Disease Characteristics of IR-CAD: a Case-control Study

The present case-control study is designed to investigate the disease characteristics of IR-CAD by comparing the demographics, clinical features, lab results, imaging findings, and prior treatment between 20 patients with IR-CAD and 10 patients with AS-CAD.

A special type of coronary artery disease (CAD) has been identified in the investigators' 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). The investigators name this special type of CAD with inflammation-associated rapidly-progressive coronary artery disease (IR-CAD). Currently, the overall disease characteristics of IR-CAD remain unknown.

The present case-control study is designed to investigate the disease characteristics of IR-CAD by comparing the demographics, clinical features, lab results, imaging findings, and prior treatment between 20 patients with IR-CAD and 10 patients with AS-CAD.

The first 20 patients who were enrolled in the IR-CAD cohort study, which included patients who met the inclusion/exclusion criteria for IR-CAD and received comprehensive treatment, will be enrolled in the case group of the present IR-CAD case-control study. Patients were diagnosed as IR-CAD if they have 1) evidence of rapidly progressive (occurred within 6 months or occurred on immunosuppressive therapy within 12 months of the last coronary revascularization) myocardial ischemia (typical symptoms and non-invasive evidence) despite standard treatment for secondary prevention of AS-CAD; 2) angiographic evidence of new coronary lesions (de novo stenosis or restenosis) considered to be relevant to myocardial ischemia; 3) evidence of inflammation (positive inflammation markers or established diagnosis of inflammatory diseases or use of immunosuppressive therapy). The comprehensive treatment for IR-CAD included: 1) intensified secondary prevention of AS-CAD; 2) immunosuppressive therapy; 3) coronary revascularization; 4) supportive therapies.

Patients who fulfill the inclusion/exclusion criteria for AS-CAD defined by the protocol of the present case-control study will be enrolled in the control group of the present case-control study. Patients will be diagnoses as AS-CAD if they 1) are ≥ 45 but \< 65 years of age; 2) are receiving standard treatment for secondary prevention of AS-CAD after the last PCI which was performed 12±6 months ago; 3) do not have evidence of rapidly progressive (occurred within 6 months or occurred on immunosuppressive therapy within 12 months of the last PCI) myocardial ischemia (typical symptoms and non-invasive evidence); 4) do not have angiographic evidence of new coronary lesions (de novo stenosis or restenosis) considered to be relevant to myocardial ischemia.

Patients in the IR-CAD cohort study underwent examinations after they met the inclusion/exclusion criteria for IR-CAD based on a protocol specifically designed for the clinical management of IR-CAD patients. The results of the above examinations will be used as the examination results of the case group of the present IR-CAD case-control study. While patients in the control group of the present case-control study will undergo similar examinations after enrollment according to the protocol of the present case-control study.

The information regarding the baseline characteristics and the examination results, including demographics, clinical features, lab results, imaging findings, and prior treatment, will be collected and compared between the case group and the control group.

The primary endpoint is the rate of elevated erythrocyte sedimentation rate (ESR).

Eligible patients will be enrolled in the case group and the control group with a 2:1 ratio. The primary endpoint of the present case-control study is elevated erythrocyte sedimentation rate (ESR), which is defined as ESR \> 15 mm for male, or ESR \> 20 mm for female. In case of normal ESR, prior use of immunosuppressive therapy or prior diagnosis of autoimmune diseases before enrollment is regarded as the equivalent to elevated ESR. Based on currently available data from the IR-CAD cohort study, the rate of elevated ESR in the case group (IR-CAD patients) is 88.9% (8/9). The investigators hypothesize that the rate of elevated ESR in the control group (AS-CAD patients) is 20%. In consequence, 20 patients in the case group and 10 patients in the control group would be required to test the difference of the rate of the primary endpoint between the two groups at a significance level of 0.05 (α = 0.05) with a power of 90% (β = 0.10) and a drop-out rate of 20%.

Continuous variables will be presented as mean ± standard deviation (SD) or median (interquartile range \[IQR\]) and compared with two-sample t-test or Wilcoxon rank sum test, as appropriate. Categorical data will be demonstrated as n (%) and compared using Chi-square test or Fisher's exact test, as appropriate.

Eligibility Criteria:
Inclusion Criteria:

Case group (IR-CAD patients):

1. 18 years of age or older, male or female.
2. Negative results of urine or blood pregnancy test for females with childbearing potential (not post-menopausal or surgically sterile).
3. Prior history of coronary revascularization (PCI or coronary artery bypass graft \[CABG\]).
4. Receiving standard treatment for secondary prevention of AS-CAD after the last coronary revascularization.
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.
6. Angiographic evidence of new coronary lesions (de novo stenosis or restenosis) considered to be relevant to myocardial ischemia.
7. Evidence of inflammation:

   * At least one of the indexes indicating active inflammation has ever been elevated (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.

Control group (AS-CAD patients):

1. ≥ 45 and \< 65 years of age (based on the age distribution of the patients currently enrolled in the IR-CAD cohort study), male or female.
2. Negative results of urine or blood pregnancy test for females with childbearing potential (not post-menopausal or surgically sterile).
3. Currently, 12±6 months after the last PCI.
4. Receiving standard treatment for secondary prevention of AS-CAD after the last PCI.
5. Coronary angiography and/or optical coherence tomography (OCT) performed during the present hospitalization.
6. No evidence of rapidly-progressive myocardial ischemia, which is defined as follows:

   * 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 PCI.
7. No angiographic evidence of new coronary lesions (de novo stenosis or restenosis) considered to be relevant to myocardial ischemia.

Exclusion Criteria:

Case group (IR-CAD patients):

1. Coronary restenosis due to mechanical factors (stent under-expansion, stent mal-apposition, stent rupture, et al).
2. Other moderate to severe heart diseases (congenital heart disease, valvular heart disease, myocarditis, cardiomyopathy, pericardial diseases, pulmonary hypertension, heart failure, arrhythmia, et al).
3. Active acute or chronic infection (human immunodeficiency virus \[HIV\], tuberculosis, et al).
4. Active malignancy (diagnosed within 12 months or with ongoing requirement for treatment).
5. Vital organ failure.
6. Life expectancy \< 1 year.
7. Contraindications for or intolerance to treatment for secondary prevention of AS-CAD, contrast agents, glucocorticoids, immunosuppressive agents.
8. In pregnancy or breast-feeding, or with intention to be pregnant during the study period.
9. Risk of non-compliance (history of drug addiction or alcohol abuse, et al).
10. Previous enrollment in this study.
11. Participation in another study within 30 days.
12. Involvement in the planning and conduct of this study (applying to investigators, contract research organization staffs, study site staffs, et al).
13. Any condition, which in the opinion of the investigators, would make it unsuitable for the patient to participate in this study.

Control group (AS-CAD patients):

The same as those for the case group (IR-CAD patients).