems influenced trial quality.

Table 2.  List of Chinese patent medicine for acute myocardial infarction licensed by SFDA
CTPM VarietiesPreparatumFormula SourceApplication ScopeReport Frequency
  1. AMI, acute myocardial infarction; SFDA, State Food and Drug Administration; CTPM, Chinese traditional patent medicine; HF, heart failure; MI, myocardial infarction.

ShenmaiinjectionShenmai powder (classic)Protect ischemic myocardium in patients with AMI9
ShenmaiinjectionShenmai powder (classic)Protect myocardium by reducing blood viscosity and improving microcirculation3
Compound DansheninjectionCompound Danshen (empirical)May improve angina symptoms and survival after a heart attack2
AcanthopanaxinjectionRadix acanthopanacis senticosi (research findings)May improve cardiac blood flow and oxygen supply1
Astragalus mongholicusinjectionAstragalus mongholicus (research findings)May improve heart function in people with HF1
XuesaitonginjectionRadix notoginseng (research findings)May prevent clots1
TongxinluocapsuleTongxinluo (empirical)Helps recover cardiac function in patients with AMI9
Wenxinkelipowder preparation for infusionWenxinkeli (empirical)May be used for tachycardia after AMI7
Compound Danshendripping pillCompound Danshen (empirical)May improve angina symptoms and survival after a heart attack1
NaoxintongcapsuleNaoxintong (empirical)Raises exercise tolerance and improves endothelial function1
LinaoxincapsuleLinaoxin (empirical)May improve angina symptoms1
Table 3.  Details of selected studies
SNAuthorsPublication dateResearch designIntervention methodHierarchy of evidence
  1. CCT, controlled clinical trials; PCI, percutaneous coronary intervention; RCT, randomized controlled trials; SB, single blind; SN, serial number.

  2. Hierarchy of evidence given in Table 1.

1Zuo (27)2006RCTRoutine +Shengmai vs RoutineGrade D Level 1
2Zhou et al (28)2005RCTShengmai + Thrombolytic vs ThrombolyticGrade D Level 1
3Liu et al (29)2005RCTRoutine +Shengmai vs RoutineGrade D Level 1
4Miao et al (30)2005RCTThrombolytic + Routine +Shengmai vs Thrombolytic + RoutineGrade D Level 1
5Li et al (31)2004RCT(SB)Shengmai vs isosorbide mononitrateGrade D Level 1
6Zhang et al (32)2004RCTRoutine +Shengmai vs RoutineGrade D Level 1
7Chen et al (33)2004Case-seriesRoutine +ShengmaiGrade D Level 4
8Zhao et al (34)2004RCTRoutine +Shengmai vs RoutineGrade D Level 1
9Jia et al (35)2003RCTShengmai+ Thrombolytic vs ThrombolyticGrade D Level 1
10Li et al (36)2006RCTShenmai vs AcanthopanaxGrade D Level 1
11Geng et al (37)2004RCTShenmai+ compound Danshen vs RoutineGrade B Level 1
12Ding (38)2003RCTRoutine +Shenmai vs RoutineGrade D Level 1
13Yan and Yang (39)2004Case-seriesAcanthopanax + ShengmaiGrade D Level 4
14Yu et al (40)2005RCTRoutine +Naoxintong vs RoutineGrade D Level 1
15Li (41)2005RCTRoutine +Astragalus mongholicus vs RoutineGrade D Level 1
16Wang et al (42)2004RCTLinaoxin vs XinnaokangGrade D Level 1
17Yuan et al (43)2003Case-seriesCompound Danshen injectionGrade D Level 4
18Qin and Wang (44)2003RCTThrombolytic + Routine + Compound Danshen vs Thrombolytic + RoutineGrade B Level 1
19Li and Jiang (45)2003RCTCompound Danshen dripping pill vs CaptoprilGrade D Level 1
20He et al (46)2004CCTRoutine +Xuesaitong vs RoutineGrade D Level 4
21Jia and Du (47)2006RCTRoutine +Wenxinkeli vs RoutineGrade D Level 1
22Liang et al (48)2005RCTRoutine + PCI +Wenxinkeli vs Routine + PCIGrade D Level 1
23Su and Li (49)2004RCTRoutine +Wenxinkeli vs RoutineGrade D Level 1
24Cai et al (50)2004RCTRoutine +Wenxinkeli vs RoutineGrade D Level 1
25Feng et al (51)2004CCTRoutine +Wenxinkeli vs Routine + metoprololGrade D Level 4
26Huang and Yang (52)2004Case-seriesRoutine +WenxinkeliGrade C Level 4
27Xu et al (53)2003RCTRoutine + Thrombolytic +Wenxinkeli vs Routine + ThrombolyticGrade D Level 1
28Shi (54)2006RCTRoutine +Tongxinluo vs RoutineGrade D Level 1
29Li et al (55)2006RCTRoutine +Tongxinluo vs RoutineGrade D Level 1
30Zhang and Yang (56)2006RCTPCI + Routine +Tongxinluo vs PCI + RoutineGrade D Level 1
31You et al (57)2005RCTRoutine +Tongxinluo vs RoutineGrade B Level 1
32You et al (58)2005RCTRoutine +Tongxinluo vs RoutineGrade B Level 1
33Zhang (59)2005CCTRoutine +Tongxinluo vs RoutineGrade D Level 4
34Xie et al (60)2005RCTRoutine + Thrombolytic +Tongxinluo vs Routine + ThrombolyticGrade D Level 1
35You et al (61)2004RCTRoutine +Tongxinluo vs RoutineGrade B Level 1
36Fan et al (62)2003RCTRoutine +Tongxinluo vs RoutineGrade D Level 1

There were six injections and five oral preparations in the proposed products. These arise from ancient formulas, research findings, or clinical expertise and have individual application scopes. Shengmai and Tongxinluo were reported most frequently among the medicines (Table 2).

We found 36 studies, of which 32 were defined as randomized controlled trials (RCTs) and four were case series. However, the methodological quality of studies described as RCTs is either unclear or poor. Few trials reported the method of randomization, and ‘concealment of randomization’ went unmentioned. Only one trial referred to ‘blinding’. In short, the position in the hierarchy of evidence for these papers is relatively low (Table 3).

Discussion and conclusion

Recently, traditional Chinese medicine has entered the global health discussion (63). TCM, which has a history lasting thousands of years, has been found to be effective in clinical practice, but currently there are deficiencies in its objective assessment. This has formed a bottleneck, which has restricted the modernization and international development of TCM. Cultural factors may be the largest obstacle in bridging the East–West gap, but in both the East and the West, we share the same goal of improving human health. A significant conclusion of our study is the need to promote a culture where patients feel comfortable in disclosing their use of CTPM therapies.

Some Chinese traditional patent medicine therapies hold promise for patients in the secondary prevention of MI. Further research is essential in all areas of traditional Chinese medicine to assess its efficacy. The shortage of high-quality clinical trials concerning the effectiveness of CTPM for the treatment of myocardial infarction, combined with the potential adverse effects (64), preclude the recommendation of potentially beneficial therapies in treating MI. The methodological quality of the studies we found was very poor, as they did not describe their methods in sufficient detail.

More emphasis is needed on research that scientifically evaluates the efficacy of CTPM for the secondary prevention of MI. The choice of indexes referring to TCM is critical to re-evaluate the efficacy of CTPM. Perhaps indices might include ‘Zheng’ (syndrome), quality of life, and patient-reported outcomes. Future trials should solve the problems presented in this paper, especially by using and reporting adequate concealment of allocation and blinding of outcome assessors. Reports from the trials should conform to the recommendations of the Consolidated Standards For Reporting Trials (CONSORT) statement or CONSORT for TCM (65).

The World Health Organization's involvement in clinical trial registration increased in October 2003 with consultations with different stakeholders to identify a potential basis for collaboration to address complex issues related to trial registration and reporting. Following the paroxetine affair (66), 14 editors from major international medical journals issued a joint statement that these journals would not publish research results unless the trials had been registered in an open access database of clinical trials.

The prospective registration of trials and the availability of good reporting guidelines are not sufficient to improve the quality of reporting. The Enhancing the Quality and Transparency of Health Research (EQUATOR) project (67,68), which receives funding from the UK National Knowledge Service, seeks to improve the reliability of medical publications by promoting transparent and accurate reporting of health research. The Chinese Evidence Based Medicine Centre took related action (69) and is committed to the harmonization of standards so that trial registers and databases worldwide can operate in a co-ordinated fashion, providing a global trial identification and search capability, and promoting compliance.

According to principles of evidence-based medicine, studies to provide objective evaluation of TCM for the secondary prevention of myocardial infarction should adopt strict diagnostic criteria for the evaluation of curative effects, be carefully designed, and be large-scale, and multi-center (70). Despite the difficulties, conforming to both traditional diagnostic and therapeutic systems, and modern methodological demands, is achievable (71). One such study is ‘myocardial infarction secondary prevention study in traditional Chinese medicine’ (MISPS-TCM), which was sponsored by the National Key Technologies R&D Program of China during the 10th Five-Year Plan. This trial will take place from December 2004 to December 2009, and it has been registered in the database of the Chinese Clinical Trials Register Centre, one of the primary registers in the WHO clinical trial registration platform (ChiCTR -TRC-00000002). Recruitment to the trial closed in July 2008 and there have so far been approximately 150 events recorded, such as nonfatal infarction, nonfatal stroke, and cardiac death. Results of the trial will be published at the end of 2009.

Acknowledgements

The research was funded by National Key Technologies R&D Program of China during the 10th Five-Year Plan, Grant #2004BA716B01, National Nature Science Foundation of China (NSFC), Grant #30600834, and China Postdoctoral Science Foundation (CPSF), Grant #20070411156.

Competing interests: None declared.

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