Compound salvia pellet, a traditional Chinese medicine, for the treatment of chronic stable angina pectoris compared with nitrates: a meta-analysis

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1 Med Sci Monit, 2006; 2(): -7 PMID: Received: Accepted: Published: Authors Contribution: A Study Design B Data Collection C Statistical Analysis D Data Interpretation E Manuscript Preparation F Literature Search G Funds Collection Compound salvia pellet, a traditional Chinese medicine, for the treatment of chronic stable angina pectoris compared with nitrates: a meta-analysis Gang Wang ABDEF, Lei Wang ABCF, Ze-Yu Xiong 2 ABF, Bing Mao BF, Ting-Qian Li ADE Department of Integrated Traditional Chinese & Western Medicine, West China Hospital, Sichuan University, P. R. China 2 Section of Immunology Allergy & Rheumatology, Department of Medicine, Baylor College of Medicine, Houston, TX, U.S.A. Source of support: This project was supported by the Chinese Cochrane Centre (0202) and in part by the Chinese Medical Board Grant on Evidence-based Medicine, New York, U.S.A. Background: Material/Methods: Results: Conclusions: key words: Summary Compound salvia pellet (CSP), consisting of active herbal ingredients extracted from Danshen (salvia miltiorrhiza), Sanqi (panax notoginseng), and Borneol (Cinnamomum camphora), is taken most frequently by patients with angina pectoris in China. To determine the efficacy and safety of CSP for the treatment of stable angina pectoris (SAP), a meta-analysis was undertaken. An extensive search including MEDLINE, EMBASE, BA, Chinese Biomedical Database (CBM), and Chinese Cochrane Centre Controlled Trials Register from 99 to 200 was performed. Data were extracted independently from the included trials by two reviewers. Statistical software (RevMan.) provided by the Cochrane Collaboration was applied. Twenty-seven randomized controlled trials (RCTs) (n=3722), regardless of language or publication status, were identified. Generally, the methodological quality of the trials, assessed by the Jadad scale, was low, except for one with 3 points. Statistical pooling of the results showed that, compared with nitrates, CSP treatment had significant effect on the improvement of angina symptoms (RR=.3, 95%CI=[.07,.20]), showed greater increased effect on the improvement of electrocardiogram (ECG) results (RR=.39, 95%CI=[.2,.50]), and the percentage of patients with adverse events was significantly decreased in the treatment of CSP in comparison with nitrates (2.% vs. 29.7%). CSP has significant effect on the improvement of angina symptoms and ECG results with few adverse events. However, the methodological quality of clinical trials with CSP for SAP needs to be improved, and the outcome measures should include mortality, quality of life, and other endpoints. compound salvia pellet stable angina pectoris organic nitrates meta-analysis randomized controlled trials Full-text PDF: Word count: 3096 Tables: Figures: 2 References: 6 Author s address: Li Ting-Qian, Department of Integrated Traditional Chinese & Western Medicine, West China Hospital, Sichuan University, 37# Guoxue Street, Chengdu 600, People s Republic of China, wunggang@hotmail.com Current Contents/Clinical Medicine SCI Expanded ISI Alerting System Index Medicus/MEDLINE EMBASE/Excerpta Medica Chemical Abstracts Index Copernicus 转载

2 Med Sci Monit, 2006; 2(): -7 BACKGROUND Chronic stable angina is a major health problem that affects over 7 million adults in the United States, with an estimated 00,000 new cases annually [], and it results in a considerable burden for both the individual and society. At present, organic nitrates are indicated as the first-line therapy for the long-term management of chronic stable angina [2 5]. It has been demonstrated that nitrate treatment provides control of anginal symptoms and improves the quality of life in patients with angina pectoris [6]. But a major limitation of the use of nitrates is the development of tolerance, defined as the loss of hemodynamic and antianginal effects during sustained therapy [7,]. According to traditional Chinese medicine (TCM), chronic stable angina pectoris belongs within the scope of pectoral pain and stuffiness (obstruction of qi and blood in the chest) and, therefore, promoting blood circulation to remove blood stasis is its therapeutic method. Radix salviae miltiorrhizae (Danshen) and its compound formula as drugs for activating blood and resolving stasis are widely used in the clinical practice of TCM for the treatment of angina pectoris in China [9]. Compound salvia pellet (CSP), produced by Tasly Group, P. R. China, since 99, which is also termed composite Danshen pill [0] or compound Danshen droplet pill [], is a herbal drug consisting of active herbal ingredients extracted from Danshen (salvia miltiorrhiza), Sanqi (panax notoginseng), and Borneol (Cinnamomum camphora) [0]. The planting, field management, collection, harvest, and storage of drug materials are the guarantee of the quality of CSP. Fingerprint analysis of CSP by high-performance liquid chromatography (HPLC) has been established (Figure ), which is good for the quality standardization of the drugs. According to TCM, salvia miltiorrhiza in this formula, which is regarded as the principal drug (known as the King ), can promote or invigorate blood flow and remove blood stasis. Experimental studies have shown that salvia miltiorrhiza can dilate coronary arteries, increase coronary blood flow [2], and scavenge free radicals[3] in ischemic diseases, so that it reduces the cellular damage from ischemia and improves heart functions. Panax notoginseng serves as the Minister to reinforce salvia miltiorrhiza s therapeutic action, which can inhibit activation of platelets and their adhesion and aggregation[], and counteract free-radical damage associated with atherogenesis [5,6]. Cinnamomum camphora, for resuscitation, is related to the heart channel and lung channel, to open and revive the spirit according to TCM. In search of better treatment options, many patients in both east and west have turned to alternative medicines in the hopes of identifying natural substances with less toxicity but equal effectiveness. Until now, many randomized controlled trials (RCTs) have been completed or published which indicate that CSP may be effective in patients with chronic stable angina pectoris compared with the organic nitrates [7]. Against these backgrounds, this study is an attempt to critically assess the therapeutic effect and safety of CSP in the treatment of chronic stable angina pectoris. MATERIAL AND METHODS Search strategy A comprehensive and exhaustive search strategy was formulated in an attempt to identify all relevant studies regardless of language or publication status (published, unpublished, in press, and in progress) [,9]. The Cochrane Heart Review group s specialized trials register and the Cochrane Controlled Trials register were searched (to 200). Systematic literature searches of MEDLINE (99 200), EMBASE (99 200), and BA (99 200) were performed to identify all RCTs of CSP for chronic stable angina pectoris. The search terms were compound salvia pellet, composite Danshen pill, or compound Danshen droplet pill. Furthermore, the Chinese Biomedical Database (CBM) (99 200) and the Chinese Cochrane Centre Controlled Trials Register (99 200) were also searched. In addition, a manual search was performed of the bibliographies of studies and reviews. Manufacturers (Tasly Group) of commercial CSP products were asked to contribute published and unpublished materials. Some trials reported data that were not suitable for statistical pooling, and the authors of those original publications were contacted to provide additional data. Finally, some trials not in Chinese or English were translated with the help of the Chinese Cochrane Centre. Selection of trials The articles were read by two reviewers (Dr. Wang G. and Wang L.) and studies were selected systematically according to predefined criteria. To be included, studies were required to involve and include: () humans with definitely defined chronic stable angina pectoris with a course of more than month, (2) the RCTs with the full text, (3) treatment with CSP compared with the nitrates or placebo, and () a duration of treatment of more than one week. Trials involving patients with heart failure or past re-vascularisation procedures were excluded. Data extraction and quality assessment of trials The following characteristics and data of all the included trials were extracted. The characteristics of methods in these trials included the randomization procedure, concealment of allocation, blinding procedure, withdrawal and reasons, protection against contamination, power calculation, sample representativeness, and length of follow-up. The information about the participants involved age, gender, ethnic origin, diagnostic procedures, and the number of patients allocated. The characteristics of interventions included route of administration, dosage and duration of therapy, kinds of nitrates, and any co-interventions. In addition, outcomes such as mortality, incidence of myocardial infarction, acute angina pectoris (duration, extent, severity, and frequency), quality of life, and adverse events were extracted at the same time. Methodological quality was evaluated using the system developed by Jadad [20], which quantifies the likelihood of bias inherent in the trials, based on the description of randomization, blinding, withdrawals, and dropouts. The scores range from one to five, one or two being considered as low quality and three to five as high quality [2,22]. In addi- 2

3 Med Sci Monit, 2006; 2(): -7 Wang G et al Compound salvia pellet for stable angina pectoris: a meta-analysis Figure B. Chemical structures of the water-soluble chemicals identified on the fingerprint. Figure A. Fingerprint of compound salvia pellet with eight characteristic peaks (No. : Danshensu; No. 2: Protocatechualdehyde; No. 3: Lithospermic acid E; No. : Salvianolic acid D; No. 5: Salvianolic acid E; No. 6: Rosmarinic acid; No. 7: Salvianolic acid B; No. : Salvianolic acid A) by high-performance liquid chromatography (HPLC). tion, concealment of the generated random allocation sequence was scored by the criteria adopted from the Cochrane Handbook and those of Schulz [23,2]. Data on the number of patients with each outcome event by allocated treatment group, irrespective of compliance or follow-up, were sought to allow an intention-to-treat analysis. If the above data were not available in the trial reports, further information was sought by correspondence with the principal investigator. Data extraction and the evaluation of methodological quality were performed independently by the two reviewers, and discrepancies were resolved through discussion. Types of outcome measures The main outcome measures which we considered important were as follows: () the score of anginal symptoms, (2) mortality due to ischemic heart disease, (3) the severity of angina pectoris (including the frequency of hospitalization and angina pectoris onset per year, the rate of myocardial infarction within 5 years, heart operation of percutaneous transluminal coronary angioplasty, heart function), the quality of life, the improvement of electrocardiogram (ECG) and exercise ECG, and () adverse events during the treatment. Data analysis In this study, the statistical software (RevMan.; Update Software Ltd, Oxford, England) provided by the Cochrane Collaboration was applied. Dichotomous data were presented as relative risk (RR), while continuous data were expressed as weighted mean differences (WMD) with 95% confidence intervals (CI) [23]. The random-effects model was used when there was heterogeneity of the results of the trials (P<0.); otherwise, the fixed-effects model was used. For dichotomous outcomes, patients with incomplete or missing data were included in sensitivity analyses by counting them as treatment failures (worst-case scenario analyses). Potential publication bias was examined by funnel plot [25], i.e. a graphical display of the logarithm of RR plotted against RR [26]. RESULTS Description of studies Our initial searches identified 9 articles concerning CSP in the treatment of chronic stable angina pectoris, 7 in English and 2 in Chinese ( translated from Russian). CSP was used in only 3 of the 7 articles in English, and the full texts were not found in 5 of 2 articles in Chinese. After the two reviewers read the abstracts and the full text according to the inclusion criteria, 22 articles were excluded as duplicates, non-clinical studies, obvious error, or study objectives different from the aim of this review. Finally, 27 RCTs [27 53] were identified with 3722 patients treated with CSP compared with nitrates, but without a multi-center study. Methodological quality of the included studies For assessing the methodological quality, the scale by Jadad et al. was used. All included studies came from China, and in general they all had low methodological quality scoring of point, except for five studies (three [3,,52] with 2 points for double-blinding, one [9] with 2 points for the description of dropouts and withdrawals, and one [27] with 3 points for double-blinding and withdrawals) (Table ). No trials described the beforehand sample size calculation in those studies. The average sample size of the included trials was 3 patients, varying from 50 to 70, and there were more than 00 subjects in 6 trials (59.3%). The word of randomization was seen in all trials, but none reported the generation of the random allocation sequence and the allocation concealment. The homogeneity test for the difference between the treatment group (CSP group) and the control group (nitrates group) with a p value was used in 6 trials, but the other trials only described the baseline levels without statistical analysis, and therefore it was difficult to make sure whether the two groups were comparable in all aspects. Furthermore, outcome measurements such as the follow-up, mortality, the rate of myocardial infarction, operation, and quality of life were not reported in any studies. In addition, no trials described the intentionto-treat (ITT) analysis. A funnel plot of all the trials is presented in Figure 2. All trials seemed evenly distributed around the WMD in symptom scores of chronic stable angina pectoris. It was indicated that there was no publication bias which would influence the overall results of this review. 3

4 Med Sci Monit, 2006; 2(): -7 Table. Characteristics of randomized controlled trials of CSP in the treatment of chronic stable angina pectoris compared with nitrates. Author [Reference] Jadad score Mean age (years) Male (%) Sample size (A/C) Active intervention Control intervention Therapy (weeks) Huang SW [26] A: 5 75; (0/3) CSP, 250 mg, tid (200) C: 7 76 Chen KY [27] A: (56/56) CSP, 250 mg, tid (200) C: NA Rong JH [2] (0/35) CSP, 250 mg, tid (200) NA He YZ [29] A: (0/20) CSP, 250 mg, tid (200) C: 2 Wang JS [30] A: (56/50) CSP, 250 mg, tid C: 6 Liu YH [3] (30/00) CSP, 250 mg, tid No Yuan XL [32] A: 50 7 A: NA (50/0) CSP, 250 mg, tid C: 55 C: No Chu XB [33] A: 56± (35/32) CSP, 250 mg, tid C: 55±3 NO Wang XL [3] A: 9 65 A: (52/50) CSP, 250 mg, tid C: 2 6 C: Li XL [35] A: (70/30) CSP, 250 mg, tid C: 0 69 NA Sun YZ [36] A: (30/30) CSP, 250 mg, tid (2002) C: C: 6 Yao YX [37] A: (50/50) CSP, 250 mg, tid (2002) C: 56. C: Yao FH [3] A: (50/50) CSP, 250 mg, tid (2002) C: 55.6 NA Wu K [39] A: (0/0) CSP, 250 mg, tid (200) C: 55 NA Dong XM [0] A: (30/30) CSP, 250 mg, tid (200) C: 57.2 C: 6 Yang SM [] A: (3/0) CSP, 250 mg, tid (200) C: 57 C: 6 Guo LX [2] A: (25/25) CSP, 250 mg, tid (200) C: 55 NA Lu J [3] (60/60) CSP, 250 mg, tid (200) C: 0 6 NO Zhu YQ [] (0/0) CSP, 250 mg, tid (200) NA Wu S [5] A: (69/66) CSP, 250 mg, tid C: 5 2 Gao B [6] A: (60/30) CSP, 250 mg, tid C: 3 72 Xu XM [7] (60/0) CSP, 250 mg, tid Sun L [] A: (2/2) CSP, 250 mg, tid C: 5. Zhang GH [9] 33(69/6) CSP, 250 mg, tid (999) Wang SQ [50] (/0) CSP, 250 mg, tid (999) Ding XM [5] (52-50) CSP, 250 mg, tid 999 Zhou YM [52] (20/60) CSP, 250 mg, tid (99) A active intervention group (CSP group); C control intervention group (Nitrates group); NA no data available; NO not described; CSP compound salvia pellet. Adverse events ; C: (including 2 withdrawals) C: 57 A: 3 C: 5 C: 3 A: 3 C: 7(including 5 withdrawals) C: 5 C: 5 C: A: 3 C: 7

5 Med Sci Monit, 2006; 2(): -7 Wang G et al Compound salvia pellet for stable angina pectoris: a meta-analysis Figure 2. Funnel plot of symptom scores of chronic stable angina pectoris in trials of CSP. A graphical display of the logarithm of relative risk (RR) plotted against RR. The vertical line indicates that there was no publication bias. Compound salvia pellet versus nitrates There were twenty-seven trials (n=3722) recruited in this meta-analysis, and symptom scores including angina episode per week and ECG test of chronic stable angina pectoris were presented as outcome measures. When the randomeffects model was used because of the heterogeneity of the results of the trials (P<0.000), compound salvia pellet had significant effect on the improvement of angina symptoms compared with nitrates (P=0.0000, RR=.3, 95%CI=[.07,.20]). There were groups with different duration of treatment in six of the twenty-seven included trials. Accordingly, stratified analysis was used in terms of the duration of treatment. Statistical pooling of the results showed a significant difference in the increase in the improvement of angina symptoms in favor of CSP compared with nitrates in both less than four-week treatment (P=0.0, RR=.3, 95%CI=[.03,.23]) and over four-week treatment (P=0.0000, RR=.5, 95%CI=[.0,.23]). The ECG test was also used in all included trials. The randomeffects model was applied due to the heterogeneity of the results of the trials (P=0.0007). The meta-analysis of the ECG test suggested that treatment with compound salvia pellet had a significant effect on improvement of ECG compared with nitrates (P<0.0000, RR=.39, 95%CI=[.2,.50]). Furthermore, CSP showed greater increased effect on the improvement of ECG with both less than four weeks and more than four weeks treatment with compound salvia pellet compared with nitrates (P=0.0, RR=., 95%CI=[.03,.26]; P<0.0000, RR=., 95%CI=[.3,.53], respectively). In the included studies, other indexes, such as hemorheology and the level of serum lipid, were also reported, but a meta-analysis of these indexes was not undertaken due to the great differences in the variables. Sensitivity analysis A sensitivity analysis was performed in order to explore the influence of RCT quality on the effect size. The description of dropouts/withdrawals was undertaken in two [27,9] of the included trials. If the withdrawals were regarded as ineffective cases, worst-case scenario analysis was used. Finally, the sensitivity analysis showed that CSP also had significant effect on the improvement of angina symptoms and ECG test compared with nitrates (RR=.3, 95%CI=[.06,.20]; RR=.2, 95%CI=[.09,.56], respectively). In this metaanalysis, the random-effects model was used due to the heterogeneity of the results of the trials (P<0.00). When the fixed-effects model was applied, CSP maintained the same greater effect on the improvement of angina symptoms and ECG test compared with nitrates (RR=.6, 95%CI=[.3,.9]; RR=.3, 95%CI=[.36,.5], respectively). Adverse events Adverse events were described in 7 of the 27 trials (63.0%). Adverse events were reported in 26 of 093 (2.%) patients treated with CSP, in whom abdominal complaints, nausea, and dyspepsia were reported most often, and which completely alleviated without any treatment. But there were no dropouts or withdrawals for adverse events in the CSP group. In patients treated with nitrates, adverse events were reported in 267 of 900 subjects (29.7%), and there were 7 withdrawals for some serious complaints such as flush, dizziness, headache, and syncope. DISCUSSION Organic nitrates have been prescribed to patients with stable angina in the last 00 years or more and are still widely used in the treatment of such patients. However, some adverse effects have also been reported. The major problem with long-term used of nitroglycerin and long-acting nitrates is development of tolerance to them. Although in some clinical trials intermittent therapy seems to be a hopeful strategy in preventing nitrate tolerance and has proved superior to continuous therapy [5,55], it still has problems, such as possible association with rebound myocardial ischemia during the nitrate-free period and adverse effects on performance on treadmill exercise tests during the period of withdrawal from nitrates [7]. CSP, as one of the alternative therapies, is widely used in China, but the efficacy and safety of CSP for the treatment of chronic stable angina pectoris remains unclear. In China, under the guidance of the National Institute for the Control of Pharmaceutical and Biological Products, a quality control system and strict Standard Operating Procedures have been established in the Tasly Danshen Plantation Base and the Tasly Notoginseng Plantation Base, which govern all procedures including seed selection (including chromosome identification), seedling growth, nursing, field management, collection, harvest,processing, storage, packing, and transportation. Moreover, HPLC is used to assay the contents of medicinal ingredients in each batch and the fingerprint of CSP is established, which puts an end to the historical practice of assessing the quality of Chinese herbal drug materials just by experience. In this meta-analysis, most of the included trials were of low quality, with one or two points of the Jadad score. There were many limitations as follows: () there were no multi-center, randomized, clinically controlled trials, (2) no trials described the beforehand sample size calculation, the generation of the random allocation sequence, and the allocation concealment [56], (3) no trial described the blind method in detail for the different forms of drugs, and () one important 5

6 Med Sci Monit, 2006; 2(): -7 additional factor was that reports with nonstandard format can decrease the quality of trials [57]. Recently, investigators and editors have developed the CONSORT (Consolidated Standards of Reporting Trials) statement to help authors improve reporting by use of a checklist and flow diagram, and now the CONSORT statement is recommended to improve the reporting of an RCT, enabling readers to understand a trial's conduct and to assess the validity of its results [5]. Patients with angina are at substantially higher risk of cardiac death or myocardial infarction than are members of the general population. Therapies for patients with chronic stable angina are aimed at reducing symptoms, reducing the risk of death and myocardial infarction, or both. Symptomatic therapy is targeted at either reducing oxygen demand by decreasing the work of the heart or increasing oxygen supply by dilating coronary arteries. Symptoms and ECG test were regarded as the efficacy markers in all the included trials, but their criteria [59,60] were different to some degree. Moreover, there were no endpoints such as mortality, incidence of myocardial infarction, and, possibly, percutaneous intervention or surgery if medical treatment failed in these trials. Accordingly the assessment of endpoints and the quality of life were not included in this meta-analysis. Heterogeneity was significant statistically in the assessment of improvement in both symptoms and ECG test. Possible reasons for the heterogeneity are: () misuse of randomization [6], (2) different criteria for assessing the therapeutic efficacy, and (3) the kinds of nitrates with different quality criteria from different pharmaceutical companies. This meta-analysis of randomized trials suggested that CSP was much more effective than nitrates in the improvement of angina symptoms and ECG test in chronic stable angina pectoris. After stratified analysis was used in terms of the duration of treatment, statistical pooling of the results showed a significant difference in the improvement of angina symptoms and ECG test in favor of CSP compared with nitrates in both less than four-week treatment (RR=.3 and RR=., respectively) and over four-week treatment (RR=.5 and RR=., respectively). Because there were no endpoint events and long-term follow-up described in all trials, investigation of differences in mortality, quality of life, and, possibly, percutaneous intervention or surgery between CSP and nitrates is warranted in the future. CSP seemed to be relatively safe, and the adverse events most often reported were abdominal complaints, nausea, and dyspepsia. Interestingly, the percentage of patients with adverse events was significantly decreased in the treatment with CSP compared with nitrates (2.% vs. 29.7%) and, moreover, there were 7 withdrawals in the nitrate group but none in the CSP group. CONCLUSIONS In conclusion, this meta-analysis suggests that compound salvia pellet has significant effect on the improvement of angina symptoms and ECG test with few adverse events and no development of tolerance compared with nitrates and may be an alternative herb for nitrates in the treatment of stable angina pectoris. However, the methodological quality of clinical trials with CSP for stable angina pectoris needs to be improved in accordance with the CONSORT statement. Especially, rigorously designed, multi-center, large, randomized, double-blind, controlled trials are required. In addition, the outcome measures should include mortality, quality of life, possibly percutaneous intervention or surgery, and other end-points. REFERENCES:. Mickie P, Ronit Peled, Matityhau L et al: Reasons for overprescription of mononitrates: the paradigm of stable angina pectoris treatment. Current Therapeutic Research, 2003; 6: Glasser SP: Clinical mechanisms of nitrate action. Am J Cardiol, 99; : 9A 53A 3. Fihn SD, Williams SV, Daley J et al: American College of Cardiology, American Heart Association, American College of Physicians- American Society of Internal Medicine Guidelines for the management of patients with chronic stable angina: Treatment. Ann Intern Med, 200; 35: North of England Stable Angina Guideline Development Group: North of England Evidence Based Guidelines Development Project: Summary version of evidence based guideline for the primary care management of angina. BMJ, 996; 32: Gibbons RJ, Abrams J, Chatterjee K et al: ACC/AHA 2002 guideline update for the management of patients with chronic stable angina-summary article: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Chronic Stable Angina). Circulation, 2003; 07: Niemeyer MG, Kleinjans HAJ, de Ree R et al: Comparison of multiple-dose and once-daily nitrate therapy in 22 patients with stable angina pectoris: effects on quality-of life indices. Angiol 997; : Parker JD, Parker JO: Nitrate therapy for stable angina pectoris. N Engl J Med, 99; 33: Thadani U: Nitrate tolerance, rebound, and their clinical relevance in stable angina pectoris, unstable angina, and heart failure. Cardiovasc Drugs Ther, 997;0: Ji XY, Tan BK, Zhu YZ: Salvia miltiorrhiza and ischemic diseases. Acta Pharmacol Sin, 2000;2: Guo ZX, Jia W, Gao WY et al.: Clinical investigation of composite danshen pill for the treatment of angina pectoris. Chin J Nat Med, 2003; : 2 2. Shi YH: Comparative study of composite danshen droplet pills and sordi in treatment of patients with chronic stable angina. Zhongguo Zhong Xi Yi Jie He Za Zhi, 997;7: Zhou W, Ruigrok TJ: Protective effect of danshen during myocardial ischemia and reperfusion: an isolated rat heart study. Am J Chin Med, 990;: Wang AM, Sha SH, Lesniak W et al.: Tanshinone (Salviae miltiorrhizae extract) preparations attenuate aminoglycoside-induced free radical formation: in Vitro and ototoxicity in Vivo. Antimicrobial Afents and Chemotherapy, 2003; 7: 36. Wang J, Xu J, Zhong JB et al: Effect of radix notoginseng saponins on platelet activating molecule expression and aggregation in patients with blood hyperviscosity syndrome. Zhongguo Zhong Xi Yi Jie He Za Zhi, 200; 2: Chan P, Thomas GN, Tomlinson B: Protective effects of trilinolein extracted from panax notoginseng against cardiovascular disease. Acta Pharmacol Sin, 2002; 23: Zhou W, Chai H, Lin PH et al: Molecular mechanisms and clinical applications of ginseng root for cardiovascular disease. Med Sci Monit, 200; 0(): RA7 RA92 7. Wang L, Xiong ZY, Wang G, Li TQ: Systematic assessment on randomized controlled trials for treatment of stable angina pectoris by compound salvia pellet. Chinese Journal of Integrative Medicine, 200; 0: 22. Sampson M, Barrowman NJ, Moher D et al: Should meta-analysts search Embase in addition to Medline? J Clin Epidemiol, 2003; 56: McAuley L, Pham B, Tugwell P et al: Does the inclusion of grey literature influence estimates of intervention effectiveness reported in Metaanalyses? Lancet, 2000; 356: Jadad AR, Moore RA, Carrol D et al: Assessing the quality of reports of randomised clinical trials: is blinding necessary? Control Clin Trials, 996; 7: 2 6

7 Med Sci Monit, 2006; 2(): -7 Wang G et al Compound salvia pellet for stable angina pectoris: a meta-analysis 2. Moher, D, Pham B, Jones A et al: Does quality of reports of randomized trials affect estimates of intervention efficacy reported in meta-analyses. Lancet, 99; 352: Kjacrgard LL, Villumsen J: Reported methodological quality and discrepancies between large and small randomized trials in meta-analyses. Ann Intern Med, 200; 35: Clarke M, Oxman AD (eds.): Cochrane Reviewers Handbook.0 (Section 6). In: The Cochrane Library [database on CDROM], The Collaboration. Update Software, Oxford, 2000, Issue 2. Schulz KF, Chalmers I, Hayes R et al: Empirical evidence of bias. JAMA, 995; 273: Vickers A, Goyal N, Harland R et al: Do certain countries produce only positive results? A systematic review of controlled trials. Control Clin Trials, 99; 9: Egger M, Smith GD, Schneider M et al.: Bias in meta-analysis detected by a simple graphical test. BMJ, 997; 35: Huang SW, Zou XQ, Li P: clinical observation on compound Danshen dropping pill and isosorbid dinitrate treating stable angina. Mod Diagn Treat, 200; 5: Chen KY: The study on the compound salvia pellet in the treatment of coronary heart disease compared with isosorbide mononitrate. Health Vocational Education, 200; 22: Rong JH, Gu JG, Qian XF: The effect of compound salvia pellet on angina symptoms and hemorheology in senile patients with coronary heart disease. Journal of Nantong Medical College, 200; 2: 30. He YZ: Clinical observation on compound salvia pellet in the treatment of angina pectoris: a report of 0 cases. Health Vocational Education, 200; 22: Wang JS, Yuan XL, Zhao XY: The study on the compound salvia pellet in the treatment of coronary heart disease compared with isosoride dinitrate. Chinese Journal of Information on traditional Chinese Medicine, 2003; 0: Liu YH, Li HS: The effect of compound salvia pellet on drug resistance and hemorheology in angina pectoris. Journal of Liaoning College of TCM, 2003; 5: Yuan XL: Clinical observation on compound salvia pellet in the treatment of effort angina. Shandong Yiyao Gongye, 2003; 22: Chu XB, Geng J: Clinical observation on compound salvia pellet in the treatment of stable angina. Heilongjiang Journal of Traditional Chinese medicine, 2003; : Wang XL, Shen LP, Yan LM: Clinical observation on compound salvia pellet in the treatment of stable angina pectoris. Acta Acad Med Neimongol, 2003; 25: Li XL, Zhou YT, Huang HF: Clinical observation on compound salvia pellet in the treatment of stable angina pectoris evaluated by exercise treadmill test. Chinese Journal of Gerontology, 2003; 23: Sun YZ: Effects of the treatment of compound Danshen dropping pills on stable angina pectoris. Theory Pract Chin Med, 2002; : Yao YX: Clinical observation on compound Danshen dropping pill treating 50 cases of angina. J Emergency Syndrome TCM, 2002; : Yao FH, Zhang YS, Huang MH et al: Treating 50 cases of stable angina pectoris with compound Danshen dropping pill. Shandong J TCM, 2002; 2: Wu K, Chen HP, Wei B et al: Research on the resistance of compound Danshen dropping pill to angina versus nitrate. Chin J Modern Applied Pharmacy, 200; : Dong XM, Zhang SX: Observation on effect of compound Danshen dropping pill treating angina. Pract Clin Med, 200; 2: 3 2. Yang SM, Huang T, Wang HW: Observation on effect of compound Danshen dropping pill and nitrate treating angina. Acta Academiae Medicinae Wannan, 200; 20: 9 3. Guo LX, Li SX, Zhang WH: Clinical observation on compound Danshen dropping pill treating angina. J Linyi Med College, 200; 23: 3 5. Lu J, Sheng HP: The summary of compound Danshen dropping pill in treating stable angina pectoris. Gansu J TCM, 200; : Zhu YQ: The effective comparison between compound Danshen dropping pill and nitrate treating stable angina pectoris. Gansu J TCM, 200; 2: Wu S, Liu HF: The analysis of long-term effects of compound Danshen dropping pill treating 35 cases of angina. Ningxia Med J, 2000; 22: Gao B, Wu YQ. The effect of 60 cases of stable angina pectoris treated with compound Danshen dropping pill. J Binzhou Med Coll, 2000; 23: 6. Xu XM: Clinical observation of 60 cases of angina pectoris treated with compound Danshen dropping pill. Chin Tradit Herbal Drugs, 2000; 3: 9. Sun L, Dai PS, Shao J: Treating 0 cases of coronary heart disease with compound Danshen dropping pill. Tianjin J Tradit Chin Med, 2000; 7: Zhang GH, Cao Y, Liu ZG: Treating 69 cases of stable angina pectoris with compound Danshen dropping pill. Jilin Journal of TCM, 999; 3: 0 5. Wang SQ, Zhou XL, Zhang YH: The effect of 0 cases of angina pectoris treated with compound Danshen dropping pill. J Changchun Coll TCM, 999; 5: Ding XM, Jia LZ, Wang CH et al: The effects of compound Danshen dropping pill treating stable angina. Acta Academiae Medcinae Suzhou, 999; 9: Zhou YM: Treating 20 cases of stable angina pectoris with compound Danshen dropping pill. Chin J New Drugs Clinical Remedies, 99; 7: Silber S. Nitrates: why and how should they be used today? Current status of the clinical usefulness of nitroglycerin, isosorbide dinitrate and isosorbide-5-mononitrate. European Journal of Clinical Pharmacology, 990; 3(Suppl.): S Todd PA, Goa KL, Langtry HD: Transdermal nitroglycerin (glyceryl trinitrate): a review of its pharmacology and therapeutic use. Drugs, 990; 0: Schulz KF, Altman DG, Moher D: Allocation concealment in clinical trials. JAMA, 2002; 2: Moher D, Altman DG, Schulz KF et al.: Opportunities and challenges for improving the quality of reporting clinical research: CONSORT and beyond. CMAJ, 200; 7: Moher D, Schulz KF, Altman DG: The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomized trials. Lancet, 200; 357: Ministty of Public Health P. R. China: Guide of drugs for good clinical practice. 993; Chen kj, Liao JZ, Xiao ZX. Research of cardio-/cerebro-vascular disease. Shanghai Scientific and Technical Publishers, 99; Liu JP, Kjaergard LL, Gluud C: Misuse of randomization: a review of Chinese randomized trials of herbal medicines for chronic hepatitis B. Am J Chin Med, 2002; 30: