Chinese medicine composition for preventing and treating arrhythmia and preparation method and use thereof

Abstract

The application discloses a traditional Chinese medicine composition for preventing and treating arrhythmia, which is prepared from raw medicinal materials in the following proportions by weight: Bupleurum 6-15, Scutellaria 12-30, Ramulus Cinnamomi 9-18, Codonopsis 15-30, Angelica 9-18, Radix Paeoniae Alba 9-18, Herba Poriae 15-30, Ossis Bezoar 15-30, Ostrea 15-30, Radix Rehmanniae Preparata 9-18, Fritillaria 15-30, Triticum 30-60, Cassia 12-30, Artemisia japonica 15-30, Salvia 15-30, Jujube 9-18, and Ginger 6-15. The traditional Chinese medicine composition has a satisfactory curative effect on treating liver depression and qi stagnation type arrhythmia, can obviously improve clinical symptoms of arrhythmia such as atrial fibrillation and premature beat of patients, and is worthy of clinical promotion and application. The application further discloses a preparation method of the traditional Chinese medicine composition and application thereof.

Description

Technical Field

[0001] This invention relates to a traditional Chinese medicine composition for the prevention and treatment of arrhythmia. In addition, this invention also relates to the preparation method and use of the traditional Chinese medicine composition. Background Technology

[0002] Cardiac arrhythmia is a cardiovascular disease that seriously endangers human health. 【1】 With the aging of my country's population and changes in people's lifestyles, the incidence of arrhythmia is constantly rising and showing a trend towards affecting younger people. 【2】 Cardiovascular disease remains the leading cause of death among Chinese residents. 【3】 Therefore, actively preventing and treating arrhythmias is of great significance to national health. Arrhythmia is a clinical syndrome characterized by abnormalities in the frequency, rhythm, pacemaker site, conduction velocity, or sequence of cardiac excitation, primarily marked by bradycardia or tachycardia with or without irregular heartbeats. 【4】 Modern medicine treats arrhythmias primarily with antiarrhythmic drugs, cardioversion, radiofrequency ablation, and surgery. While these treatments have some efficacy, drug therapy can cause arrhythmias and other toxic side effects. Cardioversion, radiofrequency ablation, and surgery also present challenges such as significant trauma, high cost, high recurrence rates, and related complications. Therefore, current treatment options for arrhythmias require further improvement.

[0003] Traditional Chinese medicine theory considers arrhythmia to fall under the category of "palpitation." This condition is caused by external or internal factors leading to deficiency of Qi, blood, Yin, and Yang, resulting in malnourishment of the heart; or by obstruction of phlegm, fluid retention, and blood stasis, causing poor circulation of the heart vessels, leading to a rapid, rapid heartbeat, anxiety, and even loss of control. While the disease is located in the heart, it is often influenced by the liver in clinical practice. The liver affects the heart through its influence on Qi, blood circulation, and emotions. In today's competitive and stressful society, modern people are prone to liver Qi stagnation, leading to Qi and blood stasis, or liver Qi stagnation transforming into fire, resulting in poor circulation of the heart vessels, malnourishment of the heart, and disturbance of the mind, thus causing palpitations. Palpitation due to liver Qi stagnation is a common and frequently occurring type of arrhythmia in contemporary society. Therefore, methods to soothe the liver, relieve stagnation, calm the mind, and stabilize palpitations are crucial for addressing the pathogenesis of palpitations and are important approaches to treating arrhythmia.

[0004] In recent years, with the application of Traditional Chinese Medicine (TCM) in the clinical treatment of arrhythmia, it has been proven that by combining disease differentiation with syndrome differentiation in TCM, Chinese medicine can effectively inhibit the occurrence and development of arrhythmia and improve patients' clinical symptoms and quality of life. Furthermore, as a "natural therapy," it has the advantages of low cost and minimal side effects. Therefore, finding and developing new, refined, effective, and safe TCM preparations from traditional Chinese medicine has significant clinical and scientific value for the prevention and treatment of arrhythmia. Currently, TCM treatment of arrhythmia mainly focuses on research on single Chinese herbs, with relatively few studies on compound preparations. Moreover, existing compound Chinese medicine preparations are mostly targeted at palpitations caused by Qi and Yin deficiency and blood stasis in the heart vessels, while few are effective for palpitations caused by liver Qi stagnation.

[0005] References:

[0006] 1. Hu Shengshou, Gao Runlin, Liu Lisheng, et al. Summary of the "China Cardiovascular Disease Report 2018" [J]. Chinese Journal of Circulation, 2019, 34(3):209-220.

[0007] 2. Lin Qian. Current status and prospect of TCM treatment for arrhythmia [J]. Journal of Integrated Traditional and Western Medicine on Cardiovascular and Cerebrovascular Diseases, 2015, 13(02): 129-131.

[0008] 3. Lin Qian. Current status and prospect of TCM treatment for arrhythmia [J]. Journal of Integrated Traditional and Western Medicine on Cardiovascular and Cerebrovascular Diseases, 2015, 13(02):129-131.

[0009] 4. Fu DG. Cardiac Arrhythmias: Diagnosis, Symptoms, and Treatments[J]. CellBiochem Biophys, 2015, 73(2):291-296. Summary of the Invention

[0010] In view of the above-mentioned shortcomings of the prior art, according to the embodiments of the present invention, it is desirable to provide a traditional Chinese medicine composition that has a significant therapeutic effect on palpitations caused by liver qi stagnation and for the prevention and treatment of arrhythmia. In addition, it is desirable to provide a method for preparing the traditional Chinese medicine composition and its uses.

[0011] According to an embodiment, the present invention provides a traditional Chinese medicine composition for preventing and treating arrhythmia, prepared from the following raw materials in parts by weight: Bupleurum chinense 6-15, Scutellaria baicalensis 12-30, Cinnamomum cassia twig 9-18, Codonopsis pilosula 15-30, Angelica sinensis 9-18, Paeonia lactiflora 9-18, Poria cocos 15-30, Os draconis 15-30, Ostrea gigas 15-30, Rehmannia glutinosa 9-18, Lilium brownii 15-30, Triticum aestivum 30-60, and other ingredients. 12-30 parts fermented soybean, 15-30 parts artemisia, 15-30 parts salvia miltiorrhiza, 9-18 parts jujube, 6-15 parts ginger; preferably prepared from the following raw materials in parts by weight: 6 parts bupleurum, 12 parts scutellaria baicalensis, 9 parts cinnamon twig, 15 parts codonopsis pilosula, 9 parts angelica sinensis, 9 parts raw white peony root, 15 parts poria cocos, 15 parts dragon bone, 15 parts oyster shell, 9 parts prepared rehmannia root, 15 parts lily bulb, 30 parts wheat, 12 parts fermented soybean, 15 parts artemisia, 15 parts salvia miltiorrhiza, 9 parts jujube, 6 parts ginger.

[0012] According to an embodiment, the present invention provides a method for preparing a traditional Chinese medicine composition granule for preventing and treating arrhythmia. The raw materials are weighed according to a specified ratio, and 6 and 5 times the amount of water are added respectively, followed by two decoctions. In the first decoction, oyster shell and dragon bone are added and decocted for 30 minutes, then the remaining ingredients are added and decocted for another 1.5 hours. In the second decoction, the decoction is decocted for 1 hour. The decoctions are filtered, the filtrates are combined, concentrated to a relative density of 1.14-1.15 (60-80℃), an appropriate amount of dextrin is added, and the mixture is wet-granulated, dried, and packaged.

[0013] This invention relates to a traditional Chinese medicine composition based on the principles of soothing the liver and strengthening the spleen, nourishing yin and clearing heat, and calming the mind and relieving palpitations. It comprises Bupleurum, Scutellaria baicalensis, Cinnamomum cassia, Codonopsis pilosula, Angelica sinensis, Paeonia lactiflora, Poria cocos, Os draconis, Ostrea gigas, Rehmannia glutinosa, Lilium brownii, Triticum aestivum, Fermented soybean, Artemisia argyi, Salvia miltiorrhiza, Ziziphus jujuba, and Zingiber officinale. In this group of herbs, Bupleurum and Paeonia lactiflora soothe the liver and relieve depression; Codonopsis pilosula, Angelica sinensis, Cinnamomum cassia, Ziziphus jujuba, and Zingiber officinale invigorate qi and strengthen the spleen; Rehmannia glutinosa, Lilium brownii, and Triticum aestivum nourish yin and generate fluids; Scutellaria baicalensis, Fermented soybean, and Artemisia argyi clear deficiency heat; and Poria cocos, Os draconis, Ostrea gigas, and Salvia miltiorrhiza calm the mind and soothe the nerves. The entire formula works synergistically to replenish deficiency and dispel pathogens, soothe the liver and clear heat, and calm the mind and soothe the nerves. Modern pharmacological studies have shown that total saponins of Bupleurum chinense and baicalin have antiarrhythmic effects and inhibit ventricular remodeling; tanshinone IIA and artemisinin can also reduce the incidence of arrhythmia, alleviate myocardial ischemia damage, and improve cardiac function; Codonopsis pilosula, Paeonia lactiflora, Angelica sinensis, Cinnamomum cassia, and Ziziphus jujuba can dilate blood vessels and increase visceral blood flow; Dragon bone, oyster shell, and Poria cocos all have sedative and tranquilizing effects; isoflavones in Rehmannia glutinosa polysaccharides, lily polysaccharides, and fermented soybean have the effects of regulating blood lipids, lowering blood sugar, and antioxidation; and lipopolysaccharides in wheat have analgesic and antiviral effects.

[0014] Subsequent examples and test cases will demonstrate that the traditional Chinese medicine composition of the present invention is effective in preventing and treating arrhythmia. It is prepared in granule form, has stable quality, constant drug concentration, is convenient to take, low in cost, has few toxic side effects, and is easy to promote. Attached Figure Description

[0015] Figure 1 This is a KM curve diagram of the endpoint event for both the unexposed and exposed groups. Detailed Implementation

[0016] The present invention will be further illustrated below with reference to specific embodiments. These embodiments should be understood as illustrative only and not as limiting the scope of protection of the present invention. After reading the description of the present invention, those skilled in the art can make various alterations or modifications to the present invention, and these equivalent changes and modifications also fall within the scope defined by the claims of the present invention.

[0017] The Bupleurum used in the following embodiments of the present invention is determined to be from Shaanxi Province and is the dried root of Bupleurum chinense DC. or Bupleurum scorzonerifolium Willd., both belonging to the Apiaceae family.

[0018] The Scutellaria baicalensis used in the following embodiments of the present invention is from Shaanxi Province and is the dried root of Scutellaria baicalensis Georgi, a plant of the Lamiaceae family.

[0019] The cinnamon twigs used in the following embodiments of the present invention are from Guangdong Province and are dried young twigs of Cinnamomum cassia Presl, a plant of the Lauraceae family.

[0020] The Codonopsis used in the following embodiments of the present invention is from Gansu Province and is the dried root of Codonopsis pilosula (Franch.) Nannf., Codonopsis pilosula Nannf. var. modesta (Nannf.) L.Shen, or Codonopsis tangshen Oliv., all belonging to the Campanulaceae family.

[0021] The Angelica sinensis used in the following embodiments of the present invention is from Gansu Province and is the dried root of Angelica sinensis (Oliv.) Diels, a plant of the Apiaceae family.

[0022] The raw white peony used in the following embodiments of the present invention is identified as originating from Anhui Province and is the dried root of Paeonia lactiflora Pall., a plant of the Ranunculaceae family.

[0023] The Poria cocos used in the following embodiments of the present invention is determined to be from Anhui Province and is the dried sclerotium of the fungus Poria cocos (Schw.) Wolf of the Polyporaceae family.

[0024] The keel used in the following embodiments of the present invention was determined to be from Gansu Province. It is a fossilized skeleton of ancient mammals such as three-toed horses, rhinoceroses, deer, cattle, and elephants, as well as fossilized elephant incisors, mainly containing calcium carbonate (CaCO3) and calcium phosphate (CaP2O5).

[0025] The oysters used in the following embodiments of the present invention were determined to be from Hebei Province and were shells of the Ostreidae species Ostrea gigas Thunberg, Ostrea talienwhanensis Crosse, or Ostrea rivularis Gould.

[0026] The prepared Rehmannia root used in the following embodiments of the present invention is determined to be from Henan Province and is the fresh or dried tuberous root of Rehmannia glutinosa Libosch., a plant of the Scrophulariaceae family.

[0027] The lilies used in the following embodiments of the present invention are determined to be from Hunan Province and are the dried fleshy scales of Lilium lancifolium Thunb., Lilium brownii FEBrown var.viridulum Baker, or Lilium pumilum DC., all belonging to the Liliaceae family.

[0028] The wheat used in the following embodiments of the present invention is determined to be from Jiangsu Province and is the dried mature fruit of Triticumaestivum L., a plant of the Poaceae family.

[0029] The fermented soybeans used in the following embodiments of the present invention are from Anhui Province and are dried products of fermented mature black seeds of soybean (Glycine max (L.) Merr.).

[0030] The Artemisia japonica Thunb. used in the following embodiments of the present invention is from Anhui Province and is the dried aerial part with flowers of Artemisia japonica Thunb., a plant of the Asteraceae family.

[0031] The Danshen used in the following embodiments of the present invention is from Shandong Province and is the dried root and rhizome of Salvia miltiorrhiza Bge., a plant of the Lamiaceae family.

[0032] The jujubes used in the following embodiments of the present invention are from Hebei Province and are the dried, mature fruits of the plant Ziziphus jujuba Mill. (family Rhamnaceae). The fruits are harvested in autumn when ripe and then sun-dried.

[0033] The ginger used in the following embodiments of the present invention was determined to be from Shandong Province and was the fresh rhizome of Zingiber officinale Rosc., a plant of the ginger family.

[0034] Example 1 (Preparation of Granules)

[0035] Weigh out 7 days' worth of raw medicinal materials: Bupleurum chinense 60g, Scutellaria baicalensis 120g, Cinnamomum cassia twig 90g, Codonopsis pilosula 150g, Angelica sinensis 90g, Paeonia lactiflora 90g, Poria cocos 150g, Os draconis 150g, Ostrea gigas 150g, Rehmannia glutinosa 90g, Lilium brownii 150g, Triticum aestivum 300g, Fermented soybean 120g, Artemisia argyi 150g, Salvia miltiorrhiza 150g, Ziziphus jujuba 90g, and Zingiber officinale 60g. Add 6 times and 5 times the amount of water respectively, and decoct twice. For the first decoction, add Ostrea gigas and Os draconis and decoct for 30 minutes, then add the remaining ingredients and continue to decoct for 1.5 hours. For the second decoction, decoct for 1 hour. The decoction is filtered, the filtrates are combined, and concentrated to a relative density of 1.14-1.15 (60-80℃). An appropriate amount of dextrin is added, and the mixture is wet-granulated, dried, and made into 1000g of granules. The granules are then packaged to obtain the granules, hereinafter referred to as Liver-Soothing and Palpitation-Relieving Granules.

[0036] Experimental Example 1 (Clinical observation of the efficacy of the Liver-Soothing and Palpitation-Relieving Granules of this Invention on Liver Qi Stagnation Type Arrhythmia)

[0037] 1. Case selection

[0038] Diagnostic criteria: The diagnosis of premature contractions in arrhythmias is based on the relevant criteria in "Dynamic Electrocardiography". The diagnosis of liver qi stagnation syndrome in Traditional Chinese Medicine is based on the relevant criteria in "Traditional Chinese Medicine Syndrome Differentiation". The severity grading criteria for arrhythmias are determined using the results of dynamic electrocardiography. ① Mild: No obvious symptoms, average premature beats ≤ 5 times / min; ② Moderate: Average premature beats > 5 times / min, or bigeminy or trigeminy; ③ Severe: The electrocardiogram shows R waves above the T peak, with a prolonged QT period, or multiple premature beats or two or more consecutive premature beats.

[0039] Inclusion criteria: ① Meeting the above-mentioned disease and TCM syndrome diagnosis criteria; ② Atrial premature beats or ventricular premature beats > 720 times in 24-hour Holter monitoring; ③ Age 18-65 years, gender not limited; ④ Informed consent form signed before inclusion.

[0040] Exclusion criteria: ① Patients with serious primary diseases of the cerebrovascular, liver, kidney and hematopoietic systems, severe cardiac dysfunction, or severe electrolyte imbalance; ② Patients with a heart rate below 60 beats / min (such as sick sinus syndrome, atrioventricular or intraventricular conduction block, etc.); ③ Patients with malignant or fatal arrhythmias; ④ Pregnant or lactating women, or those with allergic constitution.

[0041] Dropout criteria: ① Those who did not take the medication as prescribed and whose efficacy could not be determined; ② Those who were lost to follow-up or whose data were incomplete and affected the determination of efficacy; ③ Those who took other antiarrhythmic Western medicines or similar traditional Chinese medicines on their own during the trial.

[0042] 2. General Information

[0043] The 60 included cases were all patients with premature contractions due to liver qi stagnation type arrhythmia admitted to the Department of Cardiology, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine from May 2013 to May 2014. They were randomly divided into a treatment group and a control group, with 30 cases in each group. During the trial, one patient dropped out of the treatment group and one patient dropped out of the control group; ultimately, 29 patients completed the trial in both groups. In the treatment group, there were 14 males and 15 females; the mean age was (45.3±15.7) years; the arrhythmia was classified as mild in 21 cases, moderate in 5 cases, and severe in 3 cases; there were 2 supraventricular premature contractions and 27 ventricular premature contractions. In the control group, there were 11 males and 18 females; the mean age was (50.5±14.2) years; the arrhythmia was classified as mild in 20 cases, moderate in 4 cases, and severe in 5 cases; there were 3 supraventricular premature contractions and 26 ventricular premature contractions. There were no statistically significant differences between the two groups in terms of general characteristics such as gender, age, and severity of illness (P > 0.05), indicating they were comparable.

[0044] 3. Treatment methods

[0045] Control group: Received conventional Western medicine propafenone (Propafenone, Shanghai Xinyi Pharmaceutical Factory) orally, 150mg / time, 3 times daily. Treatment continued for 4 weeks (1 month).

[0046] Treatment group: In addition to the treatment measures of the control group, patients were given Shugan Dingji granules. Prescription: Bupleurum chinense 6g, Scutellaria baicalensis 12g, Cinnamomum cassia 9g, Codonopsis pilosula 15g, Angelica sinensis 9g, Paeonia lactiflora 9g, Poria cocos 15g, Os draconis 15g, Ostrea gigas 15g, Rehmannia glutinosa 9g, Lilium brownii 15g, Triticum aestivum 30g, Fermented soybean 12g, Artemisia argyi 15g, Salvia miltiorrhiza 15g, Ziziphus jujuba 9g, Zingiber officinale 6g. Administer 2 packets twice daily, dissolved in water, for 4 weeks (1 month).

[0047] 4. Observation Indicators and Methods

[0048] Clinical efficacy: Patients underwent 24-hour Holter monitoring before and after treatment. At the end of the treatment course, clinical efficacy was assessed according to the relevant standards in the "Recommendations for Evaluation Methods of Cardiovascular Drug Clinical Trials". ① Marked effect: Holter monitoring showed a reduction of ≥90% in the number of premature beats compared to before treatment; ② Effective: Holter monitoring showed a reduction of ≥50% and <90% in the number of premature beats compared to before treatment; ③ Ineffective: Holter monitoring showed a reduction of <50% in the number of premature beats compared to before treatment, or no change, or worsening of premature beats.

[0049] Traditional Chinese Medicine (TCM) syndromes: Before and after treatment, the changes in the patient's TCM syndromes were evaluated using a scoring method, including palpitations, chest and rib pain, lower abdominal distension and pain, and restless sleep.

[0050] Safety: During the trial, patients' general condition indicators, such as heart rhythm, heart rate, and blood pressure, were recorded every two weeks. Before and after treatment, patients' blood routine tests, liver and kidney function tests, and other drug safety indicators were measured.

[0051] 5. Test Results

[0052] Clinical efficacy and changes in premature beat frequency: The total effective rates in the treatment group and the control group were 65.5% and 37.9%, respectively; the difference in clinical efficacy between the groups was statistically significant (P < 0.05). See Table 1. Within-group comparisons before and after treatment, the differences in the number of premature beats on 24-hour Holter monitoring between the two groups were statistically significant (P < 0.05); between-group comparisons after treatment, the difference in the number of premature beats on 24-hour Holter monitoring was statistically significant, with the treatment group showing significantly fewer premature beats than the control group (P < 0.05). See Table 2.

[0053] Table 1 Comparison of clinical efficacy between the two groups (cases)

[0054]

[0055] Table 2 Comparison of the changes in the number of premature beats in the two groups over 24 hours ( Second-rate)

[0056]

[0057] Note: Compared with the group before treatment, *P<0.05; compared with the control group after treatment, #P<0.05

[0058] Changes in TCM syndrome scores: Within-group comparisons before and after treatment, the treatment group showed statistically significant differences in scores and total scores for palpitations, chest and rib pain, depression and irritability, insomnia, frequent sighing, and breast and lower abdominal pain (P < 0.05), while the control group showed statistically significant differences in scores and total scores for depression and irritability, frequent sighing, and breast and lower abdominal pain (P < 0.05). Between-group comparisons after treatment showed statistically significant differences in scores and total scores for palpitations, chest and rib pain, depression and irritability, insomnia, and frequent sighing, with the treatment group showing significantly better improvement in TCM syndrome scores than the control group (P < 0.05). See Table 3.

[0059] Table 3 Comparison of changes in TCM syndrome scores between the two groups ( point)

[0060]

[0061] Note: Compared with the group before treatment, *P<0.05; compared with the control group after treatment, #P<0.05

[0062] Comparison of drug safety: No abnormalities were found in blood routine tests and liver and kidney function tests in both groups of patients before and after treatment.

[0063] The experimental results indicate that the liver-soothing and palpitation-relieving granules of this invention have a satisfactory therapeutic effect on premature contractions in patients with liver qi stagnation type arrhythmia, and can significantly improve clinical symptoms such as premature beats, making them worthy of clinical promotion and application.

[0064] Experimental Example 2 (A retrospective cohort study of the effects of the Liver-Soothing and Palpitation-Relieving Granules of this invention on paroxysmal atrial fibrillation of the Liver Qi Stagnation type)

[0065] 1. Case selection

[0066] Diagnostic criteria: The diagnostic criteria for palpitation are based on the relevant content of "Guiding Principles for Clinical Research on New Traditional Chinese Medicine for the Treatment of Palpitation" in the "Guiding Principles for Clinical Research on New Traditional Chinese Medicine" (Volume 2) [Zheng Xiaoyu. Guiding Principles for Clinical Research on New Traditional Chinese Medicine (Volume 2) [M]. 1995, 1(1)-. Beijing: China Medical Science and Technology Press, 1995-.], that is, the patient feels palpitations, anxiety and restlessness during an attack. The diagnostic criteria for liver qi stagnation type are based on the relevant content of "Liver Qi Stagnation Syndrome" in "Traditional Chinese Medicine Diagnostics" [Li Candong. Traditional Chinese Medicine Diagnostics [M]. 2016, 1(1)-. Beijing: China Traditional Chinese Medicine Press, 2016-.] and the results of a questionnaire survey on the diagnostic criteria for palpitation (liver qi stagnation type) completed by 60 chief physicians of cardiovascular TCM across the country. The main symptoms include depression, frequent sighing, chest and rib pain, throbbing pain, foreign body sensation in the throat, chest tightness and chest pain, irritability, belching and bitter taste in the mouth, and insomnia. In summary, the patient presents with the primary symptom, two or more secondary symptoms, and, based on tongue and pulse diagnosis, the condition is classified as palpitation due to liver qi stagnation. The diagnostic criteria for paroxysmal atrial fibrillation are based on the 2020 European Society of Cardiology Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. [J]. Eur Heart J, 2021, 42: 373-498.: (1) Electrocardiographic manifestations: P waves disappear and are replaced by f waves, and the RR interval is absolutely irregular; (2) The duration of atrial fibrillation does not exceed 7 days.

[0067] Inclusion criteria: (1) meeting the diagnostic criteria for paroxysmal atrial fibrillation; (2) diagnosed by traditional Chinese medicine syndrome as liver qi stagnation type; (3) aged between 18 and 90 years old, regardless of gender.

[0068] Exclusion criteria: (1) Long-term persistent atrial fibrillation and permanent atrial fibrillation; (2) Having a serious primary disease or a serious disease that affects their survival; (3) Poor adherence to traditional Chinese medicine treatment and failure to complete 4 weeks of traditional Chinese medicine treatment; (4) Use of other traditional Chinese medicine or proprietary Chinese medicine during treatment; (5) Seriously missing medical records.

[0069] 2. General Information

[0070] This study included 200 patients with paroxysmal atrial fibrillation of the liver qi stagnation type who met the study criteria. Based on whether they used Shugan Dingji granules, the patients were divided into an exposed group (Shugan Dingji granules combined with conventional Western medicine treatment drugs) of 100 cases and a non-exposed group (using conventional Western medicine treatment drugs alone) of 100 cases.

[0071] 3. Treatment methods

[0072] Both groups of patients received standard Western medicine basic treatment, including: (1) anticoagulants such as warfarin, rivaroxaban, edoxaban, dabigatran etexilate, etc.; (2) antiarrhythmic drugs such as amiodarone, propafenone, beta-blockers, calcium channel blockers, digitalis preparations, etc. The exposed group received additional liver-soothing and palpitation-relieving granules in addition to basic Western medicine treatment, taken orally twice a day, two packets each time, divided into morning and evening doses, for a continuous period of 4 weeks. The non-exposed group maintained basic Western medicine treatment.

[0073] 4. Observation Indicators and Methods

[0074] Basic information: This mainly includes the patient's gender, age, body mass index (BMI), medical history (including coronary heart disease, hypertension, chronic heart failure, diabetes, sleep apnea syndrome, cerebral infarction, etc.), the course of paroxysmal atrial fibrillation, and specific treatment (drug therapy, non-drug therapy).

[0075] Main efficacy indicators: (1) Endpoint event: whether paroxysmal atrial fibrillation has recurred by 24-hour Holter monitoring or by electrocardiogram of the patient during a palpitation episode; (2) record the patient’s sinus rhythm maintenance status by 24-hour Holter monitoring, including average heart rate, number of atrial fibrillation episodes and duration.

[0076] Secondary efficacy indicators: (1) TCM syndrome score, including palpitations, depression, frequent sighing, chest and rib pain, throbbing pain, foreign body sensation in the throat, chest tightness and chest pain, restlessness, belching and bitter taste in the mouth, and insomnia; (2) Echocardiography: left atrial diameter, left ventricular end-diastolic diameter, cardiac ejection fraction, and cardiac stroke volume; (3) BNP; (4) AFEQT table.

[0077] Safety indicators: Patients were assessed for safety before and at the end of treatment, including liver function (ALT, AST, bilirubin), kidney function (BUN, creatinine, uric acid), CHA2DS2-VASc stroke risk stratification scoring system, and HAS-BLED bleeding event risk stratification scoring system.

[0078] 5. Efficacy evaluation criteria

[0079] Western medicine efficacy judgment criteria: formulated with reference to the relevant content of "Guiding Principles for Clinical Research of New Traditional Chinese Medicine for the Treatment of Palpitation" in the "Guiding Principles for Clinical Research of New Traditional Chinese Medicine" (Volume 2). (1) Marked effect: Palpitation symptoms disappear, and the results of dynamic electrocardiogram are significantly improved; paroxysmal atrial fibrillation is basically controlled, the duration of the attack is reduced by ≥80%, or the frequency of the attack changes from frequent to occasional; (2) Effective: Most palpitation symptoms disappear, and the results of dynamic electrocardiogram are improved; 50% ≤ the number and duration of paroxysmal atrial fibrillation attacks are reduced by <80%, and the frequency of the attack changes from frequent to multiple or multiple to occasional; (3) Ineffective: Palpitation symptoms do not change or worsen, dynamic electrocardiogram also does not change or worsens, and the number and duration of atrial fibrillation attacks are reduced by <50%. Total effective rate % = (number of markedly effective cases + number of effective cases) / total number of cases × 100%.

[0080] The criteria for evaluating the efficacy of TCM syndromes are formulated with reference to the relevant content of "Guiding Principles for Clinical Research on New Chinese Medicines for the Treatment of Palpitation" in the "Guiding Principles for Clinical Research on New Chinese Medicines" (Volume 2). (1) Marked effect: efficacy index ≥ 70%; (2) Effective: 30% ≤ efficacy index < 70%; (3) Ineffective: efficacy index < 30%. Efficacy index = (pre-treatment score - post-treatment score) / pre-treatment score × 100%, expressed as a percentage. Total effective rate % = (number of markedly effective cases + number of effective cases) / total number of cases × 100%.

[0081] 6. Test Results

[0082] 6.1 Endpoint Event Analysis

[0083] 6.1.1 Analysis of the events leading to the finish line for both groups

[0084] This study defined recurrence of paroxysmal atrial fibrillation as the endpoint event. It recorded whether patients experienced the endpoint event and the time of its occurrence, analyzing the differences in the rate of reaching the endpoint event between the non-exposed and exposed groups. As of December 31, 2021, 49 patients in the non-exposed group and 26 patients in the exposed group reached the endpoint event. Log-rank test showed that the overall survival time of patients in the exposed group was significantly longer than that in the non-exposed group (χ2 = 11.211, P = 0.001 < 0.01). Figure 1 .

[0085] 6.1.2 Cox Regression Analysis of the Terminal Event

[0086] Univariate Cox regression analysis showed that the following factors may influence the occurrence of endpoint events in patients with paroxysmal atrial fibrillation of the liver-qi stagnation type: administration of modified Shugan Dingji Decoction, age, disease duration, hypertension, diabetes, chronic heart failure, left atrial diameter, and SV (split ventricle). (P < 0.05) Multivariate Cox regression analysis showed that the risk of endpoint events was significantly lower in the exposed group of patients with paroxysmal atrial fibrillation of the liver-qi stagnation type than in the unexposed group. Patients with paroxysmal atrial fibrillation (P < 0.01) and those with a disease duration > 12 months had a significantly higher risk of endpoint events than those with a disease duration ≤ 12 months (P < 0.01). Compared with patients with hypertension, patients with paroxysmal atrial fibrillation without hypertension had a lower risk of endpoint events (P = 0.043 < 0.05). Patients with a left atrial diameter > 40 mm had a significantly higher risk of endpoint events than those with a left atrial diameter ≤ 40 mm (P = 0.003 < 0.01). See Table 6-1 for details.

[0087] Table 6-1 Univariate and multivariate Cox regression analyses of the endpoint event.

[0088]

[0089] Continued from Table 6-1: Univariate and Multivariate Cox Regression Analysis of the Endpoint Event

[0090]

[0091] 6.2 Results of therapeutic efficacy indicators

[0092] 6.2.1 Results of TCM efficacy indicators

[0093] 6.2.1.1 Comparison of TCM syndrome scores

[0094] Regarding the total TCM syndrome score, before treatment, the score was 14.96±2.24 in the non-exposed group and 15.42±2.06 in the exposed group (F=0.192, P=0.132>0.05), indicating comparability. After treatment, the total TCM syndrome score in the exposed group was significantly lower than that in the non-exposed group (F=-4.159, P<0.01). Within-group comparisons, the total TCM syndrome scores in both the non-exposed and exposed groups decreased after treatment, with statistically significant differences (P<0.01). Before treatment, there were no statistically significant differences in individual TCM syndrome scores between groups, indicating comparability (P>0.05). After treatment, there were statistically significant differences in the four items of palpitation, depression, frequent sighing, and irritability (P<0.01), as well as in the throat foreign body sensation (P<0.05). Within-group comparisons showed that all individual items of TCM syndrome scores decreased after treatment in both the non-exposed and exposed groups, with statistically significant differences (P < 0.01). See Table 6-2 for details.

[0095] Table 6-2 Comparison of total TCM syndrome scores between the non-exposed group and the exposed group

[0096]

[0097] 6.2.1.2 Comparison of overall effective rates of TCM syndromes

[0098] Regarding the efficacy rate of TCM syndromes, the non-exposed group included 25 cases with significant improvement, 46 cases with improvement, and 29 cases with no improvement, with a total effective rate of 71.00%; the exposed group included 42 cases with significant improvement, 46 cases with improvement, and 12 cases with no improvement, with a total effective rate of 88.00%. The total effective rate of TCM syndromes in the exposed group was significantly higher than that in the non-exposed group, with a statistically significant difference (χ2 = 11.362, P = 0.003 < 0.01), as detailed in Table 6-3.

[0099] Table 6-3 Comparison of the overall effective rate of TCM syndromes between the non-exposed group and the exposed group (number of cases)

[0100]

[0101] 6.2.2 Results of Western Medicine Efficacy Indicators

[0102] 6.2.2.1 Comparison of the overall effective rate of Western medicine

[0103] The non-exposed group included 23 cases with significant effect, 45 cases with effect, and 32 cases with no effect, with a total effective rate of 68.00%. The exposed group included 38 cases with significant effect, 44 cases with effect, and 18 cases with no effect, with a total effective rate of 82.00%. The effective rate of the exposed group was significantly higher than that of the non-exposed group (χ2 = 7.620, P = 0.022 < 0.05), as detailed in Table 6-4.

[0104] Table 6-4 Comparison of 24-hour Holter monitoring efficacy between the non-exposed and exposed groups (number of cases)

[0105]

[0106] 6.2.2.2 24-hour Holter monitoring

[0107] Comparison of mean ventricular rate: Before treatment, the median mean ventricular rate was 76.50 bpm in the non-exposed group and 74.50 bpm in the exposed group (Z = -1.289, P = 0.197 > 0.05), indicating comparability. After treatment, the mean ventricular rate in the exposed group was lower than that in the non-exposed group, with a statistically significant difference (Z = -2.307, P = 0.021 < 0.05). Within-group comparison, the mean ventricular rate in the non-exposed group decreased significantly after treatment (Z = -2.346, P = 0.019 < 0.05); the mean ventricular rate in the exposed group decreased significantly after treatment (Z = -2.820, P = 0.005 < 0.01). See Table 6-5 for details.

[0108] Table 6-5 Comparison of mean ventricular rates between the non-exposed and exposed groups [M(Q1, Q3)]

[0109]

[0110] 6.2.2.3BNP

[0111] Before treatment, the median BNP level in the non-exposed group was 163.50 pg / ml, and the median BNP level in the exposed group was 132.00 pg / ml (Z = -1.214, P = 0.225 > 0.05), indicating comparability. After treatment, the BNP level in the exposed group was lower than that in the non-exposed group, and the difference was statistically significant (Z = -2.489, P = 0.013 < 0.05). Within-group comparisons, the BNP level in the non-exposed group was slightly higher after treatment than before, but the difference was not statistically significant (Z = -1.755, P = 0.079 > 0.05); the BNP level in the exposed group decreased after treatment, and the difference was statistically significant (Z = -2.075, P = 0.038 < 0.05). See Table 6-6 for details.

[0112] Table 6-6 Comparison of BNP levels between the unexposed and exposed groups [M(Q1, Q3)]

[0113]

[0114] 3.2.2.4 Transthoracic echocardiography

[0115] ① Left atrial diameter (LAD): In the non-exposed group, the median LAD before treatment was 37.00 mm, and the median after treatment was also 37.00 mm; in the exposed group, the median LAD before treatment was 36.00 mm, and the median after treatment was 35.00 mm. There were no statistically significant differences between or within the groups before and after treatment (P > 0.05). See Tables 6-7 for details.

[0116] Table 6-7 Comparison of LAD in the unexposed and exposed groups [M(Q1, Q3)]

[0117]

[0118] ② Left ventricular end-diastolic diameter (LVDd): In the non-exposed group, the median LVDd before treatment was 49.00 mm, and the median after treatment was also 49.00 mm; in the exposed group, the median LVDd before treatment was 50.00 mm, and the median after treatment was 49.00 mm. There were no statistically significant differences between or within the groups before and after treatment (P > 0.05). See Table 6-8 for details.

[0119] Table 6-8 Comparison of LVDd between the unexposed and exposed groups [M(Q1, Q3)]

[0120]

[0121] ③ Stroke volume (SV): In the non-exposed group, the median SV before treatment was 76.00 ml, and the median after treatment was 72.00 ml; in the exposed group, the median SV before treatment was 77.00 ml, and the median after treatment was 73.00 ml. There were no statistically significant differences between or within the groups before and after treatment (P > 0.05). See Table 6-9 for details.

[0122] Table 6-9 Comparison of SV (Short-Term Values) between the Unexposed and Exposed Groups [M(Q1, Q3)]

[0123]

[0124] ④ Ejection fraction (EF): In the non-exposed group, the mean EF before treatment was 67.32±8.66, and after treatment it was 65.02±8.85; in the exposed group, the mean EF before treatment was 67.05±8.69, and after treatment it was 65.15±7.36. There were no statistically significant differences between the groups before and after treatment (P>0.05). Within the groups, the EF in the non-exposed group decreased significantly after treatment (P<0.05); the EF in the exposed group decreased slightly after treatment, but the difference was not statistically significant (P>0.05). See Table 6-10 for details.

[0125] Table 6-10 Comparison of EF between the unexposed group and the exposed group

[0126]

[0127] 3.2.3 Results of other therapeutic indicators

[0128] 3.2.3.1 AFEQT Scale

[0129] Before treatment, the total score of the AFEQT scale was 77.64±8.42 in the non-exposed group and 79.50±7.43 in the exposed group (F=1.634, P=0.099>0.05), indicating comparability. After treatment, the total score of the AFEQT scale in the exposed group was significantly lower than that in the non-exposed group (P<0.01). Within-group comparisons, the total scores of both the non-exposed and exposed groups decreased after treatment, with statistically significant differences (P<0.01). See Table 6-11 for details.

[0130] Table 6-11 Comparison of total scores on the AFEQT scale between the unexposed and exposed groups.

[0131]

[0132] 3.3 Safety Indicator Results

[0133] Safety indicators were measured in both groups before and after treatment, mainly including liver function (alanine aminotransferase, aspartate aminotransferase, total bilirubin) and kidney function (blood urea nitrogen, creatinine, uric acid). There were no statistically significant differences in any of the safety indicators between the two groups before and after treatment (P > 0.05). See Table 6-12 for details.

[0134] Table 6-12 Comparison of liver and kidney function between the non-exposed and exposed groups [M(Q1, Q3)]

[0135]

[0136] The trial results suggest that taking Shugan Dingji Granules is an independent protective factor against reaching the endpoint event in patients with paroxysmal atrial fibrillation of the liver qi stagnation type. Shugan Dingji Granules can significantly reduce the TCM syndrome score, AFEQT total score, mean ventricular rate, and BNP level in patients with paroxysmal atrial fibrillation of the liver qi stagnation type, helping to improve clinical symptoms and quality of life, and has no impact on safety indicators in patients with paroxysmal atrial fibrillation, making it worthy of clinical promotion and application.

Claims

1. A traditional Chinese medicine composition for preventing and treating arrhythmia, characterized in that, It is prepared from the following raw materials in parts by weight: Bupleurum chinense 6-15, Scutellaria baicalensis 12-30, Cinnamomum cassia 9-18, Codonopsis pilosula 15-30, Angelica sinensis 9-18, Paeonia lactiflora 9-18, Poria cocos 15-30, Os draconis 15-30, Ostrea gigas 15-30, Rehmannia glutinosa 9-18, Lilium brownii 15-30, Triticum aestivum 30-60, Fermented soybean 12-30, Artemisia argyi 15-30, Salvia miltiorrhiza 15-30, Ziziphus jujuba 9-18, and Zingiber officinale 6-15.

2. The traditional Chinese medicine composition for preventing and treating arrhythmia according to claim 1, characterized in that, It is prepared from the following raw materials in parts by weight: Bupleurum chinense 6, Scutellaria baicalensis 12, Cinnamomum cassia 9, Codonopsis pilosula 15, Angelica sinensis 9, Paeonia lactiflora 9, Poria cocos 15, Os draconis 15, Ostrea gigas 15, Rehmannia glutinosa 9, Lilium brownii 15, Triticum aestivum 30, Fermented soybean 12, Artemisia argyi 15, Salvia miltiorrhiza 15, Ziziphus jujuba 9, and Zingiber officinale 6.

3. The method for preparing the granules of the traditional Chinese medicine composition for preventing and treating arrhythmia as described in claim 1 or 2, characterized in that, Weigh the raw materials according to the proportions, add 6 times and 5 times the amount of water respectively, and decoct twice. For the first decoction, add oyster shell and dragon bone and decoct for 30 minutes, then add the remaining ingredients and continue to decoct for 1.5 hours. For the second decoction, decoct for 1 hour. Filter the decoction, combine the filtrates, concentrate to a relative density of 1.14-1.15 (60-80℃), add an appropriate amount of dextrin, wet granulate, dry, and make into granules for packaging.

4. Use of the traditional Chinese medicine composition according to claim 1 or 2 in the preparation of a medicament for treating arrhythmia caused by liver qi stagnation.

5. The use of the traditional Chinese medicine composition according to claim 1 or 2 in the preparation of a medicament for treating paroxysmal atrial fibrillation of the liver qi stagnation type.

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