Description

I. Background and Rationale Acute Coronary Syndrome (ACS) is a severe form of coronary artery disease characterized by the rupture or erosion of atherosclerotic plaques, followed by the formation of occlusive or non-occlusive thrombi. Encompassing unstable angina, acute ST-segment elevation myocardial infarction, and non-ST-segment elevation myocardial infarction, ACS remains a leading cause of morbidity and mortality globally. Percutaneous Coronary Intervention (PCI) is a cornerstone therapeutic strategy for ACS, enabling rapid revascularization and myocardial reperfusion. However, as an invasive procedure, combined with patients' concerns regarding postoperative complications, stent longevity, medication side effects, and treatment costs, PCI is frequently associated with significant emotional disturbances in the postoperative period. Meta-analyses have shown that the prevalence of depression among post-PCI patients ranges from 20% to 82%, while the incidence of anxiety is between 25% and 37%. Notably, the rates of depression and anxiety can surge to 44.7% and 54.7%, respectively, on the first day after PCI. Clinical evidence confirms that post-PCI depression and anxiety substantially reduce treatment adherence and increase the risk of Major Adverse Cardiovascular Events (MACE): patients with anxiety face a 3.742-fold higher risk of MACE compared to those without anxiety, while depressed patients have a 3.087-fold higher risk, and the combined effect of anxiety and depression elevates this risk to 7.303-fold. These emotional disorders are thus recognized as crucial predictors of poor prognosis in post-PCI patients. Nevertheless, conventional antidepressant therapies have inherent limitations: antidepressant medications yield a response rate of only 50%-67%, require at least 4 weeks to exert therapeutic effects, and are associated with common side effects such as nausea, cardiovascular reactions, and sexual dysfunction, leading to poor medication adherence. Cognitive behavioral therapy, on the other hand, is hindered by its complexity and high cost, limiting its accessibility in primary care settings. Vagus Nerve Stimulation (VNS) is an FDA-approved somatic therapy for treatment-resistant depression (TRD), demonstrating clinically significant antidepressant efficacy. However, invasive VNS (iVNS) is less appealing due to surgical risks, high costs (ranging from $30,000 to $50,000), and potential side effects, resulting in low clinical utilization. To overcome these barriers, non-invasive transcutaneous auricular Vagus Nerve Stimulation (taVNS) has been developed and garnered increasing attention. Anatomical studies have identified the ear as the only body surface region innervated by afferent vagus nerve fibers. Based on the "bottom-up" mechanism of the central nervous system, electrical stimulation propagates retrogradely from peripheral nerves to brainstem and central structures, mimicking the antidepressant effects of conventional VNS without the burden of surgical intervention. Since the first clinical study on taVNS for depression in 2009, a series of trials have validated its efficacy in ameliorating depressive symptoms. However, research on taVNS for treating depression in ACS patients after PCI remains scarce. Therefore, this randomized controlled trial aims to investigate the efficacy and safety of taVNS in this specific population, providing a novel therapeutic option for clinical practice. II. Study Objectives (A) Primary Objective To evaluate the antidepressant efficacy of transcutaneous auricular Vagus Nerve Stimulation (taVNS) in ACS patients with mild-to-moderate depression after PCI, using the change in Hamilton Depression Rating Scale (HAMD-17) scores from baseline to week 8 as the primary outcome measure. (B) Secondary Objectives To assess the effects of taVNS on anxiety, post-traumatic stress disorder (PTSD), and quality of life in the study population; To observe the impacts of taVNS on physiological indicators, including heart rate variability (HRV), cardiac function, and inflammatory factors; To verify the clinical safety of taVNS (adverse events, MACE incidence) and relevant efficacy metrics (HAMD response rate, remission rate). III. Study Endpoints (A) Primary Endpoint Change in Hamilton Depression Rating Scale (HAMD-17) scores from baseline to week 8: The HAMD-17 is a validated tool for assessing depressive symptoms, with the following grading criteria: no depression (total score ≤7), mild depression (8-17), moderate depression (18-24), and severe depression (\>24). The difference between week 8 and baseline scores directly reflects the degree of improvement in depressive symptoms. (B) Secondary Endpoints Depression-related indicators: HAMD response rate (≥50% reduction in scores from baseline to week 8), HAMD remission rate (total score ≤7 at week 8), and change in Beck Depression Inventory (BDI) scores from baseline (BDI criteria: no depression \[0-4\], mild depression \[5-7\], moderate depression \[8-15\], severe depression \[≥16\]); Anxiety-related indicators: Change in Hamilton Anxiety Rating Scale (HAMA) scores from baseline (HAMA criteria: severe anxiety \[≥29\], marked anxiety \[21-28\], definite anxiety \[14-20\], possible anxiety \[8-13\], no anxiety \[\<7\]) and change in Generalized Anxiety Disorder-7 (GAD-7) scores from baseline (GAD-7 criteria: no generalized anxiety \[0-4\], mild \[5-9\], moderate \[10-14\], severe \[15-21\]); Other psychological indicators: Change in Posttraumatic Stress Disorder Checklist-Civilian Version (PCL-C) scores from baseline (PCL-C criteria: no significant symptoms \[17-37\], mild-to-moderate symptoms \[38-49\], significant symptoms \[50-85\]) and change in 36-Item Short Form Health Survey (SF-36) scores from baseline (comprising 8 domains, scored on a 100-point scale, with higher scores indicating better quality of life); Physiological indicators: Change in heart rate variability (HRV, including time-domain parameters such as SDNN and SDANN, and frequency-domain parameters such as TP and HF) from baseline; change in echocardiographic indices (left ventricular end-diastolic/systolic diameter, left ventricular ejection fraction) from baseline; change in venous blood markers (cardiac troponin I, N-terminal pro-B-type natriuretic peptide \[NT-proBNP\], interleukin-1 \[IL-1\], interleukin-6 \[IL-6\], tumor necrosis factor-α \[TNF-α\], C-reactive protein \[CRP\]) from baseline; Clinical outcomes: Incidence of Major Adverse Cardiovascular Events (MACE) during the intervention period (up to the 16-week follow-up), including death, myocardial infarction, and target vessel revascularization (as defined by the Academic Research Consortium \[ARC\] criteria). IV. Study Population (A) Inclusion Criteria Age ≥18 years; Meeting the diagnostic criteria for ACS; 14 days to 12 months after successful PCI, with stable vital signs; Meeting the diagnostic criteria for depression according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V); HAMD-17 score ≥7 and \<24 (mild-to-moderate depression), with HAMA score \60 years) and gender (male, female), resulting in 4 subgroups. Random sequences with variable block sizes will be generated using R software. Concealment of random allocation: Random sequences will be generated and stored by personnel not involved in the trial. After confirming patient eligibility, investigators will obtain allocation information via a central telephone randomization system to ensure allocation concealment. Blinding design: A double-blind design will be adopted, with blinding of patients, investigators, and data analysts. (B) Intervention Measures All patients will receive standard ACS treatment and routine medications for secondary prevention of coronary heart disease, with the following additional interventions: Active stimulation group (Group A): Transcutaneous auricular Vagus Nerve Stimulation (taVNS) using the Xidian Keyue BS-TVNS600 device. Operational procedure: Disinfection of electrodes and the target area of the left ear with 75% alcohol → abrasion of the left cymba concha and tragus with abrasive paste → re-disinfection with alcohol → application of conductive gel to electrodes → placement of electrodes on the left tragus → gradual increase of current to the patient's tolerable threshold. Parameter settings: Pulse frequency 20 Hz, pulse width 250 ms, current 0.5-3 mA, stimulation cycle (30 s on, 30 s off). Treatment frequency: Twice daily, 20 minutes per session, for 8 consecutive weeks. Sham stimulation group (Group B): Sham taVNS treatment with the same device, wearing method, and parameter adjustments as Group A. However, stimulation will only be delivered for the first 5 seconds, with no subsequent electrical output. Treatment frequency will be identical to that of Group A. (C) Patient Training and Management All patients will receive training on device operation (power on/off, electrode application, stimulation site positioning, intensity adjustment) and will perform self-administration at home. A diary card will be provided to record daily treatment date, duration, adverse events, and suggestions, which will be reviewed during follow-up. During the follow-up period, patients will also receive medication guidance and lifestyle interventions (popularization of coronary heart disease knowledge, diet and exercise advice, sleep guidance, smoking cessation, alcohol restriction, and weight management). VI. Study Procedures and Follow-Up Schedule (A) Enrollment Process Outpatients or inpatients who are 2 weeks to 12 months after ACS PCI will undergo DSM-V diagnosis and HAMD/HAMA assessments by psychiatric physicians. Patients with mild-to-moderate depression who refuse conventional antidepressant treatment will be further screened against inclusion and exclusion criteria. Eligible patients will sign the informed consent form, undergo baseline data collection (scale assessments: HAMD, HAMA, BDI, GAD-7, PCL-C, SF-36; physiological tests: HRV, echocardiography, venous blood tests), be randomly assigned to a group, and initiate intervention. (B) Follow-Up Schedule Week 4: Scale assessments (HAMD, HAMA, BDI, GAD-7, PCL-C, SF-36), vital sign monitoring, adverse event recording, and diary card review; Week 8: Scale assessments (same as week 4), HRV testing, venous blood tests, adverse event recording, and diary card review (primary follow-up point for assessing the primary endpoint); Week 12: Scale assessments (same as week 4), echocardiography, adverse event recording, and evaluation of lifestyle improvements; Week 16: Scale assessments (same as week 4), HRV testing, venous blood tests, collection of MACE data, adverse event recording, and study conclusion (final follow-up). VII. Safety Management (A) Definition and Grading of Adverse Events Adverse event: Any unfavorable medical occurrence in a subject after intervention, including symptoms, diseases, or laboratory abnormalities, regardless of causal relationship with the intervention; Serious adverse event: An adverse event involving death, life-threatening conditions, permanent or severe disability/incapacity, hospitalization or prolonged hospitalization, or congenital anomalies/birth defects; Grading: Mild (tolerable, no special treatment required), moderate (intolerable, requiring special treatment), severe (life-threatening, requiring emergency treatment). (B) Recording and Reporting of Adverse Events Adverse events will be documented in detail, including onset time, clinical manifestations, treatment course, duration, and outcome; Laboratory abnormalities will be followed up until recovery to normal levels, baseline values, or confirmation of no association with the intervention; Serious adverse events will be reported to the clinical research center and ethics committee within 24 hours. (C) Risk Prevention Measures The clinical trial will be initiated only after obtaining approval in accordance with regulatory requirements; Strict implementation of inclusion and exclusion criteria to minimize baseline risks; Enhanced patient training on device operation to reduce human-induced risks; Appointment of a quality control supervisor (familiar with taVNS operation) to promptly address treatment-related risks; Provision of an emergency contact number for patients to ensure timely communication and management of adverse events. VIII. Data Management and Statistical Analysis (A) Data Management Data will be entered using Excel software with double data entry and verification to ensure accuracy; A data access permission system will be established, allowing only authorized personnel to access and modify data; Data will be backed up twice (locally and in the cloud) and regularly verified to prevent loss or tampering; Logical checks will be performed after data entry, with abnormal data traced and corrected promptly. (B) Statistical Analysis Sample size calculation: This randomized controlled trial will adopt a significance level (α) of 0.05 and a power (1-β) of 0.80. Based on a reported effect size of 57% for taVNS in alleviating depression, PASS software estimates a baseline sample size of 50 patients per group (100 total). Considering a 10% dropout/loss-to-follow-up rate and the need for stratification by age and gender, the final sample size will be 120 patients (60 per group). Analysis populations: Intent-to-Treat (ITT) set: All randomly assigned patients who receive at least one intervention will be included. Primary efficacy analysis will be performed according to the initial grouping to retain the advantages of randomization and reduce bias; Per-Protocol (PP) set: Patients who complete the full treatment course without major protocol violations (e.g., non-compliance with inclusion/exclusion criteria, receipt of interfering treatments, adherence rate \<80%, key follow-up beyond the time window) will be included for sensitivity analysis to verify the robustness of results. Statistical methods: Continuous data (scale scores, physiological indicators, etc.): Normally distributed data will be presented as "mean ± standard deviation" and compared using independent samples t-tests; non-normally distributed data will be presented as "median (interquartile range)" and compared using Wilcoxon rank-sum tests; Categorical data (HAMD response rate/remission rate, MACE incidence, etc.): Presented as "n (%)" and compared using chi-square tests; The primary endpoint (change in HAMD scores from baseline to week 8) and key secondary endpoints will be analyzed using Bayesian methods, while other indicators will be analyzed using conventional statistical methods; Statistical software: SPSS 26.0 or R 4.0.0 will be used, with a two-tailed P-value \<0.05 considered statistically significant. IX. Ethics and Confidentiality (A) Ethical Review The study protocol, informed consent form, and other subject-related documents must be approved in writing by the Ethics Committee of the Second Affiliated Hospital of Air Force Medical University before initiation; Annual progress reports will be submitted during the study period. Revisions to the protocol or informed consent form must be approved by the Ethics Committee (except for changes made to eliminate obvious and direct risks to subjects), with timely notification to the Ethics Committee in such cases; A final report will be submitted to the Ethics Committee upon study termination or completion. (B) Informed Consent Patients or their legal representatives will be fully informed of the study purpose, interventions, potential benefits and risks, and rights and obligations. A copy of the ethical approval certificate will be provided; Sufficient time for consideration will be granted, and patients will be enrolled only after they or their legal representatives fully understand and voluntarily sign the written informed consent form; Updated versions of the informed consent form and relevant information will be provided to subjects during the study period if applicable. (C) Confidentiality Measures All subject information will be anonymized with unique identifiers. Original data will be stored by designated personnel with restricted access; Only aggregated data will be presented in study publications or communications, with no disclosure of personal privacy information; Data access will be restricted to authorized institutions (e.g., government regulatory authorities, ethics committees) in accordance with regulations, adhering to relevant confidentiality laws. X. Data Monitoring Committee Given the mild nature and low incidence of adverse events in this trial, along with its high safety profile, no independent Data Monitoring Committee will be established. Instead, an internal quality control team of the research group will conduct regular data verification and trial quality monitoring.