The Effect of Qi-Shao-Tong-Mai-An-Shen (QSTMAS) Herbal Paste in Coronary Heart Disease Patients with Depression and/or Anxiety: A Randomized Controlled Clinical Trial Protocol

doi:10.21203/rs.3.rs-2376982/v1

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Study protocol

The Effect of Qi-Shao-Tong-Mai-An-Shen (QSTMAS) Herbal Paste in Coronary Heart Disease Patients with Depression and/or Anxiety: A Randomized Controlled Clinical Trial Protocol

https://doi.org/10.21203/rs.3.rs-2376982/v1

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Background

Coronary heart disease (CHD) is a major disease threatening human life and health. Psycho-cardiology diseases aggravate not only the burden of finance but also the progression of CHD. Nowadays, a growing chorus of cardiovascular experts have come to call for an emphasis on the prevention and control of psycho-cardiology. Due to intricate adverse effects of antidepressants, it is urgent to explore a safe and effective early intervention method for psycho-cardiology diseases. Our medical team sought help from traditional Chinese medicine (TCM) and planned to explore the use of QSTMAS herbal paste in the treatment of CHD patients with Qi deficiency and blood stasis syndrome combined with depression and/or anxiety.

Methods

The single-blind, single-center, randomized controlled trial is designed to recruit 99 patients from China-Japan Friendship Hospital. All patients will be randomly assigned in a 1:2 radio. Both groups will receive standard western medicine treatment for CHD. The test group 2 will be treated with an additional 30ml QSTMAS herbal paste, orally twice daily for up to 12 weeks. The primary endpoints of the study are the changes in GAD-7 and PHQ-9 scores before and after the 12 weeks of intervention. The secondary endpoints included the clinical efficacy of TCM Syndromes of CHD, 6-minute walking test (6MWT), ISI Sleep Scale, laboratory tests, and examinations of the two groups before and after the 12 weeks intervention.

Discussion

QSTMAS herbal paste is a potential and promising treatment option for the treatment of mild and moderate psychological disorders in the cardiology department. The strict trial design will ensure the objective and scientific evaluation of the clinical efficacy and safety of the combination of QSTMAS herbal paste and standard western medicine in the treatment of CHD patients with Qi deficiency and blood stasis syndrome combined with depression and/or anxiety.

Trial registration:

China Clinical Trial Registry, ChiCTR2200065179, Version 2.0, Registered on 31 October 2022. http://www.chictr.org.cn/listbycreater.aspx.

CHD

Qi Deficiency and Blood Stasis

Depression

Anxiety

Qi-Shao-Tong-Mai-An-Shen Herbal Paste

Coronary Heart Disease (CHD) is a serious threat to human health and one of the leading causes of death worldwide[1–3]. With the increasing pressure of modern life, CHD complicated with depression and/or anxiety (namely psycho-cardiology disease) becomes more common. Cardiovascular disease and mental disorders have become two major diseases that affect the physical and mental health of mankind[4–6]. Cardiac events or cardiac surgery may be so painful life events that the incidence of mental complications in patients with cardiovascular diseases is much higher than that in the general population[7]. Mental disorders are associated with poor outcomes including increased nonfatal events[8, 9], and even greater mortality in healthy individuals and patients with CHD.[10–14]. Also, it is reported that depressive disorder is the main reason for disability. It is estimated that as many as 264 million people are suffering from depression in the world[15], and about 15% of them die of suicide.

In the UNWIND trial, escitalopram was found to be effective for CHD patients with depression or anxiety[16]. However, adverse effects (AEs) of escitalopram, such as appetite problems, weight gain, insomnia, dazzling or sleepiness, trouble those patients at the same time[17, 18]. Thus, current guidelines recommend non-psychotropic drug intervention as the initial treatment[19]. Yet, numerous clinical and experimental studies have confirmed that Traditional Chinese medicine (TCM) has a definite effect and relatively high safety in the treatment of psycho-cardiology disease[20–23]. QSTMAS herbal paste, one Chinese patent preparation summarized by Professor Huang Li based on 40 years of clinical experience, is used to treat coronary heart disease with qi deficiency and blood stasis symptoms. The effects of QSTMAS herbal paste include supplementing Qi, promoting blood circulation, nourishing the heart, and soothing the nerves. Preliminary data analysis results[24] showed that the core components of QSTMAS herbal paste were also effective for emotional problems or serious insomnia, and no serious adverse effects have been observed. On this basis, optimizing this recipe is expected to obtain a better clinical curative effect.

Whether QSTMAS Herbal Paste can be recommended for the management of CHD with Qi deficiency and blood stasis syndrome combined with depression and/or anxiety in the clinical situation is still absent of advanced evidence-based clinical proofs. Hence, we plan to conduct a single-center, single-blind, randomized controlled trial to verify the efficacy of QSTMAS herbal paste on this kind of patients mentioned above.

Objective

This trial aims to evaluate the curative effect of QSTMAS herbal paste for CHD patients with Qi deficiency and blood stasis syndrome combined with depression and/or anxiety.

Study design

It is a single-center, single-blind, randomized controlled trial is an exploratory clinical study, which is approved by ethics committee of China-Japan Friendship Hospital (No.2022-KY-174-1, September 23, 2022). A total of 99 CHD patients with Qi deficiency and blood stasis syndrome combined with depression and/or anxiety in China-Japan Friendship Hospital will be enrolled from November 2022 to August 2024 will be randomized 1:2 into the test group 1 and the test group 2 and then receive their respective interventions for 12 weeks. Figure 1 presents the schedule of evaluations.

Inclusion criteria

Confirmed to the diagnostic criteria of CHD,
Confirmed to TCM syndrome of Qi deficiency and blood stasis,
Confirmed to the diagnostic criteria of mild and moderate depression and/or anxiety using psychological evaluation scales and the early warning system of China-Japan Friendship Hospital,
Age 18-65 years old,
Accept and cooperate with the trial scheme；
Volunteer to participate in this study and sign the informed consent forms,

People who meet the above requirements will be included in this study.

Exclusion criteria

Patients who are receiving anxiolytics, antidepressants or drugs for other mental disorders within one month,
Combined with severe cardiac insufficiency, such as Killip grade II and above, NYHA grade III and above,
Combined with other serious diseases, such as severe liver and kidney dysfunction (ALT > 3 × upper limits of normal, SCR > 221 μ mol/L), Severe consumption state or malignant tumor,
Pregnant or lactating women, or those with pregnancy plans,
Suspicious or definite allergy to TCM or proprietary Chinese medicine,
Those who use TCM with similar efficacy within 2 weeks,
Those who are participating in other clinical studies now or within one month.

People who meet any of the above conditions will be excluded.

Outcome measures

Efficacy evaluation index

Primary endpoint

GAD-7 and PHQ-9 scale scores before and after intervention.

Secondary endpoints

A quantitative score of TCM syndrome classification of CHD
6-minute walk test (6-MWT)
24h Holter and Heart Rate Variability (HRV)
Insomnia severity index (ISI) score
Laboratory tests: blood glucose, blood lipid, blood coagulation function, markers of myocardial infarction (Myo, CK-MB, cTnI (or cTnT) and NT-proBNP (or BNP)), FGF21, β-klotho, BDNF, COR,5-HT, DA).
Examination: echocardiography,12 leads ECG.

Safety index

Vital signs, the occurrence of cardiovascular adverse events, blood, urine and stool routine, blood coagulation, liver and kidney function as well as 12 leads ECG changes.

Other indexes

Other index includes social impact scale (SIS) score.

Interventions

Test group 1: Take standard western medicine treatment for CHD regularly within 12 weeks, including antiplatelet agents, anticoagulants, β receptor blockers, nitrates, statins and other drugs recommended by guidelines and consensus. Routine coronary intervention is also acceptable according to the condition.

Test group 2: Standard western medicine treatment for CHD as mentioned above combined with QSTMAS herbal paste. Take QSTMAS herbal paste regularly for 80% or more of 12 weeks.

Randomization and blinding

Using the random number generator in SPSS (version 26.0), the corresponding random numbers of 99 patients are generated. Using the random case sample function, 99 patients are randomly divided into test group 1 and test group 2 in the ratio of 1:2. Test group 1 is recorded as 1 and the test group 2 is recorded as 2. This study adopts the single-blind method, that is, the blind endpoint. Only the outcome evaluators are blind. The outcome evaluators and data analysts are third-party personnel, and they are unaware of the grouping of subjects and the allocation of intervention measures.

Recruitment, Study plan and follow-up

Before recruitment, a written informed consent form will be obtained from all eligible patients. Patient Consent Form (PCF) will be given to every participant. Investigators explain the trial design and describe what the data is used in detail. Subsequently, all enrolled patients are screened for 7 ± 3 days (V0). During this period, their western medicine use will be checked and regulated according to their clinical conditions according to the 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes[25]. Standardized western medicine treatment includes antiplatelet, anticoagulant β-blockers, nitrates, statins, etc.

After the screening, enrolled patients will be randomized to test group 1 or 2 at the baseline visit (V1). Besides standardized western medicine, patients assigned to the test group 2 should also take one packet (30ml) of QSTMAS herbal paste twice daily.

In the 12-week course of treatment, this trial has three visits. Participants can withdraw from the study whenever they want. Patients will be followed by investigators via telephone calls, patient medical records, and/or clinic visits for approximately 4weeks (±3 days) until all-cause death, withdrawal of consent, loss of follow-up, or end of the study. All the visits and contents are described in Table 1.

Table 1. Study visits

Study phase Item	Screening	Baseline	Treatment phase
Time	-1 week ± 3days	0week ± 3days	4 week ± 3days	8 week ± 3days	12 week ± 3days
Study visits	V0	V1	V2	V3	V4
Written informed consent	√
Inclusion and exclusion criteria		√
General data		√
Blood pressure, Heart rate	√	√	√	√	√
History of present illness		√
History of past medical and allergies		√
History of personal and family		√
Medication records of CHD		√	√	√	√
Combined disease and medication records		√	√	√	√
Blood, urine, stool routine		√			√
Blood biochemistry (liver and kidney function, blood glucose, blood lipid)	√	√			√
Six-coagulation		√			√
Myocardial infarction four		√			√
FGF21、β-klotho、BDNF		√			√
COR		√			√
5-HT, DA		√			√
24h Holter + Heart Rate Variability		√			√
Echocardiography		√			√
ECG(12 leads)		√	√	√	√
Quantitative score of TCM syndrome grading		√	√	√	√
6-MWT		√			√
Score of GAD-7、PHQ-9 and ISI		√	√	√	√
Score of SIS		√			√
MACE			√	√	√

The study medication should be taken routinely for 12 weeks unless disallowed because of certain clinical conditions. In the case of comorbidities (such as hypertension or diabetes) and complications, appropriate western medicine can be given concerning the relevant guidelines. All drugs used should be recorded up to date by the investigators. Patients should not hesitate to seek emergency care if necessary.

Sample size estimation

The principle of minimum sample size is adopted. The dropout rate is calculated as 10%, and the patients are randomly divided into groups according to the ratio of 1:2. It is planned to include 99 cases, 33 cases in the test group 1, and 66 cases in the test group 2.

Data collection and Statistical analysis

Patients will be followed up by a study investigator until the end of the trial. All general data and outcome evaluations will be recorded in the case report form (CRF) at each study visit. The CRF will be carefully archived to protect its confidentiality. Investigators will also update an electronic database using SPSS (version 26.0). Only investigators, researchers and statistical analysts have access to the final trial dataset.

Statistical analysis for the trial will be performed by a third statistical team. Statistics software SPSS (version 26.0) will be used for the data analysis. Calculations for the outcomes will be based on a two-tailed test, except for the primary outcome, which will be a one-tailed test (level of significance α = 0.05). Besides the statistical comparison between baseline variables, the change in depression and anxiety score outcomes among baseline, 4, 8, and 12 weeks during the treatment phase will be performed using analysis of covariance adjusted for baseline and treatment to improve the efficiency and power of the tests. Survival analysis will be conducted using Kaplan-Meier and Cox regression models. The missing data analysis of the outcome measures will be adjusted using an estimating equation or statistical model. Sensitivity analysis will also be performed to assess the robustness of the data.

Supervision and quality control

A guideline of Standard Operating Procedure is set for every trained investigators. Regular supervision will be executed by the quality test group 1 and the monitors appointed by China-Japan Friendship Hospital. If it is really needed to communicate important protocol modifications, relevant parties should be informed the applicant in writing.

Ethical consideration and dissemination of information

This study is carried out under the guidance of Good Clinical Practice and the Helsinki Declaration[26, 27]. It adheres to the Standard Protocol Items: Recommendations for Interventional Trials Statements (SPIRIT)[28]. Strictly follow the 2017 Consolidated Standards for Extension Reports of Chinese Herbal Medicine Formulation Tests (CONSORT-CHM Formulas 2017)[29]. It is approved by ethics committee of China-Japan Friendship Hospital (No.2022-KY-174-1, September 23, 2022). Any modifications to the protocol will be reported to this committee, and amendment approval should be obtained before any changes can take place. Participants will be informed that the confidentiality of all information and data will be maintained anonymously. Consent forms should be signed by the participants before the study. All information will be encrypted and only the involved investigators can have access. Participants are free to withdraw at any time without giving a reason or punishment.

The concept of psycho-cardiology medicine proposed by Chinese Professor Hu Dayi in 1997, fundamentally broke through the limitation of biomedicine and promoted the development of the bio-psycho-social model[30]. Psycho-cardiology medicine has been paid more and more attention to by clinicians owing to the universality and high incidence of psycho-cardiology disease. According to a large global study[31], the secondary prevention of CHD should highlight the psychosocial burden except for known risk factors and treatment methods. Cardiovascular diseases and psychosocial diseases are closely related and mutually causal[32, 33]. Cardiovascular diseases characterized by a long course and repeated illness may easily induce psychological problems such as depression and/or anxiety and thus affect the outcome of cardiovascular diseases[34]. Early identification and intervention of depression and anxiety are of great significance for the prevention and treatment of psycho-cardiology disease[31]. Even though antidepressants reduce depressive symptoms, they are often associated with poor cardiovascular outcomes[35]. While the Chinese expert consensus on psychological prescriptions for patients in the cardiovascular department (version 2020) recommended syndrome differentiation and treatment of Chinese medicine for patients with mild and moderate mental disorders by trained cardiologists[36].

In this study, CHD patients with Qi deficiency and blood stasis syndrome combined with depression and/or anxiety will be enrolled. Relying on the psychological evaluation and early warning system of Sino-Japanese Friendship Hospital, the effect of QSTMAS herbal paste on psycho-cardiology disease patients with Qi deficiency and blood stasis syndrome will be explored. Hypotheses of this study are listed as follows: (1) The depression and anxiety scores of CHD patients with qi deficiency and blood stasis syndrome combined with depression and/or anxiety will significantly decrease after 12 weeks of QSTMAS herbal paste intervention; (2) TCM syndrome score, angina pectoris recurrence and sleep status will be significantly improved after 12 week of QSTMAS herbal paste intervention; (3) The laboratory tests and examination indexes will be significantly improved after 12 weeks of QSTMAS herbal paste intervention.

The innovation of this study includes the following two aspects: a) improvement of screening efficiency: relying on China-Japan Friendship Hospital psychological assessment and early warning system-outpatient subsystem to screen suspicious patients, the screening efficiency and the detection rate of depression and anxiety are improved while liberating medical personnel; b) expected considerable results: early detection of CHD patients with Qi deficiency and blood stasis syndrome combined with depression and/or anxiety and early intervention using TCM can improve the clinical efficacy of psychological and cardiac rehabilitation for CHD patients and improve the quality of life. Thus, QSTMAS herbal paste is also expected to reduce the incidence of MACE in the long term.

Currently, there is still no proprietary medicine suitable for CHD patients with Qi deficiency and blood stasis syndrome combined with depression and/or anxiety. When encountering patients with psycho-cardiology disease, doctors still need to combine psychotropic drugs with standard drug treatment for CHD. Therefore, the strength of this study is to explore the clinical curative effect of a clinical empirical formula for treating such types of patients. However, there are still some limitations: first, this study is an exploratory study, that is, no similar studies for reference. Calculation of sample size had not been carried out. After discussion with statistical experts, it is suggested that the principle of minimum sample size should be adopted, and clinical patients should be recruited at the ratio of 1 to 2. Secondly, placebo, which may lead to bias caused by psychological factors and other influences, was not set up to control the placebo effects. Yet, statistical analysts blinded to the intervention can guarantee to avoid the influence of subjective bias on research results.

Trial Status

This study plans to recruit patients from November 2022. The completion date is estimated at August 2024.

CHD

Coronary heart disease

CRF

Case report form

GAD-7

Generalized Anxiety Disorder-7-item (assessment)

HRV

Heart rate variability

ISI

Insomnia severity index

MACE

Major adverse cardiovascular events

6MWT

6-minute walking test

PCF

Patient consent Form

PHQ-9

Patient Health Questionnaire-9-item (assessment)

SIS

Social impact scale

TCM

Traditional Chinese medicine.

Acknowledgments

We thank the China-Japan Friendship Hospital for supporting the study. We also appreciate the involvement of all authors in this study.

Authors’ contributions

YC and XX contributed to the initial conception and design of the research. YC, XX, CXX, and were responsible for the collection, collation, and writing of the original manuscript. XX is the Research leader and critically revised the manuscript for important intellectual content. SLZ provided methodological guidance. QH, RQY and GYZ provided help to design and edited the manuscript. LH were responsible for managing and supervising the processes of the clinical research. All authors approved the final manuscript.

Funding

This study belongs to “A Study on the Transformation of the Psychological Assessment and Early Warning System of China-Japan Friendship Hospital in the Grading Management of Chinese and Western Medicine Cooperation of Patients”. This work was supported by National High Level Hospital Clinical Research Funding (2022-NHLHCRF-YXHZ-03).

Availability of data and materials

The study results will be available as the manuscripts, and no additional unpublished data are available.

Ethics approval and consent to participate

This study is carried out under the guidance of Good Clinical Practice and the Helsinki Declaration[26, 27]. It is approved by ethics committee of China-Japan Friendship Hospital (No.2022-KY-174-1, September 23, 2022). Before recruitment, a written informed consent form will be obtained from all eligible patients. Any changes to the protocol will be reported to the Committee.

Consent for publication

Not applicable.

Conflict of interest

The authors declared no conflict of interest.

Author details

¹Graduate School, Beijing University of Chinese Medicine, Beijing 100029, China.

²China-Japan Friendship Clinical Medical College, Beijing University of Chinese Medicine, Beijing 100029, China

³Department of Integrative Cardiology, China-Japan Friendship Hospital/National Center for Integrative Medicine, Yinghuadong Road No.2, Chaoyang District, Beijing 100029, China.

⁴Computer & Information Management Center, Tsinghua University, Beijing 100084, China

⁺These authors have contributed equally to this work

^*Corresponding author: Li Huang, Email: [email protected]

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No competing interests reported.

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You are reading this latest preprint version

The Effect of Qi-Shao-Tong-Mai-An-Shen (QSTMAS) Herbal Paste in Coronary Heart Disease Patients with Depression and/or Anxiety: A Randomized Controlled Clinical Trial Protocol

Status:

Version 1

Abstract

Background

Methods

Discussion

Trial registration:

Figures

Background

Objective

Methods/design

Study design

Inclusion criteria

Exclusion criteria

Outcome measures

Efficacy evaluation index

Safety index

Other indexes

Interventions

Randomization and blinding

Recruitment, Study plan and follow-up

Sample size estimation

Supervision and quality control

Ethical consideration and dissemination of information

Discussion

Trial Status

Abbreviations

Declarations

Acknowledgments

Authors’ contributions

Funding

Availability of data and materials

Ethics approval and consent to participate

Consent for publication

Conflict of interest

Author details

References

Additional Declarations

Supplementary Files

Status:

Version 1