Efficacy and Safety of Comprehensive Treatment in Patients With IR-CAD: a Self-controlled Cohort Study

Study Overview
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Brief Summary
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This is a self-controlled cohort study to evaluate the efficacy and safety of comprehensive treatment in patients with inflammation-associated rapidly-progressive coronary artery disease (IR-CAD) by comparing the study endpoints before treatment with those after treatment in the same group of patients.

Detailed Description
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A special type of coronary artery disease (CAD) has been identified in our clinical practice, which has completely different clinical features from those of typical atherosclerotic coronary artery disease (AS-CAD). The patients often have sterile inflammatory diseases and/or clinical evidence of inflammation, whose CAD progresses rapidly, recurs frequently, and responds poorly to intensified secondary prevention of AS-CAD, especially after percutaneous coronary intervention (PCI). We name this special type of CAD inflammation-associated rapidly-progressive coronary artery disease (IR-CAD). The optimal treatment for IR-CAD remains unknown. We hypothesize that the rapid progression of IR-CAD might be associated with inflammation considering that: 1) inflammation is associated with poor prognosis in CAD patients after PCI; 2) IR-CAD patients often have sterile inflammatory diseases and/or clinical evidence of inflammation; 3) the disease progression of IR-CAD can be controlled to some extent with corticosteroids and immunosuppressive agents. Therefore, we incorporate immunosuppressive therapy into the overall management strategy of IR-CAD patients in clinical practice, developing comprehensive treatment, including: 1) intensified secondary prevention of AS-CAD; 2) immunosuppressive therapy; 3) coronary revascularization; 4) supportive therapies. The present self-controlled cohort study is designed to evaluate the efficacy and safety of comprehensive treatment in about 39 IR-CAD patients by comparing the outcomes before with those after the initiation of comprehensive treatment in the same group of patients. All patients who were admitted to the Department of Cardiology, Peking Union Medical College Hospital on and after January 1, 2022 will be screened for study participation. Patients were diagnosed as IR-CAD if they presented with 1) rapidly progressive myocardial ischemia (typical symptoms and non-invasive evidence) despite standard treatment for secondary prevention of AS-CAD after the last coronary revascularization; 2) angiographic evidence of new coronary lesions (de novo stenosis or restenosis) related to myocardial ischemia; 3) evidence of inflammation (positive inflammation markers or established diagnoses of inflammatory diseases or use of immunosuppressive therapy). IR-CAD patients who have received comprehensive treatment will be enrolled in the present cohort study. The eligible patients will be followed for 24 months since the initiation of comprehensive treatment. The primary efficacy endpoint is major adverse cardiovascular events (MACE). The key secondary efficacy endpoint is target vessel related major adverse cardiovascular events (TV-MACE). Other secondary efficacy endpoints include individual components of MACE and TV-MACE, exercise capacity, angiographic metrics of coronary lesions, and inflammation markers. The safety endpoints are major bleeding events and severe infection events. For endpoints which are categorical variables, e.g., MACE, survival analysis will be used to compare the survival curves before treatment (from the last coronary revascularization before the initiation of comprehensive treatment to the first occurrence of MACE) with those after treatment (from the initiation of comprehensive treatment to the first occurrence of MACE, or the last follow-up visit, or the end of 24-month follow-up, which occurs first). Event-free survival rates and relative risk will be calculated. For endpoints which are continuous variables, e.g., inflammation markers, paired t-test or paired rank sum test will be used to compare the endpoint levels before treatment (before the initiation of comprehensive treatment or at baseline) with those after treatment (the first occurrence of MACE, or the last follow-up visit, or the end of 24-month follow-up, which occurs first, after the initiation of comprehensive treatment).

Official Title
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Efficacy and Safety of Comprehensive Treatment in Patients With Inflammation-associated Rapidly-progressive Coronary Artery Disease (IR-CAD): a Self-controlled Cohort Study

Conditions
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Coronary Artery Disease, Coronary Artery Stenosis, Coronary Artery Restenosis, Coronary Artery Disease Progression, Inflammation, Inflammatory Disease, Inflammation Vascular

Intervention / Treatment
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* Behavioral: Healthy life style
* Drug: Secondary prevention for atherosclerotic coronary artery disease
* Drug: Immunosuppressive therapy
* Procedure: Coronary revascularization
* Drug: Supportive therapies


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Fulfilling all the following criteria before initiation of comprehensive treatment: 1.1 18 years of age or older, male or female. 1.2 Negative result of urine or blood pregnancy test for females with childbearing potential (not post-menopausal or surgically sterile). 1.3 Prior history of coronary revascularization (percutaneous coronary intervention [PCI] or coronary artery bypass graft [CABG]). 1.4 Receiving standard treatment for secondary prevention of atherosclerotic coronary artery disease (AS-CAD) after the last coronary revascularization. 1.5 Hospitalization due to rapidly-progressive myocardial ischemia: Typical symptoms of angina (Canadian Cardiovascular Society [CCS] III-IV) and non-invasive evidence of myocardial ischemia; and Occurred within 6 months or occurred on immunosuppressive therapy within 12 months of the last coronary revascularization. 1.6 Angiographic evidence of new coronary lesions (de novo stenoses or restenoses): Occurred after the last coronary revascularization; and Related to myocardial ischemia (location, extent, severity, et al). 1.7 Evidence of inflammation: At least one of the markers indicating active inflammation has ever been elevated (erythrocyte sedimentation rate [ESR], high-sensitivity C-reactive protein [hs-CRP], interleukin [IL]-6, tumor necrosis factor [TNF]-α, ferritin, et al); or Established diagnosis of systemic autoimmune disease or systemic vasculitis; or Receiving immunosuppressive therapy. Receiving comprehensive treatment, including ischemia-driven PCI which was performed no earlier than 40 days of the initiation of immunosuppressive therapy. Exclusion Criteria: Coronary restenosis due to mechanical factors (stent under-expansion, stent mal-apposition, stent rupture, et al). Other moderate to severe heart diseases (congenital heart disease, valvular heart disease, myocarditis, cardiomyopathy, pericardial diseases, pulmonary hypertension, heart failure, arrhythmia, et al). Active acute or chronic infection (human immunodeficiency virus [HIV], tuberculosis, et al). Active malignancy (diagnosed within 12 months or with ongoing requirement for treatment). Vital organ failure. Life expectancy < 1 year. Contraindications for or intolerance to treatment for secondary prevention of AS-CAD, contrast agents, glucocorticoids, immunosuppressive agents. In pregnancy or breast-feeding, or with intention to be pregnant during the study period. Risk of non-compliance (history of drug addiction or alcohol abuse, et al). Previous enrollment in this study. Participation in another study within 30 days. Involvement in the planning and conduct of this study (applying to investigators, contract research organization staffs, study site staffs, et al). Any condition, which in the opinion of the investigators, would make it unsuitable for the patient to participate in this study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Pre-treatment Group<br>IR-CAD patients before receiving comprehensive treatment. | Behavioral: Healthy life style<br>* Healthy diet, regular exercise, and quitting smoking<br>Drug: Secondary prevention for atherosclerotic coronary artery disease<br>* Antiplatelet therapy, as well as medications for control of heart rate, blood pressure, low-density lipoprotein cholesterol, and blood glucose<br>Procedure: Coronary revascularization<br>* Percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG).<br>Drug: Supportive therapies<br>* Medical interventions for prevention and treatment of the side effects of the above treatment, such as abnormal liver function, hypocalcemia, hypokalemia, peptic ulcer, infection, et al.<br>|
| Post-treatment Group<br>IR-CAD patients after receiving comprehensive treatment. | Behavioral: Healthy life style<br>* Healthy diet, regular exercise, and quitting smoking<br>Drug: Secondary prevention for atherosclerotic coronary artery disease<br>* Antiplatelet therapy, as well as medications for control of heart rate, blood pressure, low-density lipoprotein cholesterol, and blood glucose<br>Drug: Immunosuppressive therapy<br>* Glucocorticoids and/or immunosuppressive agents<br>Procedure: Coronary revascularization<br>* Percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG).<br>Drug: Supportive therapies<br>* Medical interventions for prevention and treatment of the side effects of the above treatment, such as abnormal liver function, hypocalcemia, hypokalemia, peptic ulcer, infection, et al.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Major adverse cardiovascular events (MACE) | The composite endpoint including death, or Q wave myocardial infarction, or unplanned myocardial ischemia-driven coronary revascularization (PCI or CABG), or unplanned myocardial ischemia-driven hospitalization. | Time from the last coronary revascularization to the first occurrence of MACE, or the last follow-up visit, or the end of 24-month follow-up, which occurs first, both before and after the initiation of comprehensive treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Target vessel related major adverse cardiovascular events (TV-MACE) | The composite endpoint including cardiovascular death, or target vessel related Q wave myocardial infarction, or target vessel related unplanned myocardial ischemia-driven coronary revascularization (PCI or CABG), or target vessel related unplanned myocardial ischemia-driven hospitalization. | Time from the last coronary revascularization to the first occurrence of MACE, or the last follow-up visit, or the end of 24-month follow-up, which occurs first, both before and after the initiation of comprehensive treatment. | 
| Death | All-cause death. | Time from the last coronary revascularization to the first occurrence of MACE, or the last follow-up visit, or the end of 24-month follow-up, which occurs first, both before and after the initiation of comprehensive treatment. | 
| Myocardial infarction | Myocardial injury due to myocardial ischemia. | Time from the last coronary revascularization to the first occurrence of MACE, or the last follow-up visit, or the end of 24-month follow-up, which occurs first, both before and after the initiation of comprehensive treatment. | 
| Target vessel related myocardial infarction | Myocardial infarction in the area supplied by the target vessel. | Time from the last coronary revascularization to the first occurrence of MACE, or the last follow-up visit, or the end of 24-month follow-up, which occurs first, both before and after the initiation of comprehensive treatment. | 
| Unplanned myocardial ischemia-driven coronary revascularization | Unplanned coronary revascularization (PCI or CABG) due to myocardial ischemia. | Time from the last coronary revascularization to the first occurrence of MACE, or the last follow-up visit, or the end of 24-month follow-up, which occurs first, both before and after the initiation of comprehensive treatment. | 
| Target vessel related unplanned myocardial ischemia-driven coronary revascularization | Unplanned coronary revascularization (PCI or CABG) in the target vessel due to myocardial ischemia. | Time from the last coronary revascularization to the first occurrence of MACE, or the last follow-up visit, or the end of 24-month follow-up, which occurs first, both before and after the initiation of comprehensive treatment. | 
| Unplanned myocardial ischemia-driven hospitalization | Unplanned hospitalization due to myocardial ischemia. | Time from the last coronary revascularization to the first occurrence of MACE, or the last follow-up visit, or the end of 24-month follow-up, which occurs first, both before and after the initiation of comprehensive treatment. | 
| Target vessel related unplanned myocardial ischemia-driven hospitalization | Unplanned hospitalization due to myocardial ischemia in the area supplied by the target vessel. | Time from the last coronary revascularization to the first occurrence of MACE, or the last follow-up visit, or the end of 24-month follow-up, which occurs first, both before and after the initiation of comprehensive treatment. | 
| Walking distance in 6 minutes | The result of 6-minute walk test (6MWT). | Before treatment: the timepoint before the initiation of comprehensive treatment, or at baseline. After treatment: the timepoint of the first occurrence of MACE, or the last follow-up visit, or the end of 24-month follow-up, which occurs first. | 
| Number of squats in 1 minute | The result of 1-minute squatting test (1MST). | Before treatment: the timepoint before the initiation of comprehensive treatment, or at baseline. After treatment: the timepoint of the first occurrence of MACE, or the last follow-up visit, or the end of 24-month follow-up, which occurs first. | 
| Target lesion minimal lumen area (TL-MLA) | The minimum lumen area of the target lesion on optical coherence tomography (OCT). | Before treatment: the timepoint before the initiation of comprehensive treatment, or at baseline. After treatment: the timepoint of the first occurrence of MACE, or the last follow-up visit, or the end of 24-month follow-up, which occurs first. | 
| Target lesion percent area stenosis (TL-%AS) | Percent area stenosis (% AS) = { [ ( proximal RLA + distal RLA ) - (MLA × 2) ] / ( proximal RLA + distal RLA ) } × 100% in the cross-section with the MLA of the target lesion on optical coherence tomography (OCT). RLA = reference lumen area; MLA = minimum lumen area; % AS = percent area stenosis. | Before treatment: the timepoint before the initiation of comprehensive treatment, or at baseline. After treatment: the timepoint of the first occurrence of MACE, or the last follow-up visit, or the end of 24-month follow-up, which occurs first. | 
| SYNTAX score | The result of SYNTAX score calculation. | Before treatment: the timepoint before the initiation of comprehensive treatment, or at baseline. After treatment: the timepoint of the first occurrence of MACE, or the last follow-up visit, or the end of 24-month follow-up, which occurs first. | 
| Number of vessel segments with coronary lesions | Number of vessel segments with diameter stenosis ≥ 50% on coronary angiogram. | Before treatment: the timepoint before the initiation of comprehensive treatment, or at baseline. After treatment: the timepoint of the first occurrence of MACE, or the last follow-up visit, or the end of 24-month follow-up, which occurs first. | 
| Erythrocyte sedimentation rate (ESR) | The result of erythrocyte sedimentation rate (ESR) test. | Before treatment: the timepoint before the initiation of comprehensive treatment, or at baseline. After treatment: the timepoint of the first occurrence of MACE, or the last follow-up visit, or the end of 24-month follow-up, which occurs first. | 
| High-sensitivity C-reactive protein (hs-CRP) | The result of serum high-sensitivity C-reactive protein (hs-CRP) test. | Before treatment: the timepoint before the initiation of comprehensive treatment, or at baseline. After treatment: the timepoint of the first occurrence of MACE, or the last follow-up visit, or the end of 24-month follow-up, which occurs first. | 
| interleukin (IL)-6 | The result of serum interleukin (IL)-6 test. | Before treatment: the timepoint before the initiation of comprehensive treatment, or at baseline. After treatment: the timepoint of the first occurrence of MACE, or the last follow-up visit, or the end of 24-month follow-up, which occurs first. | 
| Tumor necrosis factor (TNF)-α | The result of serum tumor necrosis factor (TNF)-α test. | Before treatment: the timepoint before the initiation of comprehensive treatment, or at baseline. After treatment: the timepoint of the first occurrence of MACE, or the last follow-up visit, or the end of 24-month follow-up, which occurs first. | 
| Birmingham vasculitis activity score | The result of Birmingham Vasculitis Activity Score (version 3) calculation. | Before treatment: the timepoint before the initiation of comprehensive treatment, or at baseline. After treatment: the timepoint of the first occurrence of MACE, or the last follow-up visit, or the end of 24-month follow-up, which occurs first. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Coronary Artery Disease, Coronary Revascularization, Progression, Disease, Inflammation