Clinical trial NCT04795193: Efficacy and Safety of Minimal Invasive Coronary Surgery in Patients With Complex Coronary Artery Lesions
Official title: Randomized Clinical Trial on Efficacy and Safety of Minimal Invasive Coronary Artery Bypass Grafting in Patients With Complex Coronary Artery Lesions
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Coronary Artery Bypass, Off-Pump
Keywords: Coronary Artery Bypass, Off-Pump
Minimally Invasive Surgical Procedures
Coronary Artery Bypass
Lead sponsor: Peking University Third Hospital
Sponsor class: OTHER
First posted: 2021-03-12
Enrollment: 200
Sex: ALL
Minimum age (years): 25
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The aim of this study is to investigate and compare the mid-term safety and efficacy end-points \[medical outcomes study-short form 36-item (SF-36) physical component summary (PCS) at 30 days after surgery, etc.\] in patients with complex coronary artery lesions \[an indication of off-pump coronary artery bypass surgery (OPCAGB)\] who received minimal invasive coronary surgery (MICS)-CABG and those who received thoracotomy OPCABG. The investigators hypothesize that patients in MICS-CABG group have superior clinical demonstrations regarding the primary endpoint than those in OPCAGB group without increased adverse outcomes. A total of 200 eligible patients are planned to be randomized to MICS-CABG or OPCABG group with an allocation ratio of 1:1. The primary endpoint is SF-36 PCS at 30 days after surgery. The analysis on primary endpoints will be conducted according to the basic principle of intention-to-treat (ITT).

Detailed description: 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 clinical demonstrations regarding the primary endpoint than those in OPCAGB group without increased adverse outcomes.

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. The allocation table will be concealed from researchers during research process.

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:

According to previous studies and reports, the average SF-36 PCS was 43 with a standard deviation of 10 at 30 days after OPCABG. Through preliminary studies, the average SF-36 PCS at 30 days after MICS-CABG was 50. The minimum clinically important difference of SF-36 PCS was 2 according to previous publications. Assuming that the lower limit of 95% confidence interval of PCS score difference between MICS-CABG group and OPCABG group is greater than 2, it is considered that the PCS score of MICS-CABG group is better than OPCABG group, with inspection level α=0.025 (one side) and inspection efficiency 1-β=0.80. The sample size of OPCABG group and MICS group is calculated to be 64 cases, with an estimated drop-out rate of 10%, and each group needs to include at least 72 people. Based on the above conclusions, the investigators calculated sample size is 100 cases in each group.

Statistical Analysis:

The primary endpoint is SF-36 PCS at 30 days 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, the difference of SF-36 PCS at 30 days after surgery between two groups with 95% confidence interval (CI) will be calculated. If the lower limit of 95%CI is greater than 2, the superiority of MICS-CABG will be established.

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 \[time to the first major adverse cardiovascular and cerebrovascular events (MACCE) within1, 3, 6, and 12 months after surgery\].

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.

Eligibility criteria: Patients are planned for undergoing off-pump coronary artery bypass surgery.

Inclusion Criteria:

* Angina that affects daily life and work and uncontrollable with conservative treatment
* Significant stenosis in left main (LM) coronary artery or LAD branch or left circumflex (LCX) branch\>70%
* Severe stenosis (stenosis degree\>75%) of three main branches of coronary artery (anterior descending branch, circumflex branch, right coronary artery) with need of undergoing off-pump coronary artery bypass surgery

Exclusion Criteria:

* Unstable preoperative hemodynamic status requiring emergency surgery
* Severe emphysema, hypoxemia \[post-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC)\<70% and FEV1%predicted\<50% or partial pressure of oxygen (pO2)\<60 mmHg or partial pressure of carbon dioxide (pCO2)\>40 mmHg without oxygen therapy\]
* Old large area myocardial infarction, no viable myocardium based on isotope and echocardiography examination, significant cardiac enlargement, cardiothoracic ratio\>0.75, EF\<30%, left ventricular diastolic diameter (LVDd)\>60 mm, left ventricular aneurysm or severe arrhythmia, prone to experience unstable preoperative hemodynamic status during surgery
* Severe pleural adhesion, chest deformity, or previous thoracic radiotherapy
* Previous open heart surgery
* Simultaneous valve or other cardiac surgery
* Planned cardiopulmonary bypass surgery
* Poor condition of myocardial infarction (MI), extensive lesion, distal or entire diffuse stenosis, or inability to match lumen due to small diameter (\<1.0 mm) or severe calcification
* Others: Terminal cancer, uncontrolled infection, bleeding, progressive degenerative systemic disease, severe brain injury, multiple organ failure and other major organ dysfunction such as severe liver dysfunction, severe heart failure or cardiogenic shock, intolerance to surgery, and other contraindications of CABG

Primary outcomes:
measure: Physical component summary (PCS) of medical outcomes study-short form 36-item (SF-36) scores at 30 days after surgery
timeFrame: 30 days after surgery
Secondary outcomes:
measure: Perioperative transfusion volume
timeFrame: Intraoperative and 14 days after surgery
measure: Incidence of cardiopulmonary bypass conversion
timeFrame: 14 days after surgery
measure: Percentage of intra-aortic balloon pump (IABP) and extracorporeal membrane oxygenation (ECMO) usage
timeFrame: 14 days after surgery
measure: Incidence of secondary surgery
timeFrame: 14 days after surgery
measure: Incidence of adverse events of wound healing
timeFrame: 14 days, 1 month, 3 months, 6 months and 12 months after surgery
measure: Percentage of perioperative graft patency (evaluated by CT or angiography)
timeFrame: 14 days after surgery
measure: Incidence of perioperative major adverse cardiovascular and cerebrovascular event (MACCE)
timeFrame: 30 days after surgery
measure: Incidence of atrial fibrillation
timeFrame: 30 days after surgery
measure: Incidence of renal failure
timeFrame: 30 days after surgery
measure: Incidence of re-intubation
timeFrame: 14 days after surgery
measure: Length of stay after surgery (days)
timeFrame: 14 days after surgery
measure: Intensive care unit (ICU) duration after surgery (hours)
timeFrame: 14 days after surgery
measure: Duration of mechanical ventilation application (hours)
timeFrame: 14 days after surgery
measure: Physical component summary (PCS) of medical outcomes study-short form 36-item (SF-36) scores
timeFrame: 7 days, 3 months, 6 months and 12 months after surgery
measure: Mental component summary (MCS) of medical outcomes study-short form 36-item (SF-36) scores
timeFrame: 7 days, 1 month, 3 months, 6 months and 12 months after surgery
measure: Physical limitation score of Seattle angina questionnaire (SAQ)
timeFrame: 1 month, 3 months, 6 months and 12 months after surgery
measure: Angina stability score of Seattle angina questionnaire (SAQ)
timeFrame: 1 month, 3 months, 6 months and 12 months after surgery
measure: Angina frequency score of Seattle angina questionnaire (SAQ)
timeFrame: 1 month, 3 months, 6 months and 12 months after surgery
measure: Treatment satisfaction score of Seattle angina questionnaire (SAQ)
timeFrame: 1 month, 3 months, 6 months and 12 months after surgery
measure: Disease perception score of Seattle angina questionnaire (SAQ)
timeFrame: 1 month, 3 months, 6 months and 12 months after surgery
measure: Time to the first major adverse cardiovascular and cerebrovascular event (MACCE) after surgery
timeFrame: 1 month, 3 months, 6 months and 12 months after surgery
measure: Incidence of readmission due to myocardial infarction (MI)
timeFrame: 1 month, 3 months, 6 months and 12 months after surgery
measure: Incidence of readmission due to heart failure
timeFrame: 1 month, 3 months, 6 months and 12 months after surgery
measure: Percentage of mid-term graft patency (evaluated by CT or angiography)
timeFrame: 12 months after surgery
Other outcomes:
Locations:
city: Beijing
country: China
facility: Peking University Third Hospital
state: Beijing
Study officials:
affiliation: Peking University Third Hospital
name: Yunpeng Ling, Doctor
role: STUDY_CHAIR
affiliation: Peking University Third Hospital
name: Yichen Gong, Doctor
role: PRINCIPAL_INVESTIGATOR
References: