Chinese patent medicine for stable angina pectoris:protocol for a systematic review and network meta-analysis

Background

Cardiovascular diseases (CVDs) are the world's leading cause of death, accounting for 31% of all deaths worldwide[1].According to the

the prevalence of CVDs is steadily rising, with an estimated 290 million population being affected, among which 11 million suffered from coronary artery diseases(CAD)[2].

Angina pectoris is the most common manifestation of CAD.It is a clinical syndrome characterised by pain or discomfort in the chest, epigastrium, mandible,shoulders, back and upper limbs [3].The global prevalence of angina caused by CAD was estimated at 112 million in 2010 (1.6% of the global population by then) [4].In China, a cross-sectional survey of 5315 elderly adults in five provinces across the Chinese mainland estimated the prevalence rate of angina to be 7.19 % [5].Stable angina is angina precipitated by physical activities, emotional stress or even heavy meals, and readily abate when the precipitant is relieved or upon administration of sublingual nitroglycerin [6].Despite recent advances in pharmacotherapy, surgical treatment and percutaneous coronary intervention, angina is a highly recurrent condition leading to poor quality of life, substantial financial costs and substantial morbidity and mortality.Pharmacological management of stable angina is effective in ameliorating symptoms and preventing cardiovascular events.However, the use of anti-ischaemic and antiplatelet drugs such as nitrates and aspirin recommended as the first-line choice by clinical practice guidelines have been found to have many drawbacks, such as inducing adverse effects including hypotension, headaches and bleeding [7].Also, non-compliance, nitric oxide resistance, nitrate tolerance and high platelet reactivity to antiplatelet agents may result in treatment failure[7,8].

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Chinese patent drugs (CPDs) for stable angina aiming at restoring global harmony while clearing heart vessel obstruction (such as blood stasis) have been proposed as an alternative treatment option,especially for those seeking holistic therapy or who could not tolerate the side effects of first-line pharmacotherapy.According to statistics,a total of 349 CPDs involving 207 different herbal formulas have gained marketing approval from the Chinese Food and Drug Administration for the management of CAD [9].These drugs have been widely prescribed for the management of stable angina in China and the Chinese communities worldwide.Some of these CPDs have gained new drug approval in many western countries[10].Clinical studies found CPDs evidently improved angina symptoms [11–14], frequency [15–18] and duration[17,19],electrocardiograph results[16,18,19,22]and reduced the consumption of glycerin trinitrates[20–22]in patients with stable angina.

A Cochrane systematic review of traditional Chinese herbal products for stable angina found 3 high-quality trials involving 216 participants and provided only qualitative analysis [23].This review searched literature published from 1994 to 2008.Data pooling was infeasible as too few studies were included.A 2013 meta-analysis investigating the add-on effect of CPDs for stable and unstable angina included 9 trials for stable angina [24].It was found that CPDs plus routine treatment is more effective in preventing total heart events (RR = 0.5, 95% CI 0.33–0.78) and improving angina (RR = 0.46, 95% CI 0.30–0.71)compared to routine treatment [24].This study restricted the literature search from database inception to 2010 and analysed CPDs as a whole.

Traditional Chinese Medicine (TCM) practitioners manage diseases according to TCM pattern diagnosis.For instance, the blood-stasis pattern will be treated using a blood-quickening formula.The blood-stasis pattern is the most representative TCM pattern in angina patients.It is present in 87.2% of angina patients according to a retrospective epidemiological analysis of 2648 inpatients [25].Currently, many blood-quickening CPDs are available to manage stable angina presenting with the blood-stasis TCM pattern.However, information on the unique therapeutic features and the comparative efficacy and safety is generally experience-based rather than evidence-based.

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Head-to-head trial findings may best inform clinical decision-making.However, not many clinical trials make direct comparisons among drugs for the same TCM pattern and will typically involve only two drugs if there are any.An alternative strategy for obtaining relative data is to perform a network meta-analysis of multiple CPDs using both direct comparisons from a parallel controlled trial and indirect comparisons across different trials, all with a common comparator.By far, there is no published systematic review and network meta-analysis investigating the relative efficacy and safety of different blood-quickening CPDs for stable angina.

The objectives of this review are:(1)to estimate the relative efficacy and safety of blood-quickening CPDs for stable angina(blood-stasis pattern);(2)to provide a clinically meaningful ranking of commonly used CPDs according to their efficacy and safety profile.

Methods and analysis

The protocol is designed following the PRISMA-P 2015 checklist [26] and the PRISMA-NMA extension[27].

Inclusion criteria

Randomised controlled trials including at least 50 participants for each arm will be considered for inclusion.The treatment period should last no less than four weeks.

Patients with a definite diagnosis of coronary artery disease and stable angina according to internationally acknowledged diagnostic criteria.All patients should be diagnosed with blood-stasis patterns according to TCM pattern differentiation.The diagnostic criteria could be from textbooks [28],clinical guidelines [7, 29, 30] and the Guideline for Clinical Research on Registered New Chinese Herbal Drug [31].No restriction will be made on age, sex or ethnicity.

Interventions and comparisons

Experimental interventions: A list of 24 widely-used blood-quickening oral CPDs was composed based on literature review and clinician consultation.Restrictions were made to avoid confounding.Only oral drugs are selected as the same formula made into different dosage forms may vary a lot in the onset and lasting time of effects.

The CPD screening and selection process involves the following steps.Firstly,the 2012 National Essential Drug List [32] and the 2015 Chinese Pharmacopoeia[33] were reviewed to form a comprehensive list of CPDs for CAD or blood-stasis pattern; Secondly, the list was narrowed down to 45 CPDs for angina with blood-stasis pattern after referring to commonly used manuals for practitioners using Chinese patent drugs[34, 35];Thirdly,two chief physicians (QX and BHW)with over 20 years experience in TCM practice for CAD were given the list and were asked to select the most commonly prescribed drugs and those well tolerated by the patients based on experience, forming a list of 24 CPDs.

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Comparators and comparisons: The comparator intervention could be any one of the 24 drugs on the list, routine treatment, active control (nitrates) or placebo control.Studies investigating the following comparisons will be included:

1.Chinese patent medicine + routine treatment v.s.another Chinese patent medicine + routine treatment;

Primary outcome: Primary outcomes are the incidence of cardiovascular events and changes in angina symptoms (including frequency, duration and intensity).Outcome indicators for measuring changes in the angina symptom could be composite indicators such as the clinical effective rate or for a specific aspect of the clinical angina symptom, for instance,angina intensity measured with the use of VAS(Visual Analogue Scale).

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2.Chinese patent medicine + routine treatment v.s.active control/blank/placebo+routine treatment;

3.Chinese patent medicine v.s.active/placebo control;

4.Chinese patent medicine v.s.another Chinese patent medicine;

By routine treatment we refer to conventional pharmacotherapy typically involve the use of anti-ischemic western drugs.

Outcome

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Secondary outcomes: Secondary outcomes include changes in TCM syndrome/symptom score,angina-specific patient-reported health status (with the use of the Seattle Angina Questionnaire),cardiac stress response (with the use of the Treadmill Exercise Test),electrocardiograph findings, reduced or discontinued use of nitroglycerin and adverse events.

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Search strategy

Two authors (XFG and JL) will independently extract data and fill in a standard data extraction form.Any discrepancy will be consulted with a third author(YHH).The following information will be retrieved:

Relevant studies will be identified by searching for papers published from January 2000 to July 2021 on PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, the web-based China National Knowledge Infrastructure,China Biology Medicine,Wanfang,and VIP databases,and the Taiwan-based Airiti Library.Published reports in English or Chinese will be included.An example of the search strategy developed for collecting randomised studies of one CPD on PubMed is shown in Table 1.

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We will also search for eligible studies from the reference list of included studies and published systematic reviews and from major registries such as the World Health Organization International Clinical Trials Registry Platform, Clinical Trials.gov and the Chinese Clinical Trials Registry.The author of a registered or published study will be contacted for additional information.The manufacturer of the 24 CPDs will be contacted for product proceedings, academic promotional materials, and published and unpublished data.

Study selection

If statistical heterogeneity is great among studies (for instance, I

is greater than 75%), subgroup analyses and network meta-regression will be performed if studies suffice.The below mentioned clinical and methodological variables will be considered as possible sources of between-study heterogeneity and network inconsistency:

Data extraction and management

The authors in charge have been trained in hands-on workshops for medical literature search previously and in a pre-study seminar.We will adopt an evidence-based search strategy especially designed for the topic in question [36] and have a medical librarian critically revise the search algorism.The search will be updated before the review is ready for publication.

1.General information (title, author, country,funding,year,trial registry);

2.Participant and intervention information(epidemiological characteristics, clinical features,the balance of baseline, sample size, diagnostic criteria,inclusion and exclusion criteria,treatment and comparator, details of routine treatment,treatment duration, dosage, regimen, follow-up,etc.);

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The Cochrane risk of bias tool [38] will be used for assessing the methodological quality of included trials.The risk of bias for each study will be assessed from the following domains: sequence generation (selection bias); allocation concealment (selection bias); blinding of participants and personnel (performance bias);blinding of outcome assessment (detection bias);incomplete outcome data (attrition bias); selective outcome reporting(reporting bias);and other biases.

4.Methodological details.

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Risk of bias assessment

3.Primary and secondary outcomes and adverse events;

Two authors (XFG and JL) will independently evaluate each study for the above aspects of risk of bias and judge them as low, unclear or high risk.

Where necessary, the authors of a primary study will be contacted for clarification of information.The results will be cross-checked, and any disagreement will be resolved through discussion or consultation with a third reviewer(YHH).

The global risk of bias for an individual study will be categorised as low if all domains are evaluated to be at low risk.Otherwise, the global risk of bias will be categorised as unclear or high.A 'Risk of bias'summary table will be presented.

Statistical analysis

.Treatment efficacy and safety will be summarised with an odds ratio (OR)and 95% confidence intervals (CI) for dichotomous data such as the total effective rate for angina improvement.Moreover, treatment effects will be summarised with mean difference (MD) or possibly standard mean difference (SMD) estimates with 95% CI for continuous data.

Additional summary measures, including the surface under the cumulative ranking curve (SUCRA) and the mean OR/MD for each pairwise comparison,will also be assessed.

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4.nitrates or placebo as the comparator intervention.

We will include cross-over and multi-arm trials.Only the first phase of a cross-over trial will be considered to avoid potential bias from the carry-over effect.Multi-arm studies will be treated as multiple pairwise comparisons in analysis.

.The author of the original study will be contacted for possible contributions of missing data.Otherwise, the worst-case scenario analysis will be adopted, in which patients lost to follow-up are considered treatment failures, for assessing the impact of missing data on the results.

Assessment of heterogeneity and inconsistency

We will check clinical and methodological heterogeneity within each comparison by comparing descriptive study statistics retrieved in the data extraction form.Statistical heterogeneity on the whole network will be assessed by the Cochran's Q test [39], and heterogeneity among included studies reporting a common outcome will be tested using a Chi

test and I

test.A statistically significant variation is assumed if the P-value of the Chi

test exceeds 0.1 or I

is above 50%.Subgroup analysis or meta-regression will be attempted in seek of the source of clinical or methodological heterogeneity.

.The assumption of transitivity will be assessed by comparing the distribution of possible effect modifiers across pairwise comparisons.In the context of this study, it is expected that this assumption will hold that the common comparator (routine treatment, for example) by which to compare different interventions indirectly is similar across studies.

.The consistency and inconsistency of evidence from comparative studies of multiple interventions and their relevant convergence will be checked in each closed loop in the evidence structure using the ADDIS software v1.16.6.

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Data synthesis

We will conduct pairwise meta-analyses with the Review Manager 5.3 software.A qualitative description will be provided for each study included if quantitative synthesis is meaningless in the case of the collection of insufficient or heterogeneous data for a specific outcome.

The Inverse Variance method will be used to pool the continuous outcome and the Mantel-Haenszel method for the dichotomous outcome.The choice between a fixed-effect and a random-effect model typically depends on the degree of statistical heterogeneity as evidenced by the I

value relative to 50%.A random-effect model will be adopted if I

is greater than 50% or a more conservative estimate of effect is wanted.

Unlike a meta-analysis that typically compares two interventions, network meta-analysis enables the simultaneous comparison of multiple treatments within a network framework,drawing upon both direct comparisons within randomised controlled trials and indirect comparisons across trials based on a common comparator [40]With the inclusion of indirect comparisons, treatment comparisons that have never been addressed directly in any research will be approached statistically [41].Besides, joint analysis of data is believed to increase precision for comparisons with few data[42].

In the present study, network meta-analyses will be performed using the WinBUGS 1.4.3 (MRC Biostatistics Unit, Cambridge University, UK)software.The Stata 13.0 software will be used to generate graphs and figures to demonstrate the results of meta-analyses,including network plots,contribution plots,funnel plots and network forests.The DIC values will be calculated and be compared to determine the use of the fixed-effect or random-effect model.

The EndNote X7 software will be used for citation management.Two reviewers (WM and DK) will independently select publications against the inclusion criteria and assess them for eligibility, first by looking through the title and abstract of studies retrieved from the literature search and then retrieving and reviewing the full text of potentially eligible studies.Permission will be asked before the use of unpublished data.Discrepancies between reviewers will be resolved by consensus or discussion with a third reviewer (YHH).The study selection process will be demonstrated in a flow chart.

1.the interventional CPD involves multiple dosage forms or manufacturers;

2.patients complicated with another specific TCM pattern other than blood-stasis (i.e.qi deficiency,qi stagnation,yin deficiency);

3.patients with a history of other diseases (i.e.myocardial infarction,heart failure);

The SUCRA will be adopted for numeric presentation of efficacy/safety ranking probabilities of multiple treatments for each outcome.SUCRA values will be expressed as percentages ranging from 0% to 100%.The greater the percentage, the superior the rank in the treatment hierarchy.

Sensitivity analysis

If necessary, sensitivity analyses will be performed for the primary outcome to investigate the possible effect of the below-mentioned factors on the pooled results:

1.exclusion of studies with small effect size and large CI;

2.fixed effect model versus random effect model;

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3.exclusion of unpublished data;

4.sole inclusion of studies with a low risk of bias.

Assessment of reporting bias

A funnel plot will be used to test small–study effect for the network meta-analysis [43].Moreover, a funnel plot for each pairwise meta-analysis will be performed to investigate publication bias if more than 10 studies reported one common outcome[44].

Quality of evidence

The web-based GRADEpro GDT [45] will be used to create a summary of findings table for important outcomes.Based on findings from randomised trials,the quality of evidence summarised has an initial high rating.It will be rated down for the following reasons:limitations in study design, imprecision, inconsistency,indirectness and publication bias.We will adopt the GRADE four-step approach for rating the quality of treatment effect estimates from NMA[46], which pays special attention to intransitivity,incoherence and other problems induced by the pooling of indirect and direct comparisons.The quality of evidence for each outcome will fall into one of the four ratings(very low,low,moderate and high).

Amendments

Any amendment to the present protocol will be explained and reported.

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Ethics and dissemination

Ethical approval is not required because no primary data is collected.This review will provide a comprehensive assessment regarding the effect of CPDs on stable angina patients presenting with the blood-stasis pattern.We will publish findings from this systematic review and network meta-analysis in a peer-reviewed scientific journal.

Patient and public involvement

We will not enlist patient and public opinion or help in the conduct of this systematic review and network meta-analysis.

Discussion and conclusion

This network meta-analysis will be among the first to provide a systematic evaluation of the relative effect of a number of commonly used Chinese patent drugs on each pre-specified outcome of stable angina and give a ranking of all interventions.The quality of primary studies could be low and the risk of publication bias high.Therefore, the authors applied strict eligibility criteria in the study selection process.All the included studies will be rigorously evaluated for methodological quality, and the quality of evidence will be assessed within the GRADE framework.The findings of this research are expected to inform practice and guideline development.

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