The study protocol has been registered in the international prospective register of systematic review (PROSPERO). The trial registration number of PROSPERO is CRD42019131346. The procedure of this protocol will be conducted according to the Preferred Reporting Item for Systematic Review and Meta-analysis Protocols (PRISMA-P) guidelines.19
Type of study
Inclusion: We will include all the RCTs that investigated the effectiveness and safety of XKS combined with conventional pharmacotherapy for the treatment of CHD patients with anxiety and depression after PCI.
Exclusion: The studies will be excluded if it is not an RCT (namely, observational cohort and case–control studies, case reports, experimental studies and reviews ).
Inclusion: The study will include adult (18–85years) CHD patients with anxiety and depression after PCI regardless of sex, ethnicity, education or economic status and whether or not they were out- or in-patients. The diagnostic criteria for CHD, anxiety and depression will be as follows.
The diagnostic criteria of CHD should be confirmed according to one of the past or current definitions: Report of the Joint International Society and Federation of Cardiology (IFSC) / World Health Organization (WHO) task force on standardization of clinical nomenclature of ischaemic heart disease, or the American College of Cardiology (ACC) / American Heart Association (AHA) guideline update for the management of patients with chronic stable angina or Chinese Association of Cardiology or unstable angina pectoris diagnosis and treatment recommendations .20-22
Anxiety and depression must be defined as anxiety disorder or clinical anxiety and depressive disorder or clinical depression diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders (DSM), the International Classification of Diseases (ICD) by a standardized interview (e.g., Structured Clinical Interview, Composite International Diagnostic Interview) or the Chinese Classification of Mental Disorders (CCMD).23-25
Exclusion: Patients with either CHD or depression or anxiety only will be excluded. Patients with severe respiratory disease, acute infectious disease, severe heart disease, severe liver disease or tumors will be excluded.
Inclusion: Eligible interventions will be those involving a combination of XKS and conventional pharmacotherapy . The same conventional pharmacotherapy must be used in the control group.
Exclusion: Trials that include other co-interventions such as another herbal formula, acupuncture, cupping, moxibustion, massage, yoga, qigong, Tai Chi, or aromatherapy will be excluded.
Inclusion: The primary outcome measures will include the following: CHD-related clinical evaluation (frequency of acute angina, severity of angina pectoris, electrocardiographic changes, dose of nitroglycerin), the scores or reduction in scales measuring depression and anxiety (i.e., the Hospital Anxiety and Depression Scale or other widely used anxiety / depression scale). The secondary outcome measures will include the following: total cholesterol(TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) levels, and the Traditional Chinese Medicine (TCM) syndrome scale. The safety outcomes will include the following: adverse events (such as digestive symptoms, headache, dizziness, skin rash etc.), liver or kidney toxicity measured by serum markers.
Exclusion: The outcome measures not requested in this study will be excluded.
The following electronic bibliographic databases will be searched from inception to July 2020: PubMed, Embase, the Cochrane Library, China National Knowledge Infrastructure (CNKI), Chinese Scientific Journals Database (VIP) Database, Chinese Biomedical Database (CBM), Chinese Biomedical Literature Service System (SinoMed) and Wanfang Database. A manual search of key journals and of the reference lists of reviews captured by the initial searches will also be performed. There will be no limits on the language of publication. Only clinical trials will be included and searched. The following sources will also be searched to identify clinical trials that are in progress or completed: Clinical Trials.gov and WHO clinical trials registry. Any additional relevant studies will also be retrieved from the reference lists of systematic reviews and included studies. If possible, we will map search terms to controlled vocabulary. In addition, the search strategy for selecting the fields of title, abstract or keyword will differ depending on the characteristics of the databases. Search terms will be grouped into three blocks (see Table 1).
(Coronary Disease OR Myocardial Ischemia OR Coronary Diseases OR Disease, Coronary OR Diseases, Coronary OR Coronary Heart Disease OR Coronary Heart Diseases OR Disease, Coronary Heart OR Diseases, Coronary Heart OR Heart Disease, Coronary OR Heart Diseases, Coronary OR CHD OR Myocardial Infarction OR Cardiovascular Stroke OR Heart Attack OR Myocardial Infarct OR Acute Coronary Syndrome OR Angina Pectoris OR Angina, Stable OR Angina, Unstable OR Angina Pectoris, Variant OR Microvascular Angina)
(Depressions OR Depressive Symptoms OR Depressive Symptom OR Symptom, Depressive OR Symptoms, Depressive OR Emotional Depression OR Depression, Emotional OR Depressions, Emotional OR Emotional Depressions OR Depressive Disorders, Major OR Depressive Disorders OR Depressive Syndrome )
(Anxiety OR Anxiety Symptoms OR Anxiety Symptom OR Symptom, Anxiety OR Symptoms, Anxiety OR Nervousness OR Social Anxiety OR Anxieties, Social OR Anxiety, Social OR Social Anxieties OR Anxiety Disorder OR Disorder, Anxiety OR Disorders, Anxiety OR Neuroses, Anxiety OR Anxiety Neuroses OR Anxiety States, Neurotic OR Anxiety State, Neurotic OR Neurotic Anxiety State OR Neurotic Anxiety States OR State, Neurotic Anxiety OR States, Neurotic Anxiety)
Xinkeshu OR Xin Ke Shu OR XKS OR Xinkeshu tablet OR Xinkeshu capsule OR XKS tablet OR XKS capsule OR Xin Ke Shu tablet OR Xin Ke Shu capsule OR Drugs, Chinese Herbal OR Chinese Drugs, Plant OR Chinese Herbal Drugs OR Herbal Drugs, Chinese OR Plant Extracts, Chinese OR Chinese Plant Extracts OR Extracts, Chinese Plant OR Medicine, Chinese Traditional OR Traditional Chinese Medicine OR Chung I Hsueh OR Hsueh, Chung I OR Traditional Medicine, Chinese OR Zhong Yi Xue OR Chinese Traditional Medicine OR Chinese Medicine, Traditional
Randomized controlled trial OR controlled clinical trial OR randomized OR placebo OR drug therapy OR randomly OR trial OR groups
Study selection and data extraction
Literature retrieved citations will be managed by EndNote X7 software. Two authors (MC and YNC) will independently screen the titles and abstracts of all the studies retrieved in the above electronic databases to identify potentially eligible studies. Articles that are duplicated or have not met the eligibility criteria, interventions and outcomes in this study will be excluded. After filtering the final eligible articles, the data from the included articles will be extracted independently by two authors (MC and LM). Disagreements will be resolved by discussion or arbitrated by a third author if needed. The following categories of data will be extracted: first author, publication year, diagnose information, age, sex, trial characteristics, interventions and controls, participants, study methodology, outcomes, and adverse events (see Fig. 1).
Risk of bias assessment
The methodological quality of the eligible studies will be evaluated according to the Cochrane Collaboration’s tool for assessing risk of bias. The assessment details include: sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessors, incomplete outcome data, selective reporting and other sources of bias. Each domain will be assessed as “low risk”, “high risk” or “unclear risk” according to the description details of eligible studies.
Data synthesis and statistical analysis
Statistical analyses will be conducted with RevMan 5.3 software provided by Cochrane Collaboration. The overall effect sizes will be determined as the mean difference (MD) for continuous outcomes, the odds ratio (OR) for dichotomous outcomes with their 95% credible intervals (CIs). The Q and I2 test statistics will be calculated to determine the amount of heterogeneity. For the Q statistic, p < 0.05 will be considered to indicate significant differences. For the I2 statistic, I2 < 25% indicates no significant heterogeneity, I2 = 25–50% is considered moderate heterogeneity and I2 > 50% indicates strong heterogeneity. We will use fixed effects models if there is no heterogeneity among studies, and random effects models if there is heterogeneity.
Sensitivity analysis, subgroup analysis and meta-regression
If the heterogeneity or inconsistency among the studies is detected, a sensitivity analysis or subgroup analysis or meta-regression (conducted by Stata 12.0) analysis will be performed. Subgroup analysis will be conducted to explore potential sources of heterogeneity according to the characteristics of studies, including sample size, types of CHD, severity of depression, severity of anxiety, dose of XKS, treatment duration and other relevant parameters. If data extraction is insufficient, we will create a qualitative synthesis.
A funnel plot will be developed to evaluate reporting bias of the included studies. We will use Egger tests (conducted by Stata 12.0) to assess funnel plot symmetry and will interpret values of p < 0.1 as statistically significant.
Quality of evidence
We will also assess the quality of evidence for the main outcomes with the Grading of
Recommendations Assessment, Development and Evaluation (GRADE) approach. Five items will be investigated, including limitations in study design, inconsistency, inaccuracies, indirectness and publication bias.
Patient and Public Involvement
The patients and / or public will not be involved because this study uses secondary sources for analysis.