A traditional Chinese medicine compound preparation for bradyarrhythmia and a preparation method thereof

Abstract

The present application relates to the technical field of traditional Chinese medicine, in particular to a traditional Chinese medicine compound preparation for slow arrhythmia and a preparation method thereof; the traditional Chinese medicine compound preparation is prepared from the following raw materials in parts by mass: 10-90 parts of Astragalus membranaceus, 1-50 parts of Rhodiola, 1-30 parts of Salvia miltiorrhiza, 1-30 parts of Cinnamomum cassia, and 1-30 parts of Herba Epimedii calcinatum; the traditional Chinese medicine compound preparation for slow arrhythmia is composed according to the theory of traditional Chinese medicine, and has remarkable effects on sinus bradycardia, sinus arrest, sinoatrial block, slow-fast syndrome, atrioventricular block and bundle branch block; no clinical adverse events have been found in the clinical application in the past 10 years; the preparation process is simple, the cost is low, the preparation is convenient to take and carry, and the quality of the finished product is stable and controllable.

Description

Technical Field

[0001] This invention relates to the field of traditional Chinese medicine technology, and in particular to a traditional Chinese medicine compound preparation for bradyarrhythmia and its preparation method. Background Technology

[0002] Bradyarrhythmia is a cardiovascular disease characterized by a heart rate of less than 60 beats per minute, caused by abnormalities in cardiac pacing and / or conduction. The pathogenesis of bradycardia is currently unclear. Clinically, this disease is more common in middle-aged and elderly patients. Most patients with bradycardia have underlying organic heart disease, such as coronary artery disease, rheumatic heart disease, acute myocardial infarction, or myocarditis. There are also patients with simple bradycardia without a clear cause or comorbidities. Clinically, bradycardia is mainly classified into types such as sick sinus syndrome, sinus bradycardia, atrioventricular block, sinoatrial block, and intra-atrial block. In March 2019, the European Heart Rhythm Association (EHRA) published the "2019 EHRA Expert Consensus on the Management of Asymptomatic Arrhythmias." The consensus states that patients with first- and second-degree Moses type I atrioventricular block and sinus bradycardia generally experience fewer clinical symptoms and rarely experience significant discomfort, thus their disease risk is relatively low. Second-degree and higher atrioventricular block, sinoatrial block, and sinus arrest are symptomatic arrhythmias. When they cause hemodynamic disturbances, patients may experience symptoms such as chest tightness, shortness of breath, dizziness, and fatigue, or a feeling of cardiac arrest, or emotional and sleep disturbances. Some patients may experience decreased exercise tolerance, while others may develop angina due to decreased cardiac output, worsening heart failure, sudden syncope, convulsions, and in the most severe cases, sudden cardiac death.

[0003] Currently, the main goals of bradycardia treatment are to improve symptoms and reduce mortality. Yao Yan, interpreting the European Heart Rhythm Society expert consensus, pointed out that for third-degree atrioventricular block and second-degree type II atrioventricular block, even without clinical discomfort, experts still recommend pacemaker treatment due to their potential severity. For patients with bradycardia who have hemodynamic instability but still have a pulse, pacing therapy should also be initiated as early as possible. This shows that when the disease symptoms are severe and the indications for pacemaker implantation are clear, textbooks and expert consensus recommend artificial pacemaker treatment as the first choice. However, pacemakers are expensive and are invasive, and currently a considerable number of patients are unwilling to undergo pacemaker treatment. Therefore, for patients who cannot afford timely pacemaker implantation or who do not meet the indications for pacemaker implantation, drug therapy is particularly important. Currently used Western medicines mainly include atropine, isoproterenol, epinephrine, and aminophylline; however, these drugs have many side effects, are not suitable for long-term use, and have unsatisfactory efficacy. Compared with Western medicine, traditional Chinese medicine has its unique advantages in treating this disease and its efficacy is considerable. Therefore, there is an urgent need in the market to explore new ideas and methods for treating bradycardia with traditional Chinese medicine. Summary of the Invention

[0004] This invention aims to provide a traditional Chinese medicine compound preparation for bradycardia and its preparation method. The traditional Chinese medicine compound preparation has significant clinical efficacy for patients with bradycardia of the heart and kidney yang deficiency and qi deficiency and blood stasis type, providing a certain theoretical basis and clinical reference value for the treatment of bradycardia.

[0005] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0006] This invention provides a traditional Chinese medicine compound preparation for bradyarrhythmia, which is prepared from the following raw materials in parts by weight:

[0007] Astragalus membranaceus 10-90 parts, Rhodiola rosea 1-50 parts, Salvia miltiorrhiza 1-30 parts, Cinnamomum cassia 1-30 parts, Epimedium brevicornu 1-30 parts, and excipients 5-50 parts.

[0008] Preferably, the excipients are one or more of the following: dextrin, lactose, starch, microcrystalline cellulose, powdered sugar, compressible starch, hydroxypropyl methylcellulose, hydroxypropyl cellulose, magnesium stearate, polyethylene glycol, povidone, sodium stearate, poloxamer, gelatin, liquid paraffin, honey, glycerin, sodium benzoate, methylparaben, ethylparaben, propylparaben, and potassium sorbate.

[0009] Preferably, the dosage form of the traditional Chinese medicine compound preparation is pills, tablets, granules, capsules, drop pills, oral liquids, or powders.

[0010] This invention provides a method for preparing the aforementioned traditional Chinese medicine compound preparation, comprising the following steps:

[0011] 1) The raw materials are crushed separately and then mixed evenly to obtain a mixture;

[0012] 2) After reflux extraction of the mixture with the extraction solvent 1 to 4 times, combine the extracts from each extraction and filter to obtain a mixed extract;

[0013] 3) After recovering the extraction solvent, the mixed extract is concentrated under reduced pressure to a concentrate with a relative density of 1.15 to 1.25 at 50 to 80°C;

[0014] 4) After drying and pulverizing the concentrated liquid, mix it with the excipients to obtain the traditional Chinese medicine compound preparation of the present invention.

[0015] Preferably, the mass ratio of the mixture to the extraction solvent in step 2) is 1:6 to 15.

[0016] Preferably, the extraction solvent is water or an aqueous ethanol solution, wherein the mass fraction of ethanol in the aqueous ethanol solution is 30-75%.

[0017] Preferably, the extraction time in step 2) is 0.5 to 2 hours and the extraction temperature is 60 to 120°C.

[0018] Preferably, the vacuum concentration temperature in step 3) is 50-80°C, and the vacuum degree is -0.06MPa to -0.12MPa.

[0019] Preferably, the drying method in step 4) is vacuum drying or spray drying, the drying temperature is 40 to 180°C, and the vacuum degree of the vacuum drying is -0.06 MPa to -0.12 MPa.

[0020] Preferably, the particle size of the pulverized material in step 4) is 80-200 mesh.

[0021] Compared with the prior art, the present invention has the following beneficial effects:

[0022] The following is a detailed introduction and function of each component:

[0023] This formula heavily utilizes Astragalus membranaceus as the chief ingredient. Astragalus membranaceus is sweet and slightly warm in nature, and enters the spleen and lung meridians. It has the effects of tonifying qi and raising yang, consolidating the exterior and stopping sweating, promoting diuresis and reducing swelling, generating fluids and nourishing blood, promoting circulation and relieving pain, promoting pus drainage and detoxification, and promoting wound healing and tissue regeneration. It is used for qi deficiency and fatigue, palpitations, poor appetite and loose stools, sinking of middle qi, spontaneous sweating due to exterior deficiency, edema due to qi deficiency, internal heat and thirst, chlorosis due to blood deficiency, hemiplegia, numbness and pain, carbuncles that are difficult to heal, and chronic ulcers that do not heal. Astragalus membranaceus can tonify qi and raise yang, promote diuresis and reduce swelling, and is good at tonifying the qi in the chest. When the qi is strong and vigorous, the blood will flow smoothly. "When the qi circulates, the stagnation will dissipate," blood stasis and phlegm will be resolved, and all symptoms will be eliminated.

[0024] In this formula, Rhodiola rosea and Salvia miltiorrhiza are used as ministerial herbs. Rhodiola rosea is sweet and bitter in taste, neutral in nature, and belongs to the lung and heart meridians. It has the effects of tonifying qi and activating blood circulation, dredging meridians and relieving asthma. It is used for syndromes such as qi deficiency and blood stasis, chest impediment pain, stroke hemiplegia, fatigue and asthma. Its tonic and strengthening effect is similar to that of ginseng and acanthopanax senticosus. It can tonify the qi of the heart, lung, spleen and kidney. In "Compendium of Materia Medica - Herb Section", Rhodiola rosea is noted as "superior herb"; according to the "Four Medical Canons" of Tibetan medicine, Rhodiola rosea is recorded as "cool in nature, clearing heat, tonifying vital energy"; "Wen Dao He" states: "Rhodiola rosea, with the effects of nourishing the lungs, clearing heat, and tonifying vital energy"; according to the "Illustrated Handbook of Higher Plants in China", Rhodiola rosea has the effects of "breaking firmness, eliminating accumulations, stopping bleeding, and relieving diarrhea". Its qi-tonifying power is extremely strong, and it can also improve the circulation of blood. Salvia miltiorrhiza is bitter and slightly cold in nature, entering the heart, pericardium and liver meridians. It has the effects of activating blood circulation and dredging collaterals, tonifying qi and nourishing blood, cooling blood and eliminating carbuncles, removing blood stasis and relieving pain, clearing the heart and relieving restlessness, calming the mind and tranquilizing the nerves, etc. It is commonly used for syndromes such as chest impediment pain, abdominal and hypochondriac pain, mass accumulation, heat arthralgia pain, restlessness and insomnia, irregular menstruation, dysmenorrhea and amenorrhea, swelling and pain of sores and ulcers, etc. In "Shennong's Classic of Materia Medica - Volume 1", it is listed as a superior herb. The blood-tonifying power of Salvia miltiorrhiza is weaker than that of Angelica sinensis, but its stasis-removing power is stronger than that of Angelica sinensis. Astragalus membranaceus, Rhodiola rosea and Salvia miltiorrhiza are mutually ministerial and assistant herbs. Qi can generate blood, and blood can nourish qi. Tonifying qi and blood simultaneously, qi and blood generate each other, to tonify the qi of the heart, lung, spleen, kidney and essence yuan, nourish the blood of the heart and liver, activate blood circulation to remove stasis, and tonify without stagnation.

[0025] In this formula, Cinnamomum cassia and Epimedium brevicornum are used as assistant and guiding herbs. Cinnamomum cassia: pungent and sweet in taste, extremely hot in nature, belonging to the kidney, spleen, heart and liver meridians, having the effects of tonifying fire and assisting yang, guiding back floating yang, dispelling cold and relieving pain, warming and dredging meridians. Cinnamomum cassia is warm and tonifying, with a thick qi and pure yang. It is commonly used for syndromes such as impotence and cold uterus, cold pain in the waist and knees, asthma due to kidney deficiency, floating yang due to deficiency, dizziness and red eyes, cold pain in the heart and abdomen, deficiency-cold vomiting and diarrhea, cold hernia pain, dysmenorrhea and amenorrhea, etc. "Shennong's Classic of Materia Medica" records that Cinnamomum cassia "is pungent and warm in taste, treating all diseases, nourishing the spirit, harmonizing the complexion, promoting joint movement, and tonifying the middle qi. It is the first to be recruited as a guiding herb for all medicines. Taking it for a long time leads to spiritual communication, light body and never aging". "Compendium of Materia Medica" states that "strengthening the muscles and bones, dredging the blood vessels, and guiding all medicines", and the ancients called it "warming the lower abdomen, strengthening the primordial yang, tonifying the ministerial fire, and assisting the monarch fire"; "Supplementary Records" states that "treating heart pain... treating middle warming... guiding all medicines, without fear". It is good at gently tonifying the kidney, guiding back floating yang, and also entering the blood aspect, being good at warming and dredging meridians. Epimedium brevicornum, pungent, sweet and warm in nature, non-toxic, belonging to the liver and kidney meridians. It has the effects of tonifying the kidney yang, strengthening the muscles and bones, and dispelling wind-dampness. It is used for kidney yang deficiency, impotence and spermatorrhea, flaccidity of muscles and bones, wind-dampness arthralgia, numbness and contracture, etc. It is also applied to heart system diseases such as chest impediment and palpitation, which are differentiated as the syndrome of heart and kidney yang deficiency. Li Shizhen said that "it is suitable for those with true yang deficiency". "Japanese Pharmacopoeia" records that "treating all wind-cold and overstrain qi, tonifying the waist and knees, strengthening the heart power...". The adverse reactions of Epimedium brevicornum are not commonly seen clinically. The medicinal property of raw Epimedium brevicornum is relatively severe, and individual patients may have symptoms such as thirst, dry throat, and dry stools. After processing with mutton fat, roasted Epimedium brevicornum has a milder medicinal effect, can increase the efficacy of the drug, and reduce adverse reactions. Therefore, when Cinnamomum cassia and roasted Epimedium brevicornum are used together in this formula, it enhances the effects of assisting yang, dispelling cold and strengthening the heart.

[0026] The traditional Chinese medicine compound preparation described in this invention is formulated based on the fundamental theories of traditional Chinese medicine and the principles of clinical diagnosis and treatment. Astragalus membranaceus is the principal ingredient, with Rhodiola rosea and Salvia miltiorrhiza as assistant ingredients, and Cinnamomum cassia and Epimedium brevicornu as adjuvant ingredients. The entire formula combines warming and tonifying herbs, addressing both essence and blood. It greatly tonifies Yang Qi without being cloying, and warms and tonifies kidney Yang without being excessively drying. The principal and secondary ingredients are clearly distinguished, the combination is rigorous, and the formula is simple yet effective. It addresses the root cause by invigorating Qi and assisting Yang, warming and tonifying the heart and kidneys, while addressing the symptoms by nourishing blood, unblocking collaterals, calming the mind, and soothing the nerves. The combination of herbs addresses both the root and symptoms, achieving the combined effects of invigorating Qi and warming Yang, warming and tonifying the heart and kidneys, nourishing blood, and unblocking collaterals. No adverse clinical events have been observed in the clinical application of this traditional Chinese medicine compound preparation in the past 10 years. It is suitable for long-term use by patients with bradycardia caused by sinoatrial node dysfunction due to deficiency of heart and kidney Yang. Detailed Implementation

[0027] The technical solutions provided by the present invention will be described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0028] Example 1

[0029] This invention provides a traditional Chinese medicine compound preparation for bradyarrhythmia, which is prepared from the following raw materials in parts by weight:

[0030] Astragalus membranaceus 10 parts, Rhodiola rosea 1 part, Salvia miltiorrhiza 1 part, Cinnamomum cassia 1 part, Epimedium brevicornu 1 part, excipients 5 parts;

[0031] The excipients consist of lactose, dextrin, and sucrose, with a mass ratio of 2:2:1.

[0032] The preparation method of the traditional Chinese medicine compound preparation includes the following steps:

[0033] 1) Accurately weigh all raw materials except for auxiliary materials, crush them separately, and then mix them evenly to obtain a mixture;

[0034] 2) Extract the mixture twice by water reflux at a temperature of 120℃. For the first extraction, add 15 times the amount of water to the mixture and extract for 2 hours. For the second extraction, add 10 times the amount of water to the mixture and extract for 2 hours. After extraction, combine the two extracts and filter them through a 200-mesh filter cloth to obtain a mixed extract.

[0035] 3) The mixed extract was first concentrated under reduced pressure at -0.06 MPa and 50°C to a concentration with a relative density of 1.15 (50°C), and then the concentration was vacuum dried at -0.12 MPa and 40°C to obtain a dry extract.

[0036] 4) After pulverizing the dry extract to 80 mesh, mix it with the excipients and prepare a soft material with 75% ethanol. After granulating the soft material into wet granules using a granulator, dry it at a constant temperature of 60°C to control the moisture content to 4%. Then, granulate it through a 12-mesh sieve and process it into granule dosage form, 10g per bag. Seal and dry the package to obtain the traditional Chinese medicine compound granules of the present invention.

[0037] Example 2

[0038] This invention provides a traditional Chinese medicine compound preparation for bradyarrhythmia, which is prepared from the following raw materials in parts by weight:

[0039] Astragalus membranaceus 20 parts, Rhodiola rosea 12 parts, Salvia miltiorrhiza 6 parts, Cinnamomum cassia 6 parts, Epimedium brevicornu 6 parts, and excipients 50 parts;

[0040] The auxiliary material is polyethylene glycol 400.

[0041] The preparation method of the traditional Chinese medicine compound preparation includes the following steps:

[0042] 1) Accurately weigh all raw materials except for auxiliary materials, crush them separately, and then mix them evenly to obtain a mixture;

[0043] 2) The mixture was refluxed with 75% ethanol aqueous solution three times at an extraction temperature of 60℃. The first extraction was carried out with 10 times the amount of water as the mixture for 1.5 hours, the second extraction was carried out with 8 times the amount of water as the mixture for 1 hour, and the third extraction was carried out with 6 times the amount of water as the mixture for 1 hour. After the extraction was completed, the three extracts were combined and filtered through a 200-mesh filter cloth to obtain a mixed extract.

[0044] 3) After the mixed extract is recovered by ethanol, it is first concentrated under reduced pressure at a vacuum degree of -0.08MPa and 70℃ to a concentrated solution with a relative density of 1.15 (70℃), and then the concentrated solution is spray-dried at 70℃ to obtain a dry extract.

[0045] 4) After pulverizing the dry extract to 200 mesh, mix it with the excipient polyethylene glycol 400, and then drop it into liquid paraffin at 30°C at 80°C to form pills, thus obtaining the traditional Chinese medicine compound pills of the present invention.

[0046] Example 3

[0047] This invention provides a traditional Chinese medicine compound preparation for bradyarrhythmia, which is prepared from the following raw materials in parts by weight:

[0048] Astragalus membranaceus 90 parts, Rhodiola rosea 50 parts, Salvia miltiorrhiza 30 parts, Cinnamomum cassia 30 parts, Epimedium brevicornu 30 parts, and excipients 40 parts;

[0049] The auxiliary ingredient is honey.

[0050] The preparation method of the traditional Chinese medicine compound preparation includes the following steps:

[0051] 1) Accurately weigh all raw materials except for auxiliary materials, crush them separately, and then mix them evenly to obtain a mixture;

[0052] 2) The mixture was refluxed with 30% ethanol aqueous solution four times at an extraction temperature of 70℃. For the first extraction, 10 times the amount of water as the mixture was added and the mixture was extracted for 1 hour. For the second extraction, 8 times the amount of water as the mixture was added and the mixture was extracted for 1 hour. For the third extraction, 6 times the amount of water as the mixture was added and the mixture was extracted for 1 hour. For the fourth extraction, 6 times the amount of water as the mixture was added and the mixture was extracted for 0.5 hours. After extraction, the four extracts were combined and filtered through a 300-mesh filter cloth to obtain a mixed extract.

[0053] 3) After ethanol recovery, the mixed extract is first concentrated under reduced pressure at a vacuum of -0.12 MPa and 80°C to a concentrate with a relative density of 1.15 (80°C), and then the concentrate is spray-dried at 180°C to obtain a dry extract.

[0054] 4) After pulverizing the dry extract to 200 mesh, heat the honey over a low flame, stirring constantly until the honey turns yellow and bubbles. Turn off the heat and let it cool naturally to 55°C. Finally, slowly add the honey to the dry extract powder, mix them evenly, roll them into 10g pills, and seal them separately to obtain the traditional Chinese medicine compound pills described in this invention.

[0055] Example 4

[0056] This invention provides a traditional Chinese medicine compound preparation for bradyarrhythmia, which is prepared from the following raw materials in parts by weight:

[0057] Astragalus membranaceus 15 parts, Rhodiola rosea 10 parts, Salvia miltiorrhiza 10 parts, Cinnamomum cassia 5 parts, Epimedium brevicornu 10 parts, and excipients 25 parts;

[0058] The excipients consist of lactose, dextrin, microcrystalline cellulose and silicon dioxide, and the mass ratio of lactose, dextrin, microcrystalline cellulose and silicon dioxide is 4:2:2:1.

[0059] The preparation method of the traditional Chinese medicine compound preparation includes the following steps:

[0060] 1) Accurately weigh all raw materials except for auxiliary materials, crush them separately, and then mix them evenly to obtain a mixture;

[0061] 2) Extract the mixture once by water reflux at a temperature of 120℃, add 15 times the amount of water to the mixture and extract for 1.5 hours, then filter through a 300-mesh filter cloth to obtain the filtrate;

[0062] 3) The mixed extract was first concentrated under reduced pressure at -0.08 MPa and 70°C to a concentrate with a relative density of 1.25 (70°C), and then the concentrate was vacuum dried at -0.06 MPa and 60°C to obtain a dry extract.

[0063] 4) After the dry extract is pulverized to 100 mesh, it is mixed evenly with the excipients in a powder mixer and then fed into a dry granulator. The granulation conditions are set as follows: roller pressure of 2 MPa, feeding speed of 15 rpm, tableting speed of 10 rpm, granulation speed of 120 rpm, and sieve mesh of 20 mesh. The traditional Chinese medicine compound tablets of the present invention are obtained, each tablet weighing 0.5 g. The tablets are sealed and stored in a dry place.

[0064] Experimental Example 1

[0065] This trial used Xinbao Pill as a positive control drug and followed the principles of randomization and parallel control. Subjects who met the criteria of bradycardia and were diagnosed with heart and kidney yang deficiency and qi deficiency and blood stasis syndrome according to traditional Chinese medicine were included. The changes in minimum heart rate, average heart rate, maximum heart rate and traditional Chinese medicine syndrome score before and after treatment were compared and analyzed between the two groups. The clinical efficacy of the traditional Chinese medicine compound preparation described in Example 4 of this invention in treating bradycardia with heart and kidney yang deficiency and qi deficiency and blood stasis syndrome was objectively evaluated.

[0066] I. Test subjects and diagnostic criteria

[0067] 1. Test subjects

[0068] Based on the inclusion and exclusion criteria, a total of 68 patients (35 years ≤ age ≤ 80 years) diagnosed with sick sinus syndrome at the Department of Cardiology, Affiliated Traditional Chinese Medicine Hospital of Xinjiang Medical University from January 2021 to January 2024, and whose TCM syndrome differentiation was classified as heart and kidney yang deficiency and qi deficiency and blood stasis, were selected.

[0069] Randomized controlled trial: Open-label study. Patients are randomly assigned using a random number table, numbered from 1 to 68. Starting from any number in the random number table, a random number is sequentially drawn for each experimental unit in the same direction. The remainder is calculated by dividing the random number by 2. If the remainder is even, the group number is determined. Grouping: Groups are formed based on the remainder.

[0070] 2. Diagnostic criteria (including Western medicine diagnostic, staging, and grading criteria, and traditional Chinese medicine syndrome differentiation criteria).

[0071] 2.1 Western Medicine Diagnostic Criteria:

[0072] This definition is based on the definitions of this disease in "Practical Cardiology" and "Huang Wan's Clinical Electrocardiography".

[0073] (1) Sinus bradycardia: resting heart rate or average heart rate <60 beats / min (heart rate <55 beats / min for those over 60 years of age);

[0074] (2) Sinus arrest: A sudden, significant long pause occurs in normal sinus rhythm; no P-QRS-T complexes appear during the long pause;

[0075] The PP interval of a long pause is not multiple of the normal sinus PP interval; after a long PP pause, escape beats or escape rhythms may occur, with atrioventricular junctional escape beats or escape rhythms being more common and ventricular or atrial escape beats being less common.

[0076] (3) Second-degree sinoatrial block: Type I: Must be sinus rhythm with sinus P waves; the sinus PP interval gradually shortens, eventually ending with a long pause without sinus P waves. The PP interval before and after the long pause is slightly shorter than twice the sinus PP interval. Type II: Sinus P waves, a long pause suddenly appears during the regular PP interval, without P-QRS-T wave complexes. The regular PP interval and the subsequent long pause have a fixed ratio, such as 2:1, 3:2, 4:3, 5:4, etc. The long PP interval is an integer multiple of the short PP interval, commonly twice the length of the short PP interval.

[0077] (4) Slow-fast syndrome: Sinus bradycardia with short runs of atrial fibrillation, atrial flutter, and supraventricular tachycardia, with sinus beat recovery time >2s at the end of the episode.

[0078] 2.2 Traditional Chinese Medicine Diagnostic Criteria:

[0079] Refer to the second edition of "Traditional Chinese Medicine Diagnostics" and "Traditional Chinese Medicine Diagnosis and Treatment Plans for 24 Specialties and 104 Diseases".

[0080] (1) Disease diagnosis: Main symptoms: slow pulse, less than four beats per breath. Accompanying symptoms: palpitations, chest tightness, dizziness, blurred vision, or even syncope;

[0081] (2) Syndrome diagnosis:

[0082] ① Qi deficiency and blood stasis syndrome: palpitations, chest tightness, shortness of breath and fatigue, occasional chest pain, pale complexion, or cyanosis of the lips and nails, rough and dry skin, dark purple tongue with ecchymosis, slow and hesitant or intermittent pulse.

[0083] ② Heart and Kidney Yang Deficiency Syndrome: Chest tightness, palpitations, occasional chest pain, soreness and coldness in the lower back and knees, fatigue, aversion to cold and cold limbs, pale tongue, swollen tongue body, deep and slow or intermittent pulse.

[0084] 3. Case inclusion criteria (those meeting all of the following conditions)

[0085] (1) Those who meet the diagnostic criteria for sick sinus syndrome (sinus bradycardia, sinus arrest, second-degree sinoatrial block, bradycardia-tachycardia syndrome);

[0086] (2) Patients diagnosed by traditional Chinese medicine as having palpitations due to deficiency of heart and kidney yang, or deficiency of qi and blood stasis;

[0087] (3) Those classified as mild to moderate according to the TCM symptom grading and quantification table (symptom score <17 points) should refer to the "Guiding Principles for Clinical Research of New Chinese Medicines (Trial)" (2002 edition);

[0088] (4) Age between 35 and 80 years old;

[0089] (5) Those who sign the informed consent form.

[0090] 4. Case exclusion criteria

[0091] (1) Sick sinus syndrome caused by drug, endocrine, metabolic and electrolyte disorders;

[0092] (2) Those who have high-degree sinoatrial block, third-degree sinoatrial block, or sinus arrest with an RR interval >6 seconds;

[0093] (3) Those who develop slow atrial fibrillation, severe sick sinus syndrome, or are accompanied by prodromal symptoms such as Stokes-Adams syndrome or amaurosis fugax;

[0094] (4) Patients who have already had a pacemaker implanted and patients who meet the criteria for pacemaker implantation;

[0095] (5) Those suffering from severe heart failure or severe respiratory dysfunction;

[0096] (6) Patients with severe benign prostatic hyperplasia or acute urinary retention;

[0097] (7) Patients with concurrent acute cerebrovascular disease, acute pulmonary embolism or pulmonary infarction;

[0098] (8) Those with severe infections, severe mental illnesses, or malignant tumors;

[0099] (9) Individuals with serious diseases such as liver and kidney dysfunction or hematopoietic system disorders;

[0100] (10) Those who are under 35 years of age or over 80 years of age;

[0101] (11) Pregnant or planning to become pregnant and breastfeeding women;

[0102] (12) Individuals with allergic constitutions or those allergic to any component of this drug;

[0103] (13) Patients who have participated in other clinical trials within the past three months.

[0104] 5. Conditions for subjects to discontinue or withdraw from clinical trials

[0105] (1) Serious adverse reactions or adverse events occur;

[0106] (2) Violation of the trial protocol, such as failure to receive medication after enrollment (e.g., poor compliance);

[0107] (3) The patient voluntarily withdrew from the trial;

[0108] (4) Loss to follow-up or failure of the patient to come to the hospital for follow-up visit on time.

[0109] 6. Case exclusion criteria, case dropout and handling

[0110] (1) Serious adverse reactions or adverse events occur;

[0111] (2) Violation of the trial protocol, such as failure to receive medication after enrollment (e.g., poor compliance);

[0112] (3) The patient voluntarily withdrew from the trial;

[0113] (4) Loss to follow-up or failure of the patient to come to the hospital for follow-up visit on time.

[0114] II. Experimental Procedure

[0115] 1. Experimental Design

[0116] This is a prospective, randomized, controlled clinical trial. The trial will be conducted in phases:

[0117] (1) Screening period: Subjects sign informed consent forms, the inclusion criteria are initially assessed, relevant examinations are conducted, and the induction period begins;

[0118] (2) Introduction period: Subjects enter a 1-week introduction period to determine their inclusion criteria and clinical stability. No investigational drug is administered to subjects during the introduction period. After the introduction period, subjects who meet the inclusion criteria and do not meet any exclusion criteria are randomly assigned (1:1) to the treatment group or the control group.

[0119] (3) Treatment period: 8 weeks.

[0120] 2. Experimental grouping and drug administration

[0121] 2.1 Drug Source

[0122] (1) Treatment group medication: The traditional Chinese medicine compound preparation described in Example 1 of this invention;

[0123] (2) Control group drug: Xinbao Pill, Guangdong Taiantang Pharmaceutical Co., Ltd., batch number Z44022728, specification: 60mg / pill;

[0124] The instructions for use of Xinbao Pills state: Usage: Oral administration. Dosage is as follows: ① For severe cases of sick sinus syndrome, 300-600 mg (5-10 pills) three times a day, for a course of 3-6 months. ② For other arrhythmias (extra-term contractions), atrial fibrillation, myocardial ischemia, or angina pectoris, 120-240 mg (2-4 pills) three times a day, for a course of 1-2 months.

[0125] 2.2 Dosing regimen

[0126] (1) Treatment group: 2 packets twice a day, taken with hot water half an hour after breakfast and dinner;

[0127] (2) Control group: The control group was formulated according to the instructions and the severity of the patients' conditions in this experiment. The dosage of Xinbao Pills was 3 pills / time, 3 times a day, half an hour after meals.

[0128] 3. Observation period

[0129] After screening and enrollment, patients were observed three times: 4 weeks ± 3 days after starting medication, 8 weeks ± 3 days after starting medication, and 12 ± 3 days after stopping medication.

[0130] 4. Clinical observation indicators

[0131] 4.1 Safety Observation

[0132] 4.1.1 Demographic data

[0133] This includes age, gender, ethnicity, smoking history, medical history, medication history, family history, etc.

[0134] 4.1.2 Auxiliary Inspections

[0135] Routine blood, urine, and stool tests; liver function tests (ALT, AST); kidney function tests (BUN, Cr); electrolytes; thyroid function tests (five items); blood pressure; and blood glucose levels.

[0136] 4.1.3 Observation of adverse reactions / events

[0137] If an adverse event occurs during the experiment, fill out the Adverse Event Report Form truthfully, recording in detail the date and time of the event, its severity, the handling measures, and the outcome.

[0138] 4.2 Observation of therapeutic efficacy

[0139] 4.2.1 Observation Indicators

[0140] (1) Main therapeutic indicators

[0141] 24-hour Holter monitoring: minimum heart rate, average heart rate, maximum heart rate, and total heart rate.

[0142] (2) Secondary efficacy indicators

[0143] ①Minnesota Quality of Life Scale (refer to "Guiding Principles for Clinical Research of New Traditional Chinese Medicines (Trial)" [M]. Zheng Xiaoyu. China Medical Science and Technology Press, 2002, 81.);

[0144] ② Quantitative Table of Symptom Grading in Traditional Chinese Medicine (Refer to "Guiding Principles for Clinical Research of New Traditional Chinese Medicines (Trial)" [M]. Zheng Xiaoyu. China Medical Science and Technology Press, 2002, 84.).

[0145] 4.3 Observation Time Point

[0146] (1) 24-hour Holter monitoring: once before medication and once after treatment;

[0147] (2) Minnesota Quality of Life Scale: Observations were conducted three times: before medication, 4 weeks ± 3 days after medication, 8 weeks ± 3 days after medication, and 12 weeks ± 3 days after medication discontinuation.

[0148] (3) Traditional Chinese medicine syndrome score: The observation was conducted 3 times: before medication, 4 weeks ± 3 days after medication, 8 weeks ± 3 days after medication, and 12 weeks ± 3 days after medication was stopped.

[0149] (4) Safety indicators observation: one test before medication and one test after treatment.

[0150] 5. Efficacy evaluation criteria

[0151] 5.1 Evaluation criteria for the efficacy of 24-hour Holter monitoring

[0152] (1) Recovery: The average heart rate over 24 hours is 60 beats / min or higher and the minimum heart rate, average heart rate or visit heart rate over 24 hours increases by ≥5 beats / min.

[0153] (2) Significant effect: The minimum or average heart rate increases by ≥10 beats / min in 24 hours.

[0154] (3) Effective: The minimum or average heart rate increases by ≥5 beats / min and <10 beats / min in 24 hours.

[0155] (4) Invalid: The minimum or average heart rate increases by less than 5 beats / min in 24 hours.

[0156] 5.2 Minnesota Quality of Life Scale Therapeutic Evaluation Criteria

[0157] The Minnesota Quality of Life Scale was developed with reference to the "Guiding Principles for Clinical Research of New Traditional Chinese Medicine Drugs (Trial Implementation)" [M]. Zheng Xiaoyu. China Medical Science and Technology Press, 2002, 84. The Minnesota Quality of Life Scale (MLHFQ) is a self-assessment and scoring system based on the impact of heart failure on the user's life, assisted and recorded by a physician. The Minnesota Quality of Life Scale is divided into three domains: physical, emotional, and other. Higher scores indicate a poorer quality of life.

[0158] 5.3 Evaluation Criteria for the Therapeutic Effect of Traditional Chinese Medicine Syndromes

[0159] The criteria for evaluating the efficacy of TCM syndromes were formulated with reference to the "Syndrome and Efficacy Evaluation of Clinical Trials of New Chinese Medicines" in the 2002 "Guiding Principles for Clinical Research of New Chinese Medicines (Trial)".

[0160] Therapeutic effect index = (Total score before treatment - Total score after treatment) × 100% ÷ Total score before treatment

[0161] (1) Clinical cure: The efficacy index (score reduction) is ≥90%;

[0162] (2) Significant effect: Therapeutic effect index (score reduction) ≥70% and <90%;

[0163] (3) Effective: The efficacy index (score reduction) is ≥30% and <70%;

[0164] (4) Ineffective: The efficacy index (score decrease) <30%;

[0165] 6. Protection of Subjects' Rights

[0166] Clinical trial participants must be informed that the trial is voluntary, and that they have the right to withdraw at any stage without affecting their medical treatment and rights, and can continue with other effective treatments. Participants must also be informed that all personal data collected during the trial is confidential. The purpose of the trial and the expected benefits or potential risks must be fully explained, in accordance with the rights and obligations of participants as stipulated in the Declaration of Helsinki.

[0167] 7. Quality Control Measures

[0168] (1) Use a uniformly designed, reasonable and feasible case investigation form; (2) Fill out the case investigation form in a timely and accurate manner to ensure the authenticity and reliability of the original data; (3) The experimenters must strictly adhere to the Western medicine inclusion and exclusion criteria of this experiment to avoid selective bias; (4) During the implementation of the experiment, the dropout rate should be controlled within 20%; (5) In terms of TCM syndrome differentiation, three associate chief physicians or chief physicians should be selected to conduct syndrome differentiation. If the results are inconsistent, the more uniform syndrome type should be selected as the TCM syndrome differentiation classification of this experiment.

[0169] 8. Data processing and statistical methods

[0170] Create a database using Excel and enter the data. Quantitative data that conform to a normal distribution are represented by x±s, and non-normally distributed data are represented by the median [P25, P75].

[0171] (1) Baseline data

[0172] Statistical analysis was performed using SAS JMP (Pro 16.0) software, and t-tests and χ² tests were used. 2 The test measures whether the two groups are balanced, including: age, sex, ethnicity, body mass index (BMI), smoking history, drinking history, coronary heart disease, heart failure, atrial fibrillation, premature ventricular contractions, premature atrial contractions, hypertension, diabetes, hypothyroidism, and disease duration (months).

[0173] (2) Key outcome indicators

[0174] To assess the effectiveness of the 24-hour Holter monitoring efficacy evaluation criteria, a non-inferiority test was performed using code written in R4.3.1. The differences in heart rate between 24-hour Holter monitoring cycles were analyzed using paired t-tests.

[0175] (3) Secondary outcome indicators

[0176] The study used the Minnesota Quality of Life Scale and two sets of Traditional Chinese Medicine (TCM) symptom grading scales. Statistical analysis was performed using SAS JMP (Pro 16.0) software, and qualitative analysis was conducted using the χ² method. 2 The test does not satisfy the χ² test. 2 Fisher's exact test was used for the tests; paired t-tests were used for quantitative analysis and individual symptom analysis.

[0177] (4) Security Analysis

[0178] Using χ 2 The test does not satisfy the χ² test. 2 Fisher's exact test was used, including: hemoglobin, platelets, ALT, AST, creatinine, and blood urea nitrogen. The significance level was set at α = 0.05.

[0179] III. Statistical Analysis of Research Results

[0180] 1. Baseline Analysis

[0181] 1.1 Demographic Data Analysis

[0182] A t-test was performed to compare age, body mass index (BMI), and disease duration between the two groups, and no statistically significant differences were found (P>0.05). A χ² test was performed to compare gender, ethnicity, smoking history, and alcohol consumption history between the two groups. 2 The test showed no statistically significant difference (P>0.05), indicating that the two groups were comparable (see Table 1).

[0183] Table 1. Demographic Data

[0184]

[0185]

[0186] 1.2 Analysis of Disease-Related Test Results:

[0187] t-tests / rank-sum tests were performed on disease-related test results between the two groups, such as hemoglobin, platelets, ALT, AST, creatinine, blood urea nitrogen, serum potassium, and fasting blood glucose. No statistically significant differences were found (P>0.05). This indicates that the two groups are comparable (see Table 2).

[0188] Table 2 Analysis of Disease-Related Test Results

[0189]

[0190] & Use the rank-sum test.

[0191] 1.3 Analysis of Comorbidities

[0192] The presence or absence of coronary heart disease, heart failure, atrial fibrillation, premature ventricular contractions, premature atrial contractions, hypertension, diabetes, and hypothyroidism between the two groups was determined by a χ² test. 2 The tests revealed a statistically significant imbalance between the two groups in the presence or absence of hypothyroidism (P = 0.047). The treatment group had a higher prevalence of hypothyroidism, and patients with hypothyroidism typically have lower heart rates, indicating a worse condition in the treatment group. Therefore, this bias would not overemphasize the effect of the treatment group. Other indicators—presence or absence of coronary heart disease, heart failure, atrial fibrillation, premature atrial contractions, hypertension, and diabetes—showed no statistically significant differences between the two groups (P > 0.05), suggesting comparability between the groups (see Table 3).

[0193] Table 3. List of Comorbidities

[0194]

[0195]

[0196] *The difference was statistically significant. #Fisher's exact test was used.

[0197] 2. Therapeutic effect analysis

[0198] 2.1 Key Outcome Indicators

[0199] 2.1.1 Effectiveness of 24-hour Holter monitoring efficacy evaluation criteria

[0200] Refer to the "Evaluation Criteria for the Therapeutic Effect of 24-hour Holter Monitoring":

[0201] (1) Recovery: The average heart rate over 24 hours is 60 beats / min or higher and the minimum heart rate, average heart rate or visit heart rate over 24 hours increases by ≥5 beats / min.

[0202] (2) Significant effect: The minimum or average heart rate increases by ≥10 beats / min in 24 hours.

[0203] (3) Effective: The minimum or average heart rate increases by ≥5 beats / min and <10 beats / min in 24 hours.

[0204] (4) Invalid: The minimum or average heart rate increases by less than 5 beats / min in 24 hours.

[0205] Effectiveness rate = (cured + significantly effective + effective) × 100%.

[0206] The efficacy rates of the two groups were tested for non-inferiority using code written in R4.3.1. The results showed that the efficacy rate in the treatment group was 77.78%, and that in the control group was 71.88%, with a p-value of 0.575. The difference in efficacy between the two groups was 5.9%, with a 95% confidence interval of -11.40% to 23.37%. The non-inferiority margin was set at 15%, and the p-value for the non-inferiority test was <0.023, indicating that the efficacy rate of the treatment group was non-inferior to that of the control group.

[0207] 2.1.2 Comparison of Heart Rate Indicators in 24-hour Holter Monitoring

[0208] (1) Total heart rate

[0209] There was no statistically significant difference in total heart rate on 24-hour Holter monitoring between the two groups before treatment. After treatment, the total heart rate increased in both groups compared to before treatment, but the difference between the two groups was not statistically significant. The difference in total heart rate between the two groups after treatment and before treatment was not statistically significant (P>0.05), and the above was analyzed using a t-test. The proportion of patients with increased total heart rate after treatment was 91.67% in the treatment group, showing an increasing trend compared to 84.38% in the control group, but the difference between the groups was not statistically significant (P>0.05), and the χ² test was used (see Table 4).

[0210] Table 4 Comparison of total heartbeats on dynamic electrocardiograms

[0211]

[0212] &using χ 2 test.

[0213] (2) Mean heart rate

[0214] There was no statistically significant difference in the mean heart rate of 24-hour Holter monitoring between the two groups before treatment. After treatment, the mean heart rate of both groups increased compared to before treatment, but the difference between the two groups was not statistically significant. The difference in mean heart rate between the two groups after treatment was not statistically significant (P>0.05), and the above was analyzed using a t-test. The proportion of patients with an increased mean heart rate after treatment was 88.89% in the treatment group, showing an increasing trend compared to 84.38% in the control group, but the difference between the groups was not statistically significant (P>0.05), and the χ² test was used (see Table 5).

[0215] Table 5 Comparison of mean heartbeats from 24-hour Holter monitoring

[0216]

[0217] &using χ 2 test.

[0218] (3) Maximum heart rate

[0219] There was no statistically significant difference in maximum heart rate between the two groups before treatment. After treatment, the maximum heart rate in both groups increased compared to before treatment, but the difference between the two groups was not statistically significant. The difference in maximum heart rate between the two groups after treatment and before treatment was not statistically significant (P>0.05), and the above was analyzed using a t-test. There was no statistically significant difference in the proportion of patients with increased maximum heart rate after treatment between the groups (P>0.05), and the χ² test was used (see Table 6).

[0220] Table 6 Comparison of maximum heart rate from 24-hour Holter monitoring

[0221]

[0222] &using χ 2 test.

[0223] (4) Minimum heart rate

[0224] There was no statistically significant difference in minimum heart rate between the two groups before treatment. After treatment, the minimum heart rate in both groups increased compared to before treatment, but the difference between the two groups was not statistically significant. The difference in minimum heart rate between the two groups after treatment was not statistically significant (P>0.05), and the above was analyzed using a t-test. The proportion of patients whose minimum heart rate increased after treatment showed no statistically significant difference between the groups (P>0.05), and the χ² test was used (see Table 7).

[0225] Table 7 Comparison of minimum heart rate in 24-hour Holter monitoring

[0226]

[0227] &using χ 2 test.

[0228] 2.2 Secondary Outcome Indicators:

[0229] 2.2.1 Minnesota Quality of Life Scale

[0230] (1) Minnesota Quality of Life Scale Summary Table

[0231] The Minnesota Quality of Life Scale was used in both groups, divided into three domains: physical, emotional, and other. Higher scores indicated poorer quality of life. Paired t-tests were used for overall table analysis. Before treatment, there was no statistically significant difference in scores between the two groups, indicating they were comparable. After treatment, scores decreased in both groups, but the decrease was more significant in the treatment group, with a statistically significant difference (P < 0.001). The differences between pre-treatment and post-treatment scores were also statistically significant (P < 0.001), indicating that the treatment group was significantly better than the control group in improving quality of life (see Table 8).

[0232] Table 8. Total Score of the Minnesota Quality of Life Scale

[0233]

[0234] *The difference is statistically significant.

[0235] (2) Minnesota Quality of Life Scale (Body Domain #)

[0236] The Minnesota Quality of Life Scale's physical domain score was analyzed using paired t-tests. Before treatment, there was no statistically significant difference in scores between the two groups, indicating they were comparable. After treatment, scores decreased in both groups, but the decrease was more significant in the treatment group, with a statistically significant difference between the groups (P < 0.001). The differences between the pre-treatment and post-treatment scores were also statistically significant (P < 0.001), suggesting that the treatment group was significantly better than the control group in improving the physical domain of quality of life (see Table 9).

[0237] Table 9. Minnesota Quality of Life Scale (Physical Domain #)

[0238]

[0239] *The difference was statistically significant. #The body domain includes: items 2, 3, 4, 5, 6, 7, 12, and 13.

[0240] (3) Minnesota Quality of Life Scale (Emotional Domain #)

[0241] The Minnesota Quality of Life Scale's emotional domain was analyzed using paired t-tests. Before treatment, there was no statistically significant difference in scores between the two groups, indicating they were comparable. After treatment, scores in both domains decreased, but the decrease was more significant in the treatment group, with a statistically significant difference between the groups (P < 0.001). The difference between pre-treatment and post-treatment scores was statistically significant between the two groups (P = 0.003), suggesting that the treatment group was significantly better than the control group in improving the physical domain of quality of life (see Table 10).

[0242] Table 10 Minnesota Quality of Life Scale (Emotional Domain #)

[0243]

[0244] *The differences were statistically significant. #The emotion domain includes: items 17, 18, 19, 20, and 21.

[0245] (4) Minnesota Quality of Life Scale (Other Areas#)

[0246] Paired t-tests were used to evaluate other domains of the Minnesota Quality of Life Scale. Before treatment, there was no statistically significant difference in scores between the two groups, indicating they were comparable. After treatment, scores decreased in both groups, but the decrease was more significant in the treatment group, with a statistically significant difference between the groups (P < 0.001). The differences between the pre-treatment and post-treatment scores were also statistically significant (P < 0.001), suggesting that the treatment group was significantly better than the control group in improving other domains of quality of life (see Table 11).

[0247] Table 11 Minnesota Quality of Life Scale (Other Areas #)

[0248]

[0249] *The difference was statistically significant. #Other areas include: items 1, 8, 9, 10, 11, 14, 15, and 16.

[0250] 2.2.2 Quantitative Table of Traditional Chinese Medicine Symptom Grading

[0251] (1) Traditional Chinese Medicine Symptom Grading and Quantification Table (Total Score)

[0252] The standards were formulated with reference to the "Syndrome and Efficacy Evaluation of Clinical Trials of New Traditional Chinese Medicines" in the 2002 "Guiding Principles for Clinical Research of New Traditional Chinese Medicines".

[0253] Therapeutic effect index = (Total score before treatment - Total score after treatment) × 100% ÷ Total score before treatment

[0254] ① Clinical cure: Efficacy index (score reduction) ≥ 90%;

[0255] ②Significant effect: Therapeutic effect index (reduction in score) ≥70%, <90%;

[0256] ③ Effective: Therapeutic effect index (score reduction) ≥30%, <70%;

[0257] ④ Ineffective: Therapeutic index (score decrease) <30%;

[0258] The qualitative analysis of the total TCM syndrome efficacy scores between the two groups was performed using Fisher's exact test. No statistically significant difference was found between the two groups (P = 0.90), indicating comparable efficacy. (See Table 12)

[0259] Table 12 Total Score of TCM Syndrome Grading Quantification Table (Qualitative Analysis)

[0260]

[0261] The paired t-test was used for quantitative analysis of the total TCM syndrome efficacy scores between the two groups. Before treatment, there was no statistically significant difference in TCM syndrome efficacy scores between the two groups. After treatment, the TCM syndrome efficacy scores of both groups decreased compared to before treatment, but the difference between the two groups was not statistically significant. The difference between before and after treatment was not statistically significant (P>0.05), suggesting that the two groups had comparable efficacy in improving TCM syndrome efficacy scores (see Table 13).

[0262] Table 13 Total Score of TCM Syndrome Grading Quantitative Table (Quantitative Analysis)

[0263]

[0264]

[0265] (2) Scores of individual symptoms in TCM syndromes (see Table 14)

[0266] (a) Using paired t-tests, before treatment, there was no statistically significant difference in the scores of palpitations between the two groups. After treatment, the scores of both groups decreased, and there was no statistically significant difference between the groups. The difference between the two groups before and after treatment was not statistically significant (P>0.05), suggesting that both drugs can improve palpitations and have comparable efficacy.

[0267] (b) Before treatment for “chest tightness”: There was no statistically significant difference in scores between the two groups. After treatment: The scores in the treatment group decreased significantly compared to the control group, and the difference was statistically significant, suggesting that the medication in the treatment group was better at improving this symptom than that in the control group. However, there was no statistically significant difference in the difference between the two groups before and after treatment.

[0268] (c) Before treatment, there was no statistically significant difference in the scores of "shortness of breath / wheezing" between the two groups. After treatment, the scores of both groups decreased, and there was no statistically significant difference between the groups. The difference between the two groups before and after treatment was not statistically significant (P>0.05), indicating that both drugs can improve shortness of breath / wheezing and have comparable efficacy.

[0269] (d) Before treatment, there was no statistically significant difference in the scores of the two groups for “fatigue and weakness”. After treatment, the scores of both groups decreased, and there was no statistically significant difference between the groups. The difference between the two groups before and after treatment was not statistically significant (P>0.05), indicating that both drugs can improve fatigue and weakness and have comparable efficacy.

[0270] (e) Before treatment, there was no statistically significant difference in the scores of the two groups for “chest pain”. After treatment, the scores of both groups decreased, and there was no statistically significant difference between the groups. The difference between the two groups before and after treatment was not statistically significant (P>0.05), suggesting that both drugs can improve chest pain and have comparable efficacy.

[0271] (f) "Dizziness" Before treatment: There was no statistically significant difference in scores between the two groups. After treatment: Scores in both groups decreased, and there was no statistically significant difference between the groups. The difference between the two groups before and after treatment was not statistically significant (P>0.05), suggesting that both drugs can improve dizziness and have comparable efficacy.

[0272] (g) Before treatment, there was no statistically significant difference in scores between the two groups. After treatment, the scores of both groups decreased, and there was no statistically significant difference between the groups. The difference between the two groups before and after treatment was not statistically significant (P>0.05), indicating that both drugs can improve the condition of the blackheads and have comparable efficacy.

[0273] (h) "Insomnia" Before treatment: There was no statistically significant difference in scores between the two groups. After treatment: Scores in both groups decreased, and there was no statistically significant difference between the groups. The difference between the two groups before and after treatment was not statistically significant (P>0.05), suggesting that both drugs can improve insomnia and have comparable efficacy.

[0274] (i) Before treatment, there was no statistically significant difference in the scores of the two groups for “fear of cold and cold limbs”. After treatment, the scores of both groups decreased, and there was no statistically significant difference between the groups. The difference between the two groups before and after treatment was not statistically significant (P>0.05), indicating that both drugs can improve fear of cold and cold limbs and have comparable efficacy.

[0275] (j) Before treatment, there was no statistically significant difference in scores between the two groups for “facial edema”. After treatment, the scores of both groups decreased, and there was no statistically significant difference between the groups. The difference between the two groups before and after treatment was not statistically significant (P>0.05), suggesting that both drugs can improve facial edema and have comparable efficacy.

[0276] (k) Before treatment, there was no statistically significant difference in the scores of the two groups for “lower back and knee weakness”. After treatment, the scores of both groups decreased, and there was no statistically significant difference between the groups. The difference between the two groups before and after treatment was not statistically significant (P>0.05), indicating that both drugs can improve lower back and knee weakness and have comparable efficacy.

[0277] (l) No syncope occurred in either group before or after treatment, so it was not included in the statistics.

[0278] Table 14. Therapeutic efficacy scores for individual syndromes in Traditional Chinese Medicine (quantitative analysis)

[0279]

[0280]

[0281]

[0282] 3. Security Analysis

[0283] 3.1 Complete blood count indicators

[0284] There were no statistically significant differences in hemoglobin and platelet levels between the two groups before and after treatment (Fisher's exact test was used for both groups, P>0.05). This suggests comparable safety profiles (see Table 15).

[0285] Table 15 Comparison of blood routine indicators before and after treatment in the two groups

[0286]

[0287] Note: The normal reference range for HGB is 115-150, and the normal reference range for PLT is 125-350.

[0288] 3.2 Liver function indicators

[0289] There were no statistically significant differences in ALT and AST levels between the two groups before and after treatment (Fisher's exact test was used for both groups, P>0.05). This suggests comparable safety profiles (see Table 16).

[0290] Table 16 Comparison of liver function indicators before and after treatment in the two groups

[0291]

[0292]

[0293] Note: The normal reference range for ALT is 7-40, and the normal reference range for AST is 15-35. Both are considered abnormal if their values ​​are slightly elevated, taking into account clinical significance.

[0294] 3.3 Kidney function indicators

[0295] There were no statistically significant differences in creatinine and blood urea nitrogen between the two groups before and after treatment (Fisher's exact test was used for both groups, P>0.05). This suggests comparable safety profiles (see Table 17).

[0296] Table 17 Comparison of renal function indicators before and after treatment in the two groups

[0297]

[0298] Note: The normal reference range for creatinine is 58-96, and the normal reference range for blood urea nitrogen is 2.8-7.2. Both are considered abnormal if elevated, taking into account clinical significance.

[0299] 3.4 The proportion of each indicator that was normal before treatment and abnormal after treatment

[0300] The study focused on the proportion of patients in both groups whose hemoglobin, platelet count, ALT, AST, creatinine, and blood urea nitrogen levels were normal before treatment but abnormal after treatment, using Fisher's exact test. Results indicated that a higher proportion of patients in the control group developed abnormalities in creatinine after treatment, suggesting better safety in the treatment group. There were no statistically significant differences in the other indicators, indicating comparable safety profiles.

[0301] Table 18 Security Analysis

[0302]

[0303] IV. Adverse Events and Adverse Reactions

[0304] No serious adverse events or adverse reactions occurred in either the treatment group or the control group during the treatment process.

[0305] V. Analysis of Experimental Results

[0306] 1. Comparative analysis of the general conditions of the two groups before treatment

[0307] Before treatment, the demographic data of the two groups of patients were analyzed: ① A t-test was performed on age, body mass index (BMI), and disease duration between the two groups, and no statistically significant differences were found (P>0.05); ② A χ² test was performed on gender, ethnicity, smoking history, and alcohol consumption history between the two groups, and no statistically significant differences were found (P>0.05), indicating that the two groups were balanced and comparable (see Table 1); ③ Analysis of test results related to comorbidities: t-tests / rank-sum tests were performed on test results related to diseases such as hemoglobin, platelets, ALT, AST, creatinine, urea nitrogen, serum potassium, and fasting blood glucose between the two groups, and no statistically significant differences were found (P>0.05); ④ A χ² test was performed on the presence or absence of coronary heart disease, heart failure, atrial fibrillation, hypertension, diabetes, and hypothyroidism between the two groups. Among these, the presence or absence of hypothyroidism showed a statistically significant imbalance between the two groups (P=0.047). The treatment group had a higher prevalence of hypothyroidism, and patients with hypothyroidism typically have lower heart rates, indicating that the treatment group's condition was worse. Therefore, this bias would not overemphasize the effect of the treatment group. Other indicators—presence or absence of coronary heart disease, heart failure, atrial fibrillation, premature atrial contractions, hypertension, and diabetes—showed no statistically significant differences between the two groups (P>0.05), suggesting that the two groups were comparable. Based on the above data, the majority of patients with this condition are elderly. Therefore, bradycardia can be considered one of the common types of arrhythmias in the elderly population.

[0308] 2. Therapeutic effect analysis

[0309] 2.1 Key Outcome Indicators:

[0310] (1) Results of the efficacy evaluation criteria for 24-hour Holter monitoring

[0311] The effective rate in the treatment group was 77.78%, and the effective rate in the control group was 71.88%. The P-value for the effective rate between the two groups was 0.575. The difference in effective rate between the two groups was 5.9%, with a 95% confidence interval of -11.40% to 23.37%. The non-inferiority margin was set at 15%, and the non-inferiority test was P<0.023. The results show that the effective rate of the traditional Chinese medicine compound preparation described in this invention in the treatment group was not inferior to that in the control group.

[0312] (2) Comparison of heart rate indicators in 24-hour Holter monitoring

[0313] Before treatment, there were no statistically significant differences in total heart rate, mean heart rate, maximum heart rate, and minimum heart rate between the two groups using 24-hour Holter monitoring. After treatment, the total heart rate increased in both groups compared to before treatment, with the proportion of patients experiencing an increase in total heart rate being 91.67% in the treatment group, showing a trend of increase compared to 84.38% in the control group, but the difference between the groups was not statistically significant (P>0.05). Similarly, the mean heart rate increased in both groups after treatment, with the proportion of patients experiencing an increase in mean heart rate being 88.89% in the treatment group, showing a trend of increase compared to 84.38% in the control group, but the difference between the groups was not statistically significant (P>0.05). The maximum heart rate also increased in both groups after treatment, with the proportion of patients experiencing an increase in maximum heart rate not showing a statistically significant difference between the groups (P>0.05). Finally, the minimum heart rate increased in both groups after treatment, with the proportion of patients experiencing an increase in minimum heart rate not showing a statistically significant difference between the groups (P>0.05). In summary, both groups of drugs can effectively improve the total heart rate, average heart rate, maximum heart rate, and minimum heart rate of patients with bradycardia via 24-hour Holter monitoring. Among them, the traditional Chinese medicine compound preparation described in this invention is more significant in improving heart rate than the control group, and its clinical efficacy is comparable to that of Xinbao Pill.

[0314] 2.2 Secondary Outcome Indicators:

[0315] 2.2.1 Minnesota Quality of Life Scale

[0316] (1) Minnesota Quality of Life Scale: The Minnesota Quality of Life Scale is divided into three domains: physical, emotional, and other. After treatment, the scores of both groups decreased, but the decrease was more significant in the treatment group, and the difference between the groups was statistically significant (P < 0.001). This suggests that the treatment group was significantly better than the control group in improving quality of life (see Table 8);

[0317] (2) The scores of both groups of the Minnesota Quality of Life Scale (Body Domain #) decreased after treatment, but the decrease was more significant in the treatment group. The difference between the groups was statistically significant (P<0.001), suggesting that the treatment group was significantly better than the control group in improving the quality of life in the body domain (see Table 9).

[0318] (3) The scores of both subgroups of the Minnesota Quality of Life Scale (emotional domain #) decreased after treatment, but the decrease was more significant in the treatment group, and the difference between the groups was statistically significant (P < 0.001). The difference between the pre-treatment and post-treatment scores was statistically significant (P = 0.003), suggesting that the treatment group was significantly better than the control group in improving the physical domain of quality of life (see Table 10);

[0319] (4) The scores of both groups on the Minnesota Quality of Life Scale (Other Domains #) decreased after treatment, but the decrease was more significant in the treatment group, and the difference between the groups was statistically significant (P < 0.001). The differences between the pre-treatment and post-treatment scores were statistically significant (P < 0.001), suggesting that the treatment group was significantly better than the control group in improving other domains of quality of life (see Table 11).

[0320] In summary, the traditional Chinese medicine compound preparation described in this invention has statistically significant advantages in improving the quality of life of patients with bradycardia.

[0321] 2.2.2 Scoring of the TCM Syndrome Grading Scale

[0322] (1) TCM Symptom Grading and Quantification Table Scoring (Total Score)

[0323] Before treatment, there was no statistically significant difference in TCM syndrome efficacy scores between the two groups. After treatment, the TCM syndrome efficacy scores of both groups decreased compared to before treatment, but the difference between the two groups was not statistically significant. The difference between before and after treatment was not statistically significant (P>0.05), suggesting that the two groups had comparable efficacy in improving TCM syndrome efficacy scores.

[0324] (2) Scoring of individual symptoms in TCM syndromes

[0325] Before treatment, there was no statistically significant difference in the scores of individual symptoms of TCM syndromes such as palpitations, shortness of breath, fatigue, dizziness, blurred vision, insomnia, aversion to cold and cold limbs, facial and limb edema, and soreness and weakness of the lower back and knees between the two groups. After treatment, the scores of both groups decreased, and there was no statistically significant difference between the groups. The difference in the values ​​before and after treatment was not statistically significant between the two groups (P>0.05). This suggests that both drugs can improve individual symptoms of multiple TCM syndromes such as palpitations, indicating that the TCM compound preparation described in this invention is as effective as Xinbao Pill in improving TCM clinical symptoms. Among them, the TCM compound preparation of this invention showed better improvement in the symptom of "chest tightness" than the control group.

[0326] The above experimental results show that the traditional Chinese medicine compound preparation described in this invention can improve the TCM symptoms of patients with bradycardia of the Qi deficiency and blood stasis type and the heart and kidney Yang deficiency type, and its efficacy in improving TCM clinical symptoms is comparable to that of Xinbao Pill.

[0327] Based on the above pharmacological and clinical trial evidence, the traditional Chinese medicine compound preparation of the present invention further demonstrates that it has certain advantages in increasing patients' heart rate and improving discomfort symptoms such as chest tightness, palpitations, dizziness, and fatigue.

[0328] 3. Safety Indicator Analysis

[0329] During the trial, patients were followed up regularly. No significant changes were observed in liver and kidney function or blood routine examination results before and after treatment in either group (P>0.05). The proportion of patients with normal levels before treatment and abnormal levels after treatment (hemoglobin, platelets, ALT, AST, creatinine, and blood urea nitrogen) was closely monitored in both groups. The results indicated that more patients in the control group developed abnormal creatinine levels after treatment, suggesting better safety in the treatment group. There were no statistically significant differences in the remaining indicators, indicating comparable safety profiles.

[0330] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A traditional Chinese medicine compound preparation for bradyarrhythmias, characterized in that, The traditional Chinese medicine compound preparation is made from the following raw materials in parts by weight: 10 parts Astragalus membranaceus, 1 part Rhodiola rosea, 1 part Salvia miltiorrhiza, 1 part Cinnamomum cassia, 1 part Epimedium brevicornu (processed), and 5 parts excipients.

2. The traditional Chinese medicine compound preparation according to claim 1, characterized in that, The excipients are one or more of the following: dextrin, lactose, starch, microcrystalline cellulose, powdered sugar, hydroxypropyl methylcellulose, hydroxypropyl cellulose, magnesium stearate, polyethylene glycol, povidone, sodium stearate, poloxamer, gelatin, liquid paraffin, honey, glycerin, sodium benzoate, methylparaben, ethylparaben, propylparaben, and potassium sorbate.

3. The traditional Chinese medicine compound preparation according to claim 2, characterized in that, The dosage forms of the traditional Chinese medicine compound preparations are pills, tablets, granules, capsules, oral liquids, or powders.

4. A method for preparing a traditional Chinese medicine compound preparation according to any one of claims 1 to 3, characterized in that, Includes the following steps: 1) The raw materials are crushed separately and then mixed evenly to obtain a mixture; 2) After reflux extraction of the mixture with the extraction solvent 1 to 4 times, combine the extracts from each extraction and filter to obtain a mixed extract; 3) After recovering the extraction solvent, the mixed extract is concentrated under reduced pressure to a concentrate with a relative density of 1.15 to 1.25 at 50 to 80°C; 4) After drying and pulverizing the concentrated liquid, mix it with the excipients to obtain the traditional Chinese medicine compound preparation of the present invention.

5. The preparation method according to claim 4, characterized in that, The mass ratio of the mixture to the extraction solvent in step 2) is 1:6~15.

6. The preparation method according to claim 5, characterized in that, The extraction solvent is water or an aqueous ethanol solution, wherein the mass fraction of ethanol in the aqueous ethanol solution is 30-75%.

7. The preparation method according to claim 4, characterized in that, The extraction time in step 2) is 0.5~2h, and the extraction temperature is 60~120℃.

8. The preparation method according to claim 4, characterized in that, The vacuum concentration temperature in step 3) is 50~80℃, and the vacuum degree is -0.06 MPa~-0.12 MPa.

9. The preparation method according to claim 4, characterized in that, The drying method in step 4) is vacuum drying or spray drying, the drying temperature is 40~180℃, and the vacuum degree of vacuum drying is -0.06 MPa~-0.12 MPa.

10. The preparation method according to claim 4, characterized in that, The particle size of the pulverized material in step 4) is 80~200 mesh.

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