Anshen Buxin Liuwei Pill for the treatment of cardiac neurosis (heyisheng-type palpitation): a randomized, double-blind clinical trial

Introduction

Cardiac neurosis, also known as cardiac neurasthenia or cardiovascular neurosis, is a common functional cardiovascular disease in clinical practice. It is a special subtype of neurosis and a typical psychosomatic disorder. Its core clinical manifestations include cardiovascular symptoms such as palpitations, chest tightness, precordial pain and shortness of breath, often accompanied by autonomic nervous dysfunction and psychological abnormalities including insomnia, anxiety, depression, irritability, hyperhidrosis and fatigue. The onset and fluctuation of symptoms are mostly closely associated with emotional stimulation and mental stress. Its pathogenesis lies in central nervous dysfunction that disrupts the balance between sympathetic and parasympathetic nerves, thereby inducing circulatory dysfunction, while systematic examinations yield no objective evidence of organic heart disease (1,2). The disease predominantly affects young and middle-aged populations, with a significantly higher incidence in females, especially menopausal women. Epidemiological data indicate that approximately 22.8% of patients visiting cardiology outpatient clinics are diagnosed with cardiac neurosis, and around 30.4% of patients presenting with chest pain and normal coronary angiography results are ultimately confirmed to have this disorder (3).

The clinical diagnosis and treatment of cardiac neurosis currently face prominent challenges. First, there are no specific biomarkers or gold diagnostic criteria; diagnosis is exclusive in nature. Clinical confirmation requires sequential exclusion of organic cardiovascular and other systemic diseases via multiple examinations including electrocardiography, echocardiography, coronary imaging, thyroid function tests and blood biochemistry. This not only wastes medical resources but also prolongs the diagnostic cycle, reinforces patients’ hypochondriacal tendencies, and creates a vicious cycle: symptom onset → repeated hospital visits → normal test results → aggravated anxiety (2,3). Second, overall clinical recognition remains insufficient. Cardiologists tend to focus on excluding organic diseases and lack awareness in systematic assessment of psychological factors underlying somatic symptoms. Existing data show that 31.18% of cardiology outpatients have depressive states and 30.46% have anxiety states. Nevertheless, most patients with emotional disorders presenting mainly with cardiovascular symptoms fail to receive timely identification and standardized intervention, leading to widespread missed and misdiagnoses that severely hinder full-cycle management and rehabilitation of cardiovascular diseases (4). Third, patients have low awareness and acceptance of the condition. Due to the absence of objective organic lesions, patients often question the diagnosis of a “functional disorder” and show low willingness to accept psychological intervention. Some even seek repeated medical consultations and redundant examinations due to hypochondria, further exacerbating symptoms and increasing medical burdens (1,3).

In terms of treatment, existing intervention protocols have varying limitations, and a unified standardized diagnostic and therapeutic pathway has not yet been established. Conventional Western medicine adopts symptomatic treatment combined with psychological intervention: drugs including beta-blockers, oryzanol and B vitamins only temporarily relieve somatic symptoms such as palpitations and sympathetic overexcitation, without fundamentally regulating autonomic function and emotional status, resulting in a high symptom recurrence rate after drug withdrawal (2,5). Psychotropic agents such as flupentixol-melitracen, benzodiazepines and selective 5-hydroxytryptamine reuptake inhibitors (SSRIs) can alleviate anxiety and depression to a certain extent, yet they are associated with long treatment courses, obvious adverse reactions, poor long-term tolerability and frequent symptom relapse after discontinuation. Certain psychotropic medications may even intensify anxiety and tension in some patients and worsen their condition (2,3). For non-pharmacological therapies, psychological interventions recommended as first-line regimens by guidelines include cognitive behavioral therapy, mindfulness meditation and biofeedback. However, psychosomatic medical resources are unevenly distributed nationwide, there is a severe shortage of qualified psychosomatic practitioners, and these treatments feature long cycles and low accessibility, making them difficult to cover grassroots medical institutions and patients with mild symptoms (4). Furthermore, unified clinical pathways and specifications for cardiac neurosis are lacking domestically; the multidisciplinary collaboration mechanism between cardiology and psychiatry remains imperfect, and long-term follow-up and full-cycle management systems are inadequate. These factors lead to inconsistent clinical diagnosis and treatment quality, highlighting an urgent need to explore safer, more effective interventions with higher patient compliance (3,4).

No disease term equivalent to “cardiac neurosis” exists in traditional Mongolian medical classic literature. Based on core clinical manifestations such as palpitations, chest tightness, precordial discomfort, insomnia, anxiety and emotional lability, modern Mongolian medicine generally categorizes this disorder under illnesses including heart hey disease, main vessel hey disease, palpitation disorder and hey-type precordial stabbing pain. It is a functional psychosomatic disease triggered by the imbalance of the three fundamentals, highly consistent with the pathological feature of having no organic cardiac injury in cardiac neurosis. Mongolian medicine interprets its pathogenesis through the core theory of the three fundamentals and seven essences: the unstable balance among Hey, Shar and Badgan forms the pathogenic basis, while excessive Hey disturbing the heart and disharmony of the White Vessels constitute the core pathological mechanism. Hey governs blood circulation, emotional thinking and conduction of the White Vessels (nervous system). Internal and external predisposing factors including prolonged emotional stimulation, overthinking and fatigue, irregular rest and biased diet cause excessive Hey to migrate and invade cardiac vessels, disrupting blood circulation; involvement of the White Vessels impairs emotional and sleep regulation, ultimately presenting as a comorbid clinical state of cardiovascular somatic symptoms and psychological disorders (6,7). Clinically, four syndrome types are identified: excessive Hey, excessive Blood, excessive Heat and excessive Cold, which may intermingle and transform into one another. The excessive Hey type is the most prevalent, characterized by fluctuating symptoms, restlessness and insomnia, empty irregular pulse and clear urine with abundant foam (7). The disease is originated in the heart and closely associated with the White Vessel system as well as the liver, spleen and kidney functions. Mongolian medicine emphasizes holistic regulation of Three Fundamentals balance rather than mere symptomatic relief. Its psychosomatic concurrent treatment philosophy provides a unique ethnic medicinal approach for clinical intervention of cardiac neurosis (8).

Anshen Buxin Liuwei Pills (Mongolian medicine generic name: Jiruhe-6) is a classic Mongolian medicine formulation for the treatment of cardiac Hey disease. It is recorded in the Mongolian Medicine Volume of Drug Standards of the Ministry of Health of the People’s Republic of China with the drug standard number Z2-8324-1. In Mongolian medicine, Hey governs cardiac pulsation, qi-blood circulation, and emotional and mental activities. This formula exerts core efficacies of suppressing excessive Hey, calming the mind and soothing palpitations. It is clinically applied to relieve palpitation and shortness of breath, and simultaneously improve dual-heart comorbid symptoms including anxiety, insomnia and flustered heartbeat. Composed of six medicinal materials including ox heart, Fructus Choerospondiatis, Myristicae Semen, Caryophylli Flos, Resina Liquidambaris, and Aucklandia lappa, the formula can protect cardiac function and regulate the central nervous system, serving as a representative Mongolian medicine prescription for simultaneous regulation of heart and mind (9).

As the monarch drug in the formula, ox heart follows the Mongolian medical organ therapy of “treating visceral disorders with homologous viscera”. It specifically tonifies the heart and suppresses Hey, nourishes cardiac vessels, and relieves palpitations and activity-induced shortness of breath caused by insufficient heart qi. Rich in myocardial active proteins and trace elements, ox heart can optimize myocardial energy metabolism and alleviate symptoms such as mental restlessness and forgetfulness (9-11). As the minister drug, Fructus Choerospondiatis contains total flavonoids and ellagic acid with dual cardio-protective and sedative activities. It acts on central GABA receptors to exert sedative and anxiolytic effects and prolong slow-wave sleep. Meanwhile, it can dilate coronary arteries, inhibit myocardial calcium overload, suppress platelet aggregation, and reduce oxidative damage in ischemic myocardium (12). Myristicae Semen is a core Mongolian medicinal herb for suppressing Hey. Its volatile oil contains methylisoeugenol, which inhibits central nervous system excitation, prolongs pentobarbital-induced sleep time, dilates coronary arteries, reduces sympathetic nerve excitability, and improves functional palpitations induced by anxiety (13,14). Eugenol, the active ingredient of Caryophylli Flos, can upregulate brain-derived neurotrophic factor, inhibit neuronal apoptosis to exert antidepressant effects, scavenge oxygen free radicals, stabilize myocardial electrical activity, and play anti-oxidative and anti-arrhythmic roles (15). As an adjuvant drug, Resina Liquidambaris activates blood circulation and regulates qi movement, unblocks cardiac vessels, relieves coronary vasospasm, reduces myocardial damage through anti-oxidative and anti-inflammatory effects, and ameliorates chest distress, irritability and somatic discomfort caused by qi stagnation (16). As the guide drug, Aucklandia lappa regulates qi movement, relieves stagnation and reconciles the whole formula. It regulates the autonomic nervous system to alleviate chest distress and irritability. Its extracts can reduce the release of creatine kinase and lactate dehydrogenase, thereby mitigating cardiomyocyte damage induced by oxidative stress (17). With a compatible combination of pungent and sweet medicinal properties, the formula treats both the root and symptoms of diseases. It targets the fundamental pathogenesis of excessive Hey in Mongolian medicine, and simultaneously intervenes in cardiovascular somatic symptoms and central emotional disorders, which is highly consistent with the core pathogenesis of cardiac neurosis. We present this article in accordance with the CONSORT reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1612/rc).

Methods

Clinical trial design

Design

This study was designed as a multicenter, randomized, double‑blind, placebocontrolled clinical trial. A total of 200 patients diagnosed with cardiac neurosis were enrolled between June 2021 and December 2022. Participants were randomly assigned at a 1:1 ratio into either the Anshen Buxin Liuwei Pill treatment group or the placebo control group using stratified block randomization. This trial initially enrolled 400 patients diagnosed with cardiac neurosis who either received Anshen Buxin Liuwei Pill or placebo at a 1:1 ratio according to stratified blocked randomization. SAS 9.4 statistical software (SAS Institute Inc., Cary, NC, USA) was used to generate a random allocation schedule for 400 participants to receive treatment (200 in the experimental drug group and 200 in the control drug group); that is, the treatment assignments corresponding to serial numbers 001 to 200 were listed. Participants were centrally randomized and enrolled. After 200 cases were enrolled, an interim analysis was performed by an independent data monitoring committee, and the sample size was recalculated. This study was conducted at six centers: Fuwai Hospital Chinese Academy of Medical Sciences, The First Hospital of Hunan University of Chinese Medicine, International Mongolian Hospital of Inner Mongolia, Nanyang First People’s Hospital, The Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, and The Third Affiliated Hospital of Xinxiang Medical College. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments, and was approved by the Ethics Committee of Fuwai Hospital (No. 2018-1129). Informed consent was taken from all the patients. The other institutions were informed of and agreed with the study.

Inclusion, exclusion, and withdrawal criteria

The inclusion criteria for participants were as follows: (I) age between 18 and 75 years; (II) meeting the diagnostic criteria for cardiac neurosis, including palpitations, precordial pain, chest tightness, shortness of breath, dyspnea, dizziness, insomnia and dreaminess, cold hands and feet, hyperhidrosis, and other cardiovascular symptoms and neurological disorders; (III) meeting the diagnostic criteria of heyisheng-type palpitations in traditional Mongolian medicine; (IV) no objective diagnosis of coronary heart disease (in accordance with any of the following: negative findings in the activity flat test, lumen stenosis ≤50% on coronary angiography or coronary computed tomography angiography, and no myocardial ischemia according to exercise or drug load radionuclide examination results; (V) no intake of anti-anxiety/depression drugs or psychotropic drugs within 2 weeks before enrollment; and (VI) voluntarily participation in the study with provision of signed informed consent form.

Meanwhile, the exclusion criteria were as follows: (I) concurrent organic heart disease or severe cardiopulmonary insufficiency; (II) poor hypertension control (systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg after treatment); (III) concurrent malignant arrhythmia; (IV) use of a pacemaker; (V) hyperthyroidism; (VI) severe liver and kidney damage [alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin (TBil) >2 times the upper limit of the normal reference value or creatinine (Cr) >1.5 times the upper limit of the normal reference value]; (VII) presence of serious primary diseases such as hematopoietic system or mental illness; (VIII) a Self-Rating Anxiety Scale (SAS) score ≥70; (IX) a Self-Rating Depression Scale (SDS) score ≥73; (X) other serious diseases or conditions such as malignant tumors; (XI) pregnancy or lactation; (XII) allergy to the known ingredients of the research drug; (XIII) participation in other clinical research in the previous 3months; and (XIV) unsuitability for research observation according to the judgment of the investigators.

Regarding the discontinuation criteria, patients who had provided informed consent and undergone screening and qualification for randomization in the trial but who had not completed the prescribed treatment and observation period due to any reasons were withdrawn from the study; however, those who had voluntarily ceased medication after recovering from the disease were not.

The criteria for study withdrawal were as follows: (I) occurrence of allergic reactions or serious adverse events (AEs), as determined by the physicians; (II) deterioration of condition during the trial or a risk of a hazardous event based on medical judgment (in such cases, the treatment was considered ineffective, and alternative treatment was provided); (III) significant deviation in implementation of the clinical trial protocol, such as poor compliance, which could impede the accurate evaluation of drug efficacy; (IV) death; (V) loss to follow up, specifically, individuals who could not be reached via phone three times daily (morning, noon, and evening) within 5 working days after their scheduled follow-up date; and (VI) unwillingness to continue participation in the clinical trial and request of withdrawal to the physician in charge.

Method of blinding

A double-blind design was adopted for this study. Placebo treatments were prepared to have identical packaging appearance to that of Anshen Buxin Liuwei Pill, along with a similar color, odor, and taste. Blinding was implemented for investigators, patients, and statisticians. A two-level blinding design was used, with the first level being the code corresponding to each case number (e.g., group A or B) and the second level being the group to which each case was assigned (the trial group or the placebo group). A randomization table was established by the clinical trial data management and statistical unit, and all trial drugs were uniformly packaged and labeled to indicate their exclusive use for the clinical trial. One member of the research team was responsible for verifying the code, and the trial drugs were stored in the pharmacy of each trial center. The trial physicians strictly followed the randomization principle to enroll participants and prescribe medication. Both the physicians and the patients were blinded. Management and storage of blind codes: the randomization coding table was compiled by the Clinical Trial Data Management and Statistics Department. The sealed blind codes were made out in duplicate, properly stored separately at the lead clinical trial unit and the sponsor respectively. The entire drug coding process was documented by the blind coder in written form as a blinding record, which shall be retained as one of the official documents of this clinical trial. Emergency envelopes were stored together with trial drugs at each clinical trial site, and no personnel may open them without authorization.

Diagnostic criteria

Western medicine-informed diagnostic criteria

The diagnostic criteria for cardiac neurosis according to Western medicine were determined based on the definition of cardiac neurosis in the “Practical Internal Medicine” and are described below (18).

Symptoms

Symptoms of cardiac neurosis can be divided into cardiovascular symptoms and nervous system symptoms. The most common cardiovascular symptoms for cardiac neurosis are palpitations, precordial pain, shortness of breath, and hyperventilation. Nervous system symptoms primarily manifest as an anxious state but may also include depression, fear, obsession, etc. Varying degrees of insomnia may also ensue. In severe cases, tense facial expressions, dizziness, and excessive hand sweating can be observed.

Physical examination

For patients with cardiac neurosis, cardiovascular system physical examination is typically normal, although a few cases may exhibit mild hypertension, elevated heart rate, and occasional premature contractions. Upon auscultation, there may be an augmentation of heart sounds or the presence of a mild systolic murmur at the cardiac apex. Safety evaluation was performed via vital signs assessment including blood pressure, respiration rate, body temperature, and heart rate after 10 minutes of rest.

Auxiliary examination

A minority of patients with cardiac neurosis may have tachycardia or ST-segment and T-wave (ST-T) changes on their electrocardiogram (ECG). ST-T changes could disappear after β-blocker treatment. The results of exercise ECG testing are usually negative, although occasional positive findings may also be observed. The following tests were performed as auxiliary examination:

• Routine blood test;
• Standard 12-lead ECG;
• Liver function indicators: ALT, AST, TBil, direct bilirubin, indirect bilirubin, alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT);
• Renal function indicators: routine urine test and urine sediment microscopy, blood urea nitrogen (BUN), serum creatinine (Scr);
• Routine stool test plus fecal occult blood test.

Epidemiological characteristics

Mental and psychological factors are closely associated with the onset of cardiac neurosis, while there is no evidence that organic heart disease is a contributing factor.

Traditional Mongolian medicine-informed diagnostic criteria

In this study, the diagnostic criteria for heyisheng-type palpitation were determined according to the “Common Diseases of Ulan Mongolian Medicine” (19) and the “Encyclopedia of Traditional Chinese Medicine—Traditional Mongolian Medicine” (20). The primary symptoms included heart palpitations, chest tightness, insomnia and restlessness; the secondary symptoms included dizziness, exaggerated startle response, frequent sighing, insomnia, tinnitus, vertigo, fatigue, excessive sweating, and irritability; pulse-related symptoms included hollow or irregular pulse (in traditional Mongolian medicine, a hollow pulse refers to a floating but not solid pulse, while an irregular pulse refers to occasional irregularity in the pulse due to premature beat in contrast to knotted pulse or intermittent pulse); tongue-related symptoms included redness and dryness of the tongue and, potentially, a thin yellow coating; and urine examination findings included clear and foamy urine. The patient was diagnosed with heyisheng-type palpitation when (I) more than three types of primary symptoms were present; (II) at least two primary symptoms and at least three secondary symptoms were present; or (III) at least one primary symptom and at least five secondary symptoms were present.

Trial drug and treatment course

Trial drug

The trial group received oral administration of 15 pills of Anshen Buxin Liuwei Pill (cat. No. Z20063939; Ulanhot Sino-Mongolia Pharmaceutical Co., Ltd., Ulanhot, China) per dose, twice a day. The placebo group received placebo appearing as Anshen Buxin Liuwei Pill (Ulanhot Sino-Mongolia Pharmaceutical Co., Ltd.), of which its administration also consisted of 15 pills per dose, taken orally twice daily. Placebo pills of Anshen Buxin Liuwei Pills were prepared with edible flavors and pigments to match Anshen Buxin Liuwei Pills in appearance, color, odor and taste. Both groups were supervised by a physician who aimed to alleviate their emotional stress and encourage them to engage in appropriate physical exercise. The physician also conveyed to patients that the illness was of nonsignificant severity, thereby enhancing patients’ confidence in the therapy. If the heart rate exceeded 100 beats per minute, oral administration of β-blockers, such as metoprolol, at a dosage of 25 mg twice daily was recommended.

Treatment course

The standard treatment course consisted of 8 weeks of medication. Hospital visits were scheduled at 4, 8, and 12 weeks after the initiation of treatment.

Outcomes

Primary outcome

The primary outcome was the rate of improvement as determined by the heyisheng-type palpitation grading scale score.

Secondary outcomestha

The main secondary outcomes included the following: (I) function of the cardiac autonomic nervous system; (II) the Cardiac Neurosis Symptoms Self-Assessment Scale; (III) the SDS score; (IV) the SAS score; (V) Pittsburgh Sleep Quality Index (PSQI) score; (VI) the dosage of sedative-hypnotics (estazolam); (VII) high-sensitivity C-reactive protein (hs-CRP) level; and (VIII) 5-hydroxytryptamine (5-HT) level.

Safety indicators

For safety evaluation, the following indicators were collected: (I) complete blood count; (II) 12-lead electrocardiography findings; (III) liver function indicators, including ALT, AST, TBil, direct and indirect bilirubin, ALP, and gamma-glutamyl transferase (GGT); (IV) kidney function indicators, including urinalysis, urine sediment examination, BUN, and Scr; (V) stool routine and fecal occult blood tests; (VI) assessment of vital signs, including blood pressure, respiration rate, body temperature, and heart rate after 10 minutes of rest; and (VII) the type, severity, and incidence rate of AEs.

Statistical analysis

Sample size calculation

The trial hypothesized that Anshen Buxin Liuwei Pill could yield superior alleviation of clinical symptoms relative to placebo. Relevant published data regarding this medicinal preparation for cardiac neurosis remains insufficient. Current standard baseline interventions for the condition encompass psychological counseling, with concomitant administration of metoprolol, oryzanol, vitamin B1 and other adjunctive agents as clinically indicated. Previous literatures demonstrated that baseline therapy achieves a response rate of 67.39–77.59% in ameliorating cardiac neurosis-associated manifestations including palpitations, precordial pain, chest oppression and insomnia (21-25). Accordingly, the control group response rate was projected to be 70%, and the experimental group was expected to attain an elevated response rate of 85%.

Sample size calculation was implemented via PASS software in accordance with a group-sequential design. Statistical parameters were set as two-sided α =0.05, statistical power =0.9 (β =0.1), and a 1:1 allocation ratio between the two arms. The calculated minimal required sample size was 177 participants per group. After accounting for an anticipated 15% participant dropout rate, the planned enrollment size was adjusted to 200 subjects per group, corresponding to an overall total sample size of 400 participants.

Outcome analysis

Handling of missing values: for analyses based on the intention-to-treat (ITT) set of primary efficacy endpoints, missing data were imputed via MI for statistical analysis. No imputation was performed for secondary endpoints.

Statistical analysis methods: descriptive statistical analyses were conducted. Qualitative variables were summarized using frequency tables, percentages or constituent ratios. Quantitative variables were described by mean and standard deviation, or median, first quartile (Q1), third quartile (Q3), minimum and maximum values. For intergroup comparative analyses: Chi-squared test, Fisher’s exact test, Wilcoxon rank-sum test and Cochran-Mantel-Haenszel (CMH) test were adopted for qualitative data. For quantitative data conforming to a normal distribution, the t-test was applied. Homogeneity of variances was tested at a significance level of 0.05; the Satterthwaite corrected t-test was used if variances were unequal. The Wilcoxon rank-sum test and Wilcoxon signed-rank test were utilized for quantitative data that did not follow a normal distribution. All hypothesis tests were two-sided. Test statistics and corresponding P values were reported. A P value ≤0.05 was defined as statistically significant.

ITT set: in accordance with the ITT principle, this set included all subjects who were randomized to treatment groups.

Per protocol set (PPS): this dataset consisted of subjects with full compliance to the trial protocol to ensure that the data can adequately reflect therapeutic efficacy. Eligible subjects for PPS met the following criteria: treatment compliance ranging from 80% to 120%, no major protocol violations, and complete data for primary endpoints as well as most secondary endpoints without missing values. Subject exclusion criteria were clearly specified in the trial protocol. For any subjects excluded from the ITT set or PPS, the reasons for exclusion were clarified during the blind review and fully documented in the blind review report.

Safety set (SS): the safety population of this study comprised all randomized subjects who received at least one dose of study treatment and underwent safety assessments.

Baseline variables were analyzed based on the ITT set. Efficacy endpoints were analyzed using both the PPS population separately. All safety analyses were performed on the SS.

Results

Participants

In this trial, a total of 229 participants underwent screening for eligibility, with 29 being excluded, plus 18 participants lost to follow-up, resulting in a final enrollment of 182 participants (Figure 1). Among them, 91 participants were assigned to the trial group to receive Anshen Bu Xin Liuwei Pill (100%), and these same 91 participants were included in the PPS and SS analyses. Similarly, another set of 91 participants were assigned to the placebo group, with all of them also entering the PPS and SS analyses. The baseline demographics are summarized in Table 1. No statistically significant differences were observed between the two groups.

Figure 1 Flow diagram. ITT, intention-to-treat; PPS, per protocol set; SS, safety set.

Determination of 5-HT: 5-HT was analyzed using an Agilent 1290-6470 liquid chromatography-tandem mass spectrometry (LC-MS/MS) system (Agilent Technologies, Santa Clara, California, USA). Briefly, 100 µL sample was accurately pipetted, mixed with 300 µL methanol, and vortexed for 2 min. The mixture was centrifuged at 12,000 r/min for 10 min. The supernatant was filtered through a 0.22 µm organic filter membrane before injection. Chromatographic separation was performed on an UPLC ACQUITY BEH Amide column with electrospray ionization positive mode (ESI+). Mobile phase A was water containing 0.15% formic acid and 10 mmol/L ammonium formate; mobile phase B was aqueous solution containing 85% acetonitrile and 10 mmol/L ammonium formate. Determination of hs-CRP: hs-CRP was measured by immunoturbidimetry using a Hitachi 008AS automatic biochemical analyzer (Hitachi High-Tech Corporation, Tokyo, Japan).

The proportion of heyisheng-type palpitation patients whose symptoms improved at week 8

In the ITT (per-protocol set) group, the experimental group showed a significantly higher improvement rate in heyisheng-type palpitation scale score after 8 weeks of medication as compared to the placebo group (84.95% vs. 32.26%; P<0.001). Furthermore, ITT analysis was performed with MI for missing data, and the trial group also showed a significantly higher improvement rate [83.00%; 95% confidence interval (CI): 75.32–90.68%] compared to the placebo group (34.80%; 95% CI: 25.07–44.53%) (P<0.05).

Treatment efficacy compared to baseline (Table 2)

The change in score of the Cardiac Neurosis Symptom Self-Rating Scale at week 2 of treatment in the experimental group was 4.50 (2.00, 10.00), while that in the control group was 1.50 (0.00, 7.00). Between-group comparisons yielded a P value of 0.01, indicating a statistically significant difference.

The change in supine-to-upright heart rate difference at week 2 in the experimental group was 2.00 (−3.00, 9.50), while that in the control group was 0.00 (−5.00, 6.00). Between-group comparisons yielded a P value of 0.04, indicating a statistically significant difference.

The change in 5-HT level at week 4 after treatment in the experimental group was −0.08 (−3.85, 5.17) µmol/L, while that in the control group was −0.33 (−5.61, 4.58) µmol/L. Between-group comparisons yielded a P value of 0.82, indicating a statistically significant difference.

The change in Self-Rating Depression Scale (SDS) score at week 8 in the experimental group was 10.00 (5.00, 15.00), while that in the control group was 7.00 (−1.00, 11.00). Between-group comparisons yielded a P value of 0.01, indicating a statistically significant difference.

The changes in the Self-Rating Anxiety Scale (SAS) score at week 8 of treatment in the experimental group was 11.00 (6.00, 18.00), while that the control group was 6.00 (2.00, 12.00). Between-group comparisons yielded a P value of 0.001, indicating a statistically significant difference.

The change in the PSQI score at week 8 of treatment in the experimental group was 4.00 (2.00, 6.00), while that in the control group was 2.00 (−1.00, 4.00). Between-group comparisons yielded a P value of 0.001, indicating a statistically significant difference.

The change in 5-HT levels at week 8 of treatment in the experimental group was 3.51 (−3.51, 9.33) µmol/L, while that in the control group was 1.28 (−3.07, 11.46) µmol/L. Between-group comparisons yielded a P value of 0.82, indicating no statistically significant difference.

The change in the score of the Cardiac Neurosis Symptom Self-Rating Scale at week 12 of treatment in the experimental group 4.00 (2.00, 5.00) was higher than the control group 1.00 (0.00, 2.00). Between-group comparisons yielded a P value <0.001, indicating a statistically significant difference.

The change in SDS score at week 12 of treatment in the experimental group was 10.82±10.13, while that in the control group was 3.01±11.04. Between-group comparisons yielded a P value <0.001, indicating a statistically significant difference.

The change in SAS score at week 12 of treatment in the experimental group was 12.00 (7.00, 18.00), while that the control group was 3.50 (−1.00, 11.00). Between-group comparisons yielded a P value <0.001, indicating a statistically significant difference.

The change in supine-to-upright heart rate difference at week 12 in the experimental group was 2.58±8.68, while that in the control group was −0.01±7.80. Between-group comparisons yielded a P value of 0.04, indicating a statistically significant difference.

The change in PSQI score at week 12 of treatment in the experimental group was 4.00 (1.00, 6.00), while that in the control group was 1.00 (−1.00, 4.00). Between-group comparisons yielded a P value <0.001, indicating a statistically significant difference.

Comparison of treatment efficacy between the two groups (Table 3)

At week 4, the hs-CRP levels were 0.79 (0.32, 1.37) mg/L in the experimental group and 0.83 (0.40, 1.44) mg/L in the control group. The between-group comparison yielded a P value of 0.78, indicating no statistically significant difference. At week 4 of treatment, the 5-HT levels were 25.42±16.33 µmol/L in the experimental group and 29.98±18.08 µmol/L in the control group. Between-group comparisons yielded a P value of 0.08, indicating no statistically significant difference.

At week 8 of treatment, the SAS score was 34.00 (31.00, 39.00) in the experimental group and 38.50 (34.00, 41.00) in the control group. Between-group comparisons yielded a P value of 0.001, indicating a statistically significant difference. At week 8, the SDS score was 34.00 (30.00, 40.00) in the experimental group and 38.00 (33.00, 45.00) in the control group. Between-group comparisons yielded a P value of 0.004, indicating a statistically significant difference. At week 8, the PSQI score was 6.00 (5.00, 8.00) in the experimental group and 8.00 (5.00, 11.00) in the control group. Between-group comparisons yielded a P value of 0.003, indicating a statistically significant difference. At week 8, the score of the Cardiac Neurosis Symptom Self-Rating Scale was 3.00 (2.00, 4.00) in the experimental group and 4.00 (3.00, 5.00) in the control group. Between-group comparisons yielded a P value <0.001, indicating statistically significant difference. At week 8 after treatment, hs-CRP (mg/L) levels were 1.00 (0.47, 1.50) mg/L in the experimental group and 0.71 (0.34, 1.34) mg/L in the control group. Between-group comparisons yielded a P value of 0.29, indicating no statistically significant difference. At week 8, 5-HT levels were 17.62 (11.37, 32.26) µmol/L in the experimental group and 23.03 (11.37, 35.14) µmol/L in the control group. Between-group comparisons yielded a P value of 0.28, indicating no statistically significant difference.

At week 12 of treatment, the score of the Cardiac Neurosis Symptom Self-Rating Scale was 3.00 (2.00, 4.00) in the experimental group and 4.00 (3.00, 6.00) in the control group. Between-group comparison yielded a P value <0.001, indicating a statistically significant difference. At week 12, the SAS score was 34.00 (30.00, 39.00) in the experimental group and 39.00 (35.00, 45.50) in the control group. Between-group comparisons yielded a P value <0.001, indicating a statistically significant difference. At week 12, the SDS score was 34.00 (30.00, 36.00) in the experimental group and 38.50 (34.00, 50.00) in the control group. Between-group comparisons yielded a P value <0.001, indicating a statistically significant difference. At week 12, the PSQI score was 6.00 (4.00, 8.00) in the experimental group and 8.00 (6.00, 11.00) in the control group. Between-group comparisons yielded a P value <0.001, indicating a statistically significant difference.

Safety evaluation

During the trial, a total of 21 participants experienced a combined total of 30 AEs. Among these, three participants in the trial group (3/100, 3.00%) experienced eight AEs, including cholelithiasis (1/8), cerebral infarction (1/8), pelvic effusion (1/8), hypersensitivity reactions (1/8), abdominal pain, gastritis (1/8), ascites (1/8), and lymphadenopathy (1/8). Meanwhile, the placebo group had a significantly higher incidence of AEs compared to the trial group (P=0.001); specifically, 18 participants (18/100, 18.00%) experienced a total of 22 AEs, including nasopharyngitis (1/22), upper respiratory infection (1/22), urinary tract infection (3/22), cerebral ischemia (1/22), migraine (1/22), headache (1/22), joint pain (1/22), cough (2/22), oligomenorrhea (1/22), abdominal pain (2/22), dyspepsia (2/22), hypertension (3/22), and leukocytosis (1/22). Throughout the trial, three participants experienced serious AEs (SAEs): one participant in the experimental group (1/100, 1.00%) suffered from cerebral infarction, while two participants in the control group (2/100; 2.00%) experienced migraine (1/2) and headaches, (1/2) respectively. No statistically significant difference was observed between these groups regarding SAE incidence rate. Furthermore, during the trial, one participant in the placebo group withdrew due to an AE, whereas no withdrawals occurred in the experimental group (withdrawal rate: 1.00% vs. 0%; P>0.05). None of the 30 abovementioned AEs were considered to be adverse reactions.

Discussion

The Anshen Bu Xin Liuwei Pill was first described in Traditional Empirical Prescriptions of Mongolian Medicine (26). This formula consists of six herbs: Poëphagus mutus heart, Myristicae Semen, Fructus Choerospondiatis, Caryophylli Flos, Aucklandia lappa, and Resina Liquidambaris. Formula analysis has revealed (27-29) that the Poëphagus mutus heart nourishes the heart while alleviating cardiac pain, Fructus Choerospondiatis possesses cardiotonic and sedative effects, Myristicae Semen suppresses cardiac heyi, Caryophylli Flos suppresses aortic heyi, and Resina Liquidambaris has analgesic properties and can be combined with Aucklandia Lappa to regulate hormonal imbalances and blood circulation, promoting gastrointestinal motility and relieving pain. The combination of these herbs effectively nourishes the heart, improves cardiovascular function, enhances circulation, relieves pain, and promotes mental tranquility.

In this study, our objective was to clarify the target disease of Anshen Bu Xin Liuwei Pill and to evaluate its efficacy and safety in the treatment of cardiac neurosis (heyisheng-type palpitation). The primary outcome was the improvement in heyisheng-type palpitation scale score at week 8 after initiation of therapy. The experimental group exhibited a significantly higher improvement rate compared to the placebo group (84.95% vs. 32.26%), indicating that Anshen Bu Xin Liuwei Pill was effective in treating cardiac neurosis. Compared to the baseline values, the experimental group showed significantly greater changes in the Cardiac Neurosis Symptoms Self-Assessment Scale scores after 2 weeks of treatment compared to the placebo group, suggesting that Anshen Bu Xin Liuwei Pill is effective in treating cardiac neurosis.

Comparison of therapeutic effects versus baseline in both groups demonstrated that short-term (2 weeks) administration of Anshen Buxin Liuwei Pills effectively alleviated somatic symptoms of cardiac neurosis, regulated autonomic heart rate modulation function, and reduced inflammatory status. Continuous medium-to-long-term treatment (8 and 12 weeks) produced significant and sustained improvements in anxiety, depressive symptoms and sleep disturbances. Longer treatment duration yielded more prominent therapeutic advantages in relieving emotional distress, sleep disorders and somatic complaints. Limited experimental data failed to verify that this preparation could significantly modulate serum serotonin levels, indicating that its clinical benefits were not evidently associated with peripheral 5-HT regulation.

Intergroup comparisons between the experimental group and control group confirmed that Anshen Buxin Liuwei Pills exerted definite therapeutic efficacy for cardiac neurosis. Eight weeks of treatment simultaneously improved somatic symptoms of cardiac neurosis, relieved anxiety and depression, and ameliorated sleep disorders, with therapeutic effects sustained up to week 12. As treatment duration extended, the statistical significance of intergroup differences in all clinical indicators gradually increased, demonstrating stable long-term efficacy. Post-treatment intergroup comparisons revealed no significant modulatory effects of the drug on serum hs-CRP or serum serotonin levels. The specific biological mechanisms underlying its clinical benefits require further investigation.

This was a randomized, double-blind, placebo-controlled, multicenter clinical trial that enrolled patients with cardiac neurosis, specifically those with excessive heyisheng-type palpitations as delineated by traditional Mongolian medicine. Anshen Buxin Liuwei Pill demonstrated definitive clinical efficacy in the treatment of patients with cardiac neurosis: it effectively relieved anxiety, depression, and sleep disturbance; improved patients’ quality of life; and had favorable safety profile.

The findings of this study are mainly applicable to patients with cardiac neurosis withheyisheng-type palpitations, a population with typical clinical syndromes. The study design and intervention regimen were highly consistent with real-world clinical medication scenarios, and all study procedures complied with clinical trial norms. Thus, the results can be directly generalized and applied to the diagnosis and treatment of similar patients in secondary and higher-grade medical institutions of traditional Chinese medicine and Mongolian medicine. In the future, expanding the sample size, recruiting patients with complicated syndromes, and conducting real-world pragmatic clinical trials will further clarify the external validity of the results, substantiate the efficacy of Anshen Buxin Liuwei Pill in clinical practice, expand its application scope, and provide more generalizable evidence for the standardized application of Mongolian medicine in the treatment of cardiac neurosis.

Our study involved several limitations that should be acknowledged. First, our primary focus was on patients with cardiac neurosis (heyisheng-type palpitation); however, we did not include patients with complex syndromes in our analysis. The prevalence of patients presenting solely with heyisheng-type palpitation cardiac neurosis was relatively low, as it is more common for patients to present with complex syndromes. Therefore, future research conducted on a larger sample size is necessary to elucidate the target disease of Anshen Bu Xin Liuwei Pill. Second, the issue of multiple analyses was not addressed. Specifically, the Chi-squared test was used for primary outcome measures and the t-test for secondary outcome measures, with no adjustment for multiple comparisons. This increased the risk of type I error and false-positive results. Finally, the multicenter design did not allow for the adjustment of center effects, and the success of blinding was not formally evaluated; thus, performance bias could not be completely ruled out. Accordingly, it is recommended that future large-sample observational studies or clinical trials enroll both patients with simple and complicated heyisheng-type palpitations and adopt multiple testing correction in statistical analysis. This will enrich the evidence base in the field of traditional Mongolian medicine and further clarify the clinical utility of Anshen Buxin Liuwei Pill.

Conclusions

This randomized controlled trial (RCT) confirms prominent time-dependent advantages of Anshen Buxin Liuwei Pills for cardiac neurosis with pure excessive Heyi pattern palpitation. It takes effect rapidly within 2 weeks to relieve somatic symptoms, orthostatic heart rate difference and inflammatory status. Sustained treatment for 8–12 weeks continuously ameliorates anxiety, depression and sleep disorders, with better efficacy at longer follow-up; comprehensive symptom improvement is observed since week 8 and lasts to week 12. The incidence of AEs was comparable between groups, indicating favorable safety profile.

Two major limitations exist. First, no significant regulatory effects on peripheral hs-CRP and 5-HT were detected, so its biological mechanism remains unclear and requires further basic research. Second, only patients with pure excessive Heyi pattern were enrolled while mixed syndromes predominate clinically, which restricts the generalizability of our findings. Large-sample observational studies covering complicated patterns are recommended to define its clinical scope.

In conclusion, Anshen Buxin Liuwei Pills feature rapid onset, sustained long-term efficacy and acceptable safety. It comprehensively alleviates somatic, emotional and sleep disturbances to improve quality of life, presenting great clinical value for pure excessive Heyi pattern palpitation. Further research is needed to reveal its mechanism and verify efficacy in mixed syndromes.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CONSORT reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1612/rc

Trial Protocol: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1612/tp

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1612/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1612/prf

Funding: This study was supported by the National Key Research and Development Program of China (grant Nos. 2018YFC1708200 and 2018YFC1708206) under the project title “Study on the prescription theory and clinical value of the traditional Mongolian medicine prescriptions Zhachong Shisanwei Pill and Anshen Buxin Liuwei Pill”.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1612/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments, and was approved by the Ethics Committee of Fuwai Hospital (No. 2018-1129). Informed consent was taken from all the patients. The other institutions were informed of and agreed with the study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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(English Language Editor: J. Gray)