Huatan Dingji Decoction Intervening in Atrial Fibrillation : Protocol for a Randomized Double-Blind Single-Simulated Placebo-Controlled Clinical Trial


 Background: Atrial fibrillation (AF) is one of the most common cardiac arrhythmias and can lead to heart failure(HF), stroke, pulmonary embolism(PE) and other complications, seriously affecting people's quality of life and health.Western medicine is limited in the treatment of AF, while Traditional Chinese Medicine(TCM) has unique advantages, such as low side effects, low toxicity, long effect duration and high compliance.Huatan Dingji Decoction(HTDJ) is commonly used in the treatment of AF in our hospital, and its clinical efficacy is confirmed, but a comprehensive evaluation of the clinical efficacy is currently lacking. Method: This study adopts a randomized double-blind, single-simulated, placebo-controlled research method. Participants were randomly assigned in a 1:1 ratio through a centrally controlled, computer-generated, simple randomization schedule. Participants would take the medicine for one month and the curative effect would be evaluated. Subsequently, the participants would not take TCM and only receive western medicine treatment. They would be followed up for another 8 weeks, and a clinical evaluation would be conducted.The evaluation includes the frequency of palpitation, cumulative attack time, increase and decrease rate of western medicine, TCM symptoms, clinical quality of life, clinical endpoint events and safety. Cases are derived from outpatient and inpatient with AF in the Cardiology Department of Longhua Hospital. Evaluations would be conducted at baseline and at week 4 and 12 after randomization.Discussion:In this study, the efficacy and safety of HTDJ plus western medicine in the treatment of AF(palpitation of Qi deficiency-caused phlegm stagnation) were evaluated, so as to provide medicine evidence of short-term and medium-term clinical efficacy for the treatment of AF with integrated traditional and western medicine, and lay a foundation for further clinical development and application.Trial registration: The trial has been registered on March 5,2020 at Chinese Clinical Trial Registry (www.chictr.org.cn; ID:ChiCTR2000030517).Trial registration: This study was registered on May 15,2019 at ClinicalTrials.gov with the identifier number NCT03952676.

of Longhua Hospital. Evaluations would be conducted at baseline and at week 4 and 12 after randomization.
Discussion:In this study, the e cacy and safety of HTDJ plus western medicine in the treatment of AF(palpitation of Qi de ciency-caused phlegm stagnation) were evaluated, so as to provide medicine evidence of short-term and medium-term clinical e cacy for the treatment of AF with integrated traditional and western medicine, and lay a foundation for further clinical development and application.
Trial registration: The trial has been registered on March 5,2020 at Chinese Clinical Trial Registry (www.chictr.org.cn; ID:ChiCTR2000030517).
Trial registration: This study was registered on May 15,2019 at ClinicalTrials.gov with the identi er number NCT03952676.

Introduction:
AF refers to supraventricular tachyarrhythmia characterized by rapid, disorganized atrial electrical activity and is one of the most common cardiac arrhythmias today. It is estimated that approximately 2% of the total global population suffers from AF, and its prevalence is increasing annually. The incidence rate is expected to increase 5 times in the next 40 years [1]. AF can exacerbate HF, increase the risk of ischemic stroke and malignant arrhythmic events. Meanwhile, with the change of age, cardiac structure and function and the increase of incidence of a variety of basic diseases and bad living habits, AF will lead to the increase of hospitalization days, medical expenses and overall mortality [2].
The current western medical treatments for AF are drug therapy, Percutaneous Left Atrial Appendage Closure(LAAC) and Radiofrequency Ablation(RF). Drug therapy includes reversal of sinus rhythm and ventricular rate control. And it needs to be combined with anticoagulation therapy. However, in the course of pharmacological treatment of AF, the majority of the causes of AF cannot be removed. And the electrical and anatomical reconstructions caused by AF itself make it di cult to revert and maintain sinus rhythm. Therefore, ventricular rate control has become a choice of clinical treatment [3]. LAAC prevents the formation of thrombus during AF by blocking the left atrium, thereby reducing the risk of long-term disability or death from thromboembolism in patients with AF. RF is now the most effective method for the eradication of paroxysmal tachycardia. RF has been clinically successful in immediately restoring sinus rhythm in more than 70% of patients with paroxysmal AF, but the long-term success rate is low. And the means to treat persistent or permanent AF are limited and the effect is poor [4][5]. In recent years, through a large number of clinical studies, it has been found that TCM has unique advantages in the treatment of AF, such as low side effects, low toxicity, long effect duration and high compliance, which has played a positive role and is widely used in clinical practice.
According to the clinical symptoms and signs, AF corresponds to "palpitation" in TCM. Since Inner Canon of the Yellow Emperor, doctors of all generations have discussed palpitation. Many prescriptions and medicines have been recorded and can be used to treat palpitation, such as Zhigancao Decoction, Erchen Decoction, Taoren Honghua Decoction, etc. Modern medicine has found TCM to be effective in reducing ventricular rate, increasing the diversion rate, and improving cardiac function and its clinical symptoms.
Professor Lin Zhongxiang, a famous TCM doctor in Shanghai, has been engaged in various cardiovascular diseases including AF for a long time, and has accumulated rich clinical experience."Huatan Dingji Decoction"is the prescription for AF(palpitation of Qi de ciency-caused phlegm stagnation)established by Professor Lin Zhongxiang in combination with his long-term clinical treatment experience. It is composed of Pinellia ternata, Chen Pei, Astragalus membranaceus, Atractylodes macrocephala, Poria cocos, Coptis chinensis, Cinnamon, Keel, Oyster, Sophora avescens, Artemisia annua, Radix Po lygala, Ophiopogon, Xianling spleen, Peony skin, Jujube. HTDJ is effective in treating palpitation and has been taken by lots of patients for a long period of time, but is limited to individual clinical cases and lacking in related evidence. Therefore, this study aims to evaluate the e cacy and safety of HTDJ plus western medicine in the treatment of AF, provide medicine evidence of short-term and medium-term clinical e cacy for the treatment of AF with integrated traditional and western medicine on the basis of TCM syndrome differentiation and lay the foundation for further clinical development and application.

Methods/design Study objectives
The purpose of the experiment is to evaluate the e cacy and safety of HTDJ plus western medicine in the treatment of AF, provide medicine evidence of short-term and medium-term clinical e cacy for the treatment of AF with integrated traditional and western medicine on the basis of TCM syndrome differentiation and lay the foundation for further clinical development and application.

Study design and settings
The study will be conducted in the Department of Cardiology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, to achieve the goal of 76 participants with AF(palpitation of Qi de ciencycaused phlegm stagnation) in total. Each participant can only be grouped once. The study will include ve phases: screening/enrollment, allocation, treatment/intervention, end of intervention, and follow-up. During enrollment, all participants will undergo physical examination and assessment of eligibility in the cardiology clinics and wards before being recruited. The maximum time allowed between the assessment and the intervention is 1 week (week 0). If more than a week has passed since the assessment, the participant will have to undergo repeat assessment before being allowed to start the intervention. Eligible participants will be invited to sign the written informed consent regarding participation in the trial (procedures, risks, options for dropping out), regarding the use of laboratory data, and regarding the collection, storage, and use of biological specimens. A study investigator or medical staff member that has received adequate training will provide the participant with extensive explanations. Upon agreeing to provide consent, the participant will be invited to sign and date the informed consent form, at which time a participant identi cation (PID) number will be assigned to facilitate PID throughout the study.
The participants will be randomly assigned to the experimental or control group and undergo the corresponding intervention for a total of two treatment cycles. Participants in the experimental group will receive HTDJ, whereas those in the control group will receive placebo granules . The participants will continue to receive systemic therapy, as judged by their treating physician. All changes in symptoms, prescriptions, relevant scores, and macroscopic characteristics (based on photographic evidence), along with any adverse events( AEs), will be recorded. The experimental design is shown in Figure 1.

Diagnostic criteria
The diagnosis of atrial brillation can be con rmed based on clinical manifestations, physical examination and electrocardiographic characteristics as follows: (1) Clinical manifestations: palpitation, chest tightness, decreased exercise tolerance. (2) Physical examination:heart auscultation varies in heart rate, heart sounds vary in strength, rhythm is absolutely irregular, and pulse is short. (3) Electrocardiogram: P wave disappear, the f wave replaces it, the frequency is about 350-600 times, and the QRS complex rhythm is absolutely irregular.

Inclusion Criteria
The inclusion criteria are as follows: (1) Patient's age is 18-85 years. (2) Paroxysmal atrial brillation, seizure frequency >=2 times a month or persistent atrial brillation (at least one ECG diagnosis). (3) The main syndrome of TCM syndrome differentiation was Qi de ciency-caused phlegm stagnation. (4) Have a correct understanding of the signi cance of the study, have good compliance with the observation and evaluation of the researcher, voluntarily accept the clinical trial and ll in the clinical consent form.

Exclusion Criteria
The exclusion criteria are as follows: (1) Patients with primary diseases such as severe lung, liver, renal insu ciency and hematopoietic system or severe cardiac dysfunction (NYHA IV grade). (2) Atrial brillation caused by obvious incentives such as fatigue, mental stress, mood swings, drug poisoning, and electrolyte disturbance. (3) Mental illness and poor control of the condition. (4) Patients whose heart rate is less than 50 beats per minute (such as sick sinus syndrome, atrioventricular or intraventricular block, etc.,who intend to install a pacemaker). For abscission cases, the reasons for abscission shall be recorded in detail. If there is a review, the results of the last major e cacy test shall be taken as the nal results for statistical analysis, and the CRF table shall be kept for future reference.

Interventions
This subject adopts randomized, double-blind, single-simulated,placebo-controlled research method. 72 cases with AF(palpitation of Qi de ciency-caused phlegm stagnation)were randomly divided into two groups according to the 1:1 distribution principle. The rst group was treated with HTDJ plus western medicine. The second group was treated with placebo granules plus western medicine. Western medicine includes cardioversion drugs and heart rate control drugs, as well as myocardial energy metabolism drugs, must be in keeping with "the 2015 Atrial Fibrillation: Current Understanding and Treatment Recommendations''. The HTDJ and placebo were produced and packed in a single batch(production batch number: HTDJ: 1070649; Placebo: 1070649) by Shanghai Wan Shicheng Pharmaceutical Co.,Ltd, which has no con icts of interest relevant to this study. The test results of drug quality were consistent with the Chinese Medicine Standards of the State Food and Drug Administration. The placebo is composed of 10% crude HTDJ and 90% starch, which have the same appearance and scent as the active treatment drugs. Participants will take one bag twice a day for 4 weeks, while avoiding oral administration of other traditional Chinese medicine for e cacy evaluation. Then do not accept traditional Chinese medicine, only western medicine treatment, followed up for 8 weeks, another clinical evaluation. Outcomes 1. General information: gender, age, weight, heart rate, heart rhythm, blood pressure, etc.

Clinical symptoms:
The number and duration of atrial brillation episodes were recorded using a scoring method before and after treatment.
3. TCM syndromes: The changes in heart palpitations, shortness of breath, fatigue, coughing, spitting, salivation, body condition, tongue condition, and pulse condition were recorded before and after treatment. 10. Evaluation of Hamilton Anxiety and Depression Scale.The Hamilton Anxiety Scale (HAMA) and Hamilton Depression Scale (HAMD) are used to evaluate the emotional state of patients. HAMA is mainly used to assess the severity of the patient's anxiety symptoms, and is generally considered to be greater than 14 points Meaningful. HAMD is currently one of the most commonly used clinical scales to assess depression, and 20 points or more are considered meaningful.

11.SF-36 EVALUATION
Use the MOS item short from health survey (SF-36) to assess changes in the quality of life of patients.
12. Safety indicators: detect changes in blood routine, urine routine, liver and kidney function before and after treatment.
During the experiment, closely observe any adverse reactions/events that may occur and record them in detail and truthfully.

Observation records of adverse events
During the trial period, the adverse event record form should be lled in truthfully. The occurrence, severity, duration, measures taken and outcome of the adverse event should be recorded. Adverse events should be recorded in the designated clinical case observation form (CRF) adverse event form. The person uses mild, moderate, and severe to describe the intensity of the adverse event,and evaluates the possible association between the adverse event and the study drug and combination drug to determine whether it is an adverse reaction.

Research process record points
The subject content and data at each time point, according to the patient's hospitalization period, will be recorded as shown in Table.1. Speci cally, the screening period (-3~0 days) will be 0 to 3 days before recruitment .The 4-week treatment period was planned in two cycles of 2 weeks, with a return visit between cycles to check for AEs and monitor compliance. All interventions will be stopped after 4 weeks. Follow-up will be conducted on weeks 4 and 12.

Sample size
In order to study the e cacy and safety of HTDJ in the treatment of atrial brillation , we collected cases from outpatient and inpatient atrial brillation in Longhua Hospital, 30 cases in the test group and 30 cases in the control group, a total of two groups, considering 20% clinical shedding rate, a total of 76 patients are planned to be included.

Randomization
This study uses a center-based strati cation and block randomization method. The randomization sequence will be generated by study investigators who are statisticians. Patients will be allocated in a 1:1 ratio, aiming to balance baseline characteristics between the groups. Participants will be assigned a PID number, which will be used for subject identi cation throughout the study. Information regarding the random-number block will be delivered to the participating centers along with the intervention drugs.

Double-blind
The study is designed as a double-blind investigation. The participants, study monitors, and study investigators will be blinded throughout the duration of the study. The PID will be the only information linked to group allocation.Random codes will be maintained by Cui Xuejun, associate researcher, and director of the O ce of National Traditional Chinese Medicine Clinical Research Base of Longhua Hospital to ensure concealment.

Statistical analysis
All data are entered using excel worksheets, and SPSS22.0 statistical software is used for statistical analysis. For measurement data, t-tests are performed for those that conform to the normal distribution, and the data are represented by the mean ± standard deviation; the row-rank conversion that does not conform to the normal distribution For non-parametric test, the data are represented by M (QR). The constituent ratio data uses the χ2 test. The one-way ordered data uses the rank sum test. P>0.05 is not statistically signi cant, P<0.05 is statistically signi cant, two-sided test .

Data management and monitoring
In this study, the CRF will be lled out by the researchers in a timely manner, and by a third party is responsible for checking and checking, patient data con dentiality and through the ethics committee, the ethics committee reviews drug clinical trial scheme is scienti c and ethical rationality, audit and supervision of drug clinical trials researchers quali cation, supervision of drugs in clinical trials, ensure the independent, objective, fair and ethical review process.

Discussion
AF is the most common arrhythmia disease, with palpitate, chest tightness, shortness of breath, dizziness, amaurosis and weakness as the main clinical symptoms, which has serious complications and seriously affects people's quality of life and health [6]. AF is currently treated by western medicine, mainly through drugs and surgery, but anti-arrhythmic drugs have signi cant toxic side effects. RF is unstable and easy to relapse. People are now paying more attention to its treatment defects. The de ciency and risk of drug and surgical treatment are emerging and the advantages of TCM in the treatment of AF are gradually prominent. In recent years, through a large number of clinical studies, it has been found that TCM to be effective in reducing ventricular rate, increasing the diversion rate, and improving cardiac function and its clinical symptoms [7][8][9][10].
At present, Wenxin Granule and Shensong Yangxin Capsule are mainly aimed at patients with Qi and Yin De ciency and Blood Stasis, while "de ciency" and "phlegm" are important pathogenesis for AF. Due to the characteristics of aging population and diet structure, patients with TCM pathogenesis ("de ciency" and "phlegm") account for a certain proportion. Currently, western medicine and surgery for patients with AF cannot fundamentally change the trend of atrial brosis and body degeneration. Patients need to be maintained on drugs for a long period of time and the relapse rate is high. Long term use of amiodarone, sotalol and other western medicine has certain side effects and limitations. Therefore, this kind of treatment can not solve the practical problems of many patients, and it is in urgent need of better treatment.
Based on Shanghai's famous TCM practitioner, Lin Zhongxiang's studio, combined with the literature and long-term clinical treatment summary, HTDJ is designed from the pathogenesis of AF(palpitation of Qi de ciency-caused phlegm stagnation). In this prescription, Huanglian Wendan Decoction can clear away heat and dampness and treat distrubance of the gastric qi. Pinellia ternata and Pericarpium Citri Reticulatae are used to regulate qi-owing for removing the phlegm; Poria cocos can fortify the spleen and percolate dampness. Coptis chinensis can purge intense heat and detoxicate; Chinese date can bene t spleen and stomach. LiuJunZi Decoction can replenish qi to invigorate the spleen and remove the phlegm. On the basis of Sijunzi Decoction, increasing the dosage of Atractylodes macrocephala can improve the effect of drying dampness and resolving phlegm. Coptis chinensis, cinnamon and Jiaotai Pill can coordinate the heart and the kidney. On this basis, adding fossilizid and concha ostreae can quiet the spirit by heavy settling. Astragalus membranaceus can tonify middle-Jiao and Qi, while dwarf lilyturf tuber can nourish yin and promote the secretion of saliva. Herba Epimedii can mildly rein force the kidney yang and lightyellow sophora root can clear away heat and dampness. The prescription can replenish qi to invigorate the spleen and remove the phlegm, nourish the heart and quiet the spirit, coordinate the heart and the kidney and balance yin and yang.
Clinical and pharmacological studies have shown that Jiaotai Pill has therapeutic and anti-arrhythmic effects on AF [11,12]. Pinellia ternata and its processed products are also anti-arrhythmic [13], and Pericarpium Citri Reticulatae has vasodilatory effects that help to induce an increase in coronary ow, which may have the effect of lowering blood pressure and slowing the heart rate [14]. The effects of Coptis chinensis include blood pressure lowering, antibiosis, anti-in ammatory, anti-tumor, regulating blood lipid, anti-arrhythmia, etc [15]. Icariin can effectively avoid the damage of myocardial cells and vascular endothelium caused by adverse factors. In addition to inhibiting apoptosis in cardiac myocytes, icariin can also effectively regulate blood lipid and protect the cardiovascular system [16]. In addition, Huanglian Wendan Decoction has a certain therapeutic effect on coronary heart disease with rapid AF [17]. Matrine has antiarrhythmic and electrophysiological effects [18]. Artemisia apiacea is the main drug for clinical treatment of arrhythmia [19] and arteannuin has electrophysiological characteristics of antiarrhythmia [20].
HTDJ is effective in treating palpitations, but is lacking in related research evidence. Therefore, this study aims to evaluate the e cacy and safety of "Huatan Dingji Prescription" plus western medicine in the treatment of AF, in order to provide preliminary data for the treatment of patients with AF. It can further provide evidence for the clinical application of TCM in the treatment of AF.  Trial ow chart