복합 관상동맥 병변 환자에서 최소 침습 관상동맥 수술의 효과 및 안전성

Objective and Hypothesis: The aim of this study is to investigate and compare the mid-term safety and efficacy end-points (SF-36 PCS at 30 days after surgery, etc.) in patients with complex coronary artery lesions (an indication of OPCAGB) who received MICS-CABG and those who received thoracotomy OPCABG. The investigators hypothesize that patients in MICS-CABG group have superior 1-month PCS score assessed by SF-36 post-surgery and noninferior postprocedural angiographic graft patency rate prior to discharge.

Intervention Methods:

1. MICS-CABG (experimental group): Off-pump multi-vessel coronary artery bypass grafting via left thoracotomy under minimally invasive conditions.

   1. Surgery preparation:

      General anesthesia, double lumen tracheal intubation. In the supine position, tilt 15° to the right. An automatic defibrillation electrode is attached to the right front and left rear chest wall, and the external defibrillator is connected. A small incision of 8-10 cm into the left anterior lateral 5th intercostal space was performed into the chest.

   2. Internal mammary artery acquisition:

      After entering the chest, the internal mammary artery (IMA) is exposed through a new minimal invasive retraction system. Single or bilateral IMA is obtained as needed. Separate the IMA From the middle segment (non-fat muscle coverage area) applied with an electric scalpel (15J), and the free range was up to the first rib to the fifth or sixth intercostal (IMA bifurcation).

   3. Bypass strategy:

      All procedures were performed under a non-cardiopulmonary situation, and vascular anastomosis was performed with the aid of a laparoscopic cardiac stabilizer. The stabilizer is smaller and does not occupy the operating space. The head of stabilizer can be rotated 360 degrees and the target vessel can be fixed at any angle. Bilateral internal mammary artery, radial artery and saphenous vein can be used as graft vessels. The bypass strategy is not particularly different from conventional bypass surgery, including aorta (AO)-saphenous vein graft (SVG) or radial artery (RA)-X1-X2-...( sequential anastomosis), left internal mammary artery (LIMA)-right internal mammary artery (RIMA) -RA or SVG(Y)-X, RIMA-left anterior descending (LAD), LIMA-RA or RIMA or SVG(I)-X1-X2 and so on.

   4. Vascular anastomosis:

      The target vessel is exposed through the pericardial suture, the heart is locally fixed with the aid of a cardiac stabilizer, and the target vessel is inserted shunt to avoid hemodynamic disorder and arrhythmia. Vascular anastomosis is performed by 8-0 polypropylene suture.

   5. Aortic exposure and proximal anastomosis:

   Place gauze behind the aorta, expose the aorta with the right pericardial suspension suture, temporary block aortic anterior wall with a soft-chain sidewall clamp, Punch on the aortic anterior wall with 3.5 mm puncher, anastomose SVG or RA on AO with 6-0 polypropylene suture.

2. OPCABG (control group): Off-pump multi-vessel coronary artery bypass grafting with conventional thoracotomy.

Randomization Procedure:

Eligible patients will be randomized to MICS-CABG or OPCABG group with an allocation ratio of 1:1 after providing written informed consent. The randomization sequence will be generated by an independent statistician with block randomization method (block size=4 or 6). Each enrolled patient will be allocated to MICS-CABG or OPCABG group within 24-48 hours prior to surgery in the order of the assigned number in the allocation table uploaded in the electronic data capture (EDC) system. This is an open-label, randomized controlled trial with two co-primary endpoints.

Patient Selection:

Details are shown in the Eligibility Criteria part.

Measurements:

1. Baseline Measurements:

   1. General Information: sex, age, body mass index.
   2. Medical History and Comorbidity: smoking status, history of diabetes (oral hypoglycemic agents, insulin therapy, HbA1c greater than 7.0%, postprandial blood glucose greater than 11.1 mmol/L, fasting plasma glucose greater than 7.0 mmol/L), previous stroke, hyperlipidemia (under drug therapy, serum cholesterol greater than 5.72 mmol/L or triglyceride greater than 1.7 mmol/L at admission), hypertension (blood pressure greater than 140/90 mmHg without medication), renal insufficiency (dialysis or serum creatinine level greater than 140 mmol/L or creatinine clearance rate less than 30 mL/min), peripheral vascular disease [preoperative ultrasound or computed tomography (CT) confirmed peripheral vascular stenosis greater than 50%], previous history of cardiac surgery, previous percutaneous coronary intervention (PCI) history (balloon dilatation or stent implantation), previous myocardial infarction (MI) [pathological Q wave on ECG, definite evidence of elevation of creatine kinase (CK-MB) or troponin (cTnI) greater than 10 times of normal value with st-t segment elevation on cardiogram].
   3. Preoperative Status: SF-36, Seattle angina questionnaire (SAQ) score, classification of angina (stable angina pectoris, unstable angina pectoris, non st-t segment elevation myocardial infarction, st-t segment elevation myocardial infarction), New York Heart Association (NYHA) heart function classification, severe pulmonary insufficiency [post-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC)<70% and FEV1%predicted<50% or partial pressure of oxygen (pO2)<60 mmHg or partial pressure of carbon dioxide (pCO2)>40 mmHg without oxygen therapy].
   4. Preoperative Examination: creatinine (Cr), N-terminal pro brain natriuretic peptide (NT-proBNP), preoperative cardiac function [ejection fraction (EF)%, left ventricular end-diastolic myocardial mass (LVEDm)], SYNTAX score (evaluated by two cardiologist).
   5. Preoperative Medication (within 1 week): aspirin, P2Y12 receptor antagonist (clopidogrel, ticagrelor), glycoprotein IIb/IIIa inhibitor (abciximab, eptifibatide, tirofiban, etc.).

2. Outcomes: Details are shown in the Outcome Measures part.

Follow-ups:

Patients will be followed at 7 days, 14 days, 30 days (1 month), 3 months, 6 months, and 12 months after surgery.

Sample Size:

Trial success required both 1-month PCS superiority and graft-patency noninferiority under an intersection-union rule. Each endpoint was tested at a one-sided α of 0.025, with inference based on the corresponding two-sided 95% confidence interval (CI) (two-sided α=0.05), without additional multiplicity adjustment for the joint success claim.

1. Superiority Hypothesis:

   Objective: To establish the superiority hypothesis for PCS (Physical Component Score).

   Margin of Superiority: Set at 2, based on clinically and statistically significant differences, ethical considerations, cost, and feasibility.

   Assumptions:

   Difference between groups: 7. Estimated standard deviation: 10. Confidence interval: Two-sided 95%. Power: 90%. Calculated Sample Size: 172 patients (86 per group). Dropout Rate: Anticipated at 10%. Total Sample Size Required: 190 patients (95 per group).

2. Non-Inferiority Hypothesis:

   Objective: To establish the non-inferiority hypothesis for the overall patency rate of grafts.

   Margin of Non-Inferiority: Set at 6%.

   Assumptions:

   Expected overall patency rate: 96% in both MICS-CABG and sternotomy CABG. Power: 90%. Type 1 error: One-sided, 2.5%. Reduction in MICS-CABG: 0%. Calculated Sample Size: 496 grafts (248 per group). Dropout Rate: Allows for 10% loss to follow-up. Patients Required: Based on an average of at least 2 grafts per patient, a sample size of 248 patients (124 per group) is necessary.

   Total Sample Size Required: 248 patients with equal allocation to two arms.

3. Summary:

In June 2022, the enrollment target was reassessed using data from an independent prospective cohort study conducted separately from the present randomized trial. This external dataset included 322 patients enrolled between May 2020 and April 29, 2022, and was subsequently published in JTCVS Open in 2025. The mean number of grafts per patient was 2.98 (2.9 ± 0.8 in the minithoracotomy group and 3.1 ± 0.8 in the sternotomy CABG group), and the 1-month loss to follow-up rate was 1.9% (6 of 322). These external data provided the basis for prospectively revising the enrollment target without reference to any outcome data from the ongoing randomized trial.

On this basis, 496 grafts corresponded to approximately 166 participants (range, 160 to 172 according to group-specific graft yield), which was below the 172 participants required for PCS. Together with an observed attrition of <3%, this informed the decision to amend the enrollment target to 180 participants (90 per group).

Both co-primary endpoints, the noninferiority margin, type I error, planned power, and analysis population remained unchanged. The amended calculation assumed independent grafts without an intrapatient correlation adjustment, which may overstate the nominal 90% power. Ethics approval preceded database lock, and investigators remained blinded to accumulated randomized-trial outcomes when the amendment was made

Statistical Analysis:

The primary endpoint is SF-36 PCS at 30 days and graft patency after surgery. The analysis on the primary endpoint will be conducted according to the basic principle of ITT.

For baseline characteristics, mean and standard deviation will be described for continuous data with normal distribution, while median and interquartile range (IQR) will be used to depict continuous skewed data. Frequencies and percentages will be demonstrated for categorical variables. For group comparisons, t-test will be used for normal distributed variables, Mann-Whitney U test will be applied for skewed variables, while Pearson's chi-squared test or Fisher's exact test will be conducted for categorical variables.

For the primary endpoint: For the PCS score superiority test will be adopted, while for the patency rate of the graft, non-inferiority test will be used.

For secondary endpoints, t-test will be used for normal distributed variables, Mann-Whitney U test will be applied for skewed variables, while Pearson's chi-squared test or Fisher's exact test will be conducted for categorical variables. Survival analysis will be applied for time-to-event data [time to the first major adverse cardiovascular and cerebrovascular events (MACCE) within1, 3, 6, 12 ,36 and 60 months after surgery].

Statistical significance is defined as the two-sided p-value less than 0.05. All analyses were performed using Statistical Package for the Social Sciences (SPSS) version 26.0 or Statistical Analysis System (SAS) version 9.4 or later.