Study setting {9}
The study will be undertaken in the Department of Surgery, Fuwai Hospital, Chinese Academy of Medical Sciences, with an amount of isolated CABG over 4000 cases annually. Data will be collected both in hospital ward and outpatient clinic during follow-ups. A web-based and paperless data submission system (http://ccsr.cvs-china.com) for the study has been set up.
Eligibility criteria {10}
Inclusion criteria
Patients aged 18 or older who undergo primary isolated open-chest CABG with two vein grafts, one to the left coronary territory and the other to the right, with or without cardiopulmonary bypass.
Exclusion criteria
- Concomitant cardiac or vascular surgeries (i.e. valve repair or replacement, Maze surgery)
- Redo CABG
- Emergent CABG (cardiogenic shock, inotropic pressure support, IABP)
- Severe vein varicosity as assessed after vein harvesting and before randomization
- Use of vascular stapler for anastomosis
- Endarterectomy of coronary artery during surgery
- Left ventricular repair due to ventricular aneurysm
- Concomitant life-threatening disease likely to limit life expectancy to less than two years
- Severe renal insufficiency (i.e. creatinine >200 μmol/L)
- Contraindications for dual antiplatelet therapy, such as active gastroduodenal ulcer
- Participant of other ongoing clinical trials
All surgical procedures will be expected to complete by qualified surgeons who have performed at least 100 CABGs. Vein harvesting will be done by qualified senior residents. We identify senior residents who have performed at least 100 cases of vein harvesting in CABG and give them standard training of No-Touch vein harvesting. When they perform at least 50 cases of No-Touch vein harvesting, they are evaluated by two independent training surgeons to be qualified for vein harvesting.
Interventions
Intervention description {11a}
Surgical Procedure
Anesthetic technique and method of myocardial protection are left to individual anesthesiologists and perfusionists to decide. All patients undergo either off-pump or on-pump CABG at the surgeons’ discretion on the basis of anatomic and clinical findings.
For the No-Touch vein harvesting technique in our study, two longitudinal incisions are made on the thigh and the shank from unilateral lower limb (for harvesting of the proximal segment of saphenous vein, incision is started from about 3 or 4cms inferolateral to the pubic tubercle and then extended downward). As previously reported [11, 15], the adventitia and perivascular tissues are carefully kept intact to avoid damage. Then a margin of about 5 mm from both sides of the vein is created to include the fat pedicle using electrocautery, and all visible side branches are ligated with 4-0 silk or by metal clipping (branches are divided at the pedicle margin rather than the vein trunk). The saphenous vein is then separated from its bed using scissors and the electrocautery, together with the surrounding tissue. The vein is left in situ and covered with a saline-moistened gauze until systemic heparin is administered and graft anastomosis is ready. After removal, a small adaptor is inserted into the open distal end and secured with a ligature. The pedicled vein is stored in saline solution to which heparin (2500U) and papaverine (30mg) have been added. Since heparinized blood cannot be easily obtained during off-pump CABG, we use heparinized saline with papaverine rather than heparinized blood to store vein grafts for patients undergoing either off-pump CABG or on-pump CABG. Forced distension or flushing using a syringe is strictly prohibited. Before each anastomosis, side branches of the vein are checked by the operator and re-clipped. After proximal anastomosis is completed, each graft is re-checked for leakage due to undiscovered branches or invalid clipping and re-clipped if necessary.
Leg incisions are closed with continuous suture for both two groups. Remaining coronary bypassing techniques are according to the clinical practice of the hospital and the preference of the operators. Before chest closure, mean flow values and pulsatile index are obtained with transit-time flow measurement (Medi-stim Butterfly flowmeter, Medi-stim AS, Oslo, Norway). If mean flow value is less than 10 ml/min, or pulsatile index is greater than 5.0, or any possible graft kinking or compression is detected, the anastomosis is redone.
An intraoperative paper questionnaire is answered by the operator after completion of the surgery, to evaluate the quality of each vein graft. Vein quality is classified as good, moderate, or poor, according to whether there is varicose or aneurysmal dilatation, inflammatory wall thickness, focally thinned wall, or too-small diameter.
Although ultrasonic mapping is reported to help prevent unnecessary incision and large skin flaps [8, 16], it is not commonly used in clinical practice in China. Based on our experiences, well-trained surgeons with sufficient qualifications can harvest the veins with No-Touch technique without ultrasonic mapping. Ultrasonic mapping is not adopted in this study.
Criteria for discontinuing or modifying allocated interventions {11b}
Not applicable.
Strategies to improve adherence to interventions {11c}
Not applicable.
Relevant concomitant care permitted or prohibited during the trial {11d}
Medication
All participants are prescribed dual antiplatelet therapy with aspirin 100mg plus clopidogrel 75mg daily from the first day post-CABG until 3 months post-operation. Prescription of other concomitant medications such as β-blockers, nitrates, statins, and antihypertensive agents, is determined by local surgeons according to ACC/AHA guidelines [17].
Outcomes {12}
Primary endpoint
Major leg wound complication at 6 days postoperatively.
Major leg wound complication is defined as a leg wound that has failed to respond to conservative treatment and required subsequent surgical interventions, such as debridement, re-suture, and delayed wound closure.
Secondary endpoint
- Major leg wound complication during 3 months after the surgery.
- Graft vessel occlusion at 3 months and 1 year after the CABG (determined by multislice computed tomography angiography (MSCTA)).
Graft occlusion is identified by MSCTA. Graft assessment is carried out according to the FitzGibbon criteria [18]. Each graft is graded as A (excellent), B (fair), or O (occluded). Contrast filling of the grafts, anastomoses, and coronary arteries beyond the graft are considered in each assessment. Grade A indicates that the graft is patent with ≤50% stenosis. Grade B indicates that graft stenosis is >50% but not occluded. When a conduit does not fill with contrast at all, it is considered Grade O and included with string sign found in any segment (including proximal anastomotic site, distal anastomotic site, and main trunk). Both of these latter findings are considered together and referred to as occlusion in the analysis.
Clinical events
- Major adverse cardiac or cerebrovascular events (MACCE, including cardiovascular death, non-fatal myocardial infarction (MI), stroke and target vessel revascularization) at 3 months and 1 year after the CABG.
- Individual MACCE, including cardiovascular death, non-fatal MI, stroke and target vessel revascularization at 3 months and 1 year after surgery.
- Recurrence of angina
All clinical events including myocardial infarction, stroke, target lesion revascularization, and death will undergo central adjudication by an independent clinical events committee (CEC) according to pre-specified criteria. Definition of clinical events used in adjudication is shown in Additional file 2
Participant Timeline {13}
Participant time line is shown in Fig. 1, and flowchart of the study is shown in Fig. 2
Sample size {14}
As a pilot trial, the primary consideration for the sample size is the ability to inform the feasibility of a full-scale study. We propose a sample size of 100 vein grafts in each group with a total of 100 patients.
Recruitment {15}
Not applicable.
Assignment Of Interventions: Allocation
Sequence generation {16a}
A web-based central randomization system incorporated in the registration system is used for allocation (http://ccsr.cvs-china.com/). The randomization code with fixed block size is generated by SAS.
Concealment mechanism {16b}
Not applicable.
Implementation {16c}
Enrollment of participants are performed by investigators. Each patient will be in an individual discussion with an investigator. The nature of the study and the procedure to be conducted will be explained in a way that is not difficult to comprehend. When an eligible patient signs informed consent, the investigator logs in to the randomization webpage, and obtains the random number along with the proximal group (left or right coronary territory), automatically distributed by the system after the basic patient information was confirmed. The statistician who is responsible for the randomization code and the staff that develops the Interactive Web-based Response (IWR) system, are independent of each other.
Assignment Of Interventions: Blinding
Who will be blinded {17a}
Due to the nature of this surgery-based study, the investigators, CABG operators and vein harvesting surgeons will not be blinded. Participants will be blinded about which coronary territory his or her proximal vein segment is bypassed to during post-operative assessment and follow-up visit. Radiologists in charge of graft occlusion determining will also be blinded to the randomized allocation of each vein graft.
Procedure for unblinding if needed {17b}
Not applicable.
Data Collection And Management
Plans for assessment and collection of outcomes {18a}
A summary of the follow-up is shown in Table 1
A postoperative questionnaire regarding leg wound condition is filled before patient discharge and during follow-up visit. Visual Analogue Scale [19] is used for evaluation of leg pain, and other wound healing disturbances including surgical debridement or re-suture, hematoma, persistent exudation, numbness of the skin, and leg edema were recorded. The Questionnaire and definitions are presented in Additional file 3.
We collect relevant anatomical characteristics, e.g., sites of proximal and distal anastomosis, graft type and quality, proximal lesion stenosis rate, graft flow and pulsation index, application of sequential anastomosis. As to sequential anastomosis, one failure of distal anastomosis will be considered occlusion of the sequential graft. Coordinators and investigators are required to submit complete in-hospital data within 14 days of discharge. The study adheres to a rigorous standard for medical record transmission and data abstraction, similar to the previously published China Patient-Centered Evaluative Assessment of Cardiac Events (China PEACE)-Retrospective Acute Myocardial Infarction Study and the Percutaneous Coronary Intervention Study [20, 21].
Clinic visits are required. Study coordinators will telephone participants to recall the scheduled date of return to the hospital. The 100 randomized patients will undergo predefined clinical follow-ups at 3 months and 12 months post-procedure. Two designated attending surgeons will inspect patients’ leg wound healing at 3-month visit. MSCTA is to be performed, and image discs will be assessed by a central Core Laboratory. The results of MSCTA are independently reviewed by 2 radiologists blinded to patients’ randomized allocation. Discrepancies in occlusion judgement are reviewed by a third radiologist and resolved by consensus. At each follow-up visit, all current medications and events since the last visit are recorded and compared between the two groups. A full list of classifications of data content can be seen in Additional file 4.
Table 1
| Pre-op | Intra-op | 6th day Post-op | 3-month clinic visit (+ 1 m) | 12-month clinic visit (+ 3 m) |
Baseline characteristics | √ | | | | |
Clinical history | √ | | | | |
Physical exam | √ | | | √ | √ |
Medications | √ | | √ | √ | √ |
Operation details | | √ | | | |
Graft quality assessment | | √ | | | |
Leg wound assessment | | | √ | √ | |
MSCTA | | | | √ | √ |
Clinical events | | | | √ | √ |
Plans to promote participant retention and complete follow-up {18b}
1.The 3-month and 12-month follow-ups are routine practice of the hospital. The study does not prescribe extra costs of patients.
2.The investigators and study coordinators will keep in close touch with all the participants by establishing a Wechat group chat, which is the most popular mobile social software in China.
Data management {19}
A web-based and paperless data submission system (http://ccsr.cvs-china.com) for the study has been set up. For web-data transmission, a high-level secure socket layer is adopted. For in-hospital data collection, 12 modules have been set (preoperative saphenous vein screening, patient basic information, preoperative risk factors, cardiovascular presentation, tests and examinations, general information of operation, record of CABG, post-operative complications, preoperative medications, medication prescriptions at discharge, 3-month follow-up results and 12-month follow-up results) with over 300 items. Double-entry of data is required by designated study coordinators. All web-based records will be exported monthly for range checks of values by investigators.
Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}
Not applicable. No biological specimens will be collected.
Statistical Methods
Statistical methods for primary and secondary outcomes {20a}
The trial data will be analyzed on an intention-to-treat basis of patients included in the groups assigned to randomization, irrespective of future management and events. Any intentional or unintentional deviation from the study protocol should be documented and explained in the data collecting system. Demographic, clinical variables, in-hospital death, postoperative complications, follow-up death, and MACCE will be summarized as means (SDs) for continuous and counts (percentages) for categorical variables. A generalized-estimate-equation model will be used to estimate treatment effects on the graft level wound complications and occlusion analysis, to account for the cluster effect of grafts from the same patient. A P value of less than 0.05 will be considered as statistically significant for all analyses.
Interim analyses {21b}
Interim analysis will be carried out when 50% of subjects finish their scheduled follow-up, according to the charter of the data safety monitoring board (DSMB).
Methods for additional analyses (e.g. subgroup analyses) {20b}
Considering leg wound complications may be a function of baseline characteristics. We plan to compare the odds ratio of leg wound complications based upon different risk groups, such as male vs, female, BMI<30 vs. BMI≥30, diabetic vs. nondiabetic, smoking vs non-smoking, with vs. without peripheral artery disease. We also plan to conduct subgroup analysis by comparing odds ratios of graft occlusion and different vein graft qualities. An intraoperative questionnaire (see Additional file 3) for evaluation of the graft quality is required to be answered by the operators. Graft quality is stratified as good, moderate, or poor, according to the presence of side branch tears, inflammatory wall thickness, or signs of varicosity [22]. Subgroup analysis will be performed using generalized-estimate-equation models.
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
We consider the missing data of the primary endpoint to be minimal. If any, missing data will be handled via worst observation carried forward (WOCF).
Plans to give access to the full protocol, participant level-data and statistical code {31c}
Not applicable.
Oversight And Monitoring
Composition of the coordinating centre and trial steering committee {5d}
The role of the trial steering committee (TSC) is to monitor and supervise the progress of the study. Members of TSC are listed in Table 3. The TSC will meet prior to the start of the trial and then once every two weeks.
Table 3
Trial Steering Committee membership
Name | Role | Title | Affiliation |
Professor Shengshou Hu | Co-Principal Investigator Lead Surgeon Trial Advisor | President of Fuwai Hospital. Professor of cardiovascular surgery | Fuwai Hospital |
Professor Xianqiang Wang | Co-Principal Investigator | Professor of cardiovascular surgery | Fuwai Hospital |
Professor Liqing Wang | Surgeon | Professor of cardiovascular surgery | Fuwai Hospital |
Yang Wang. PhD | Statistician Trial Advisor | Director of Statistics Medical Research & Biometrics Center | Fuwai Hospital |
Dr Meice Tian | Principal Investigator | Surgeon of Fuwai Hospital. Professor of cardiovascular surgery | Fuwai Hospital |
Dr Zhihui Hou | Radiologist | Deputy director of Department of Radiology | Fuwai Hospital |
Composition of the data monitoring committee, its role and reporting structure {21a}
An independent data safety monitoring board (DSMB) is established before the start of recruitment. There is no pre-specified stopping rule for the primary efficacy endpoint, so there is no need to adjust the type I error rate. The DSMB members will suggest whether the study should be stopped due to unexpected risk of patients. If the safety signal is acceptable, the study will continue to the planned recruitment number and data analysis will be built on the entire population. Members of DSMB are listed in Table 4
Table 4
Data Safety Monitoring Board membership
Name | Role | Title | Affiliation |
Professor Hansong Sun | Chairman | Professor of cardiovascular surgery | Fuwai Hospital |
Professor Jing Li | Vice-chairman | Director of Clinical Trial Center | Fuwai Hospital |
Professor Jian Zhang | Vice-chairman | Consultant Cardiologist | Fuwai Hospital |
Professor Wei Li | Statistician | Director of Medical Research & Biometrics Center | Fuwai Hospital |
Adverse event reporting and harms {22}
An independent clinical events committee (CEC) will review adverse events during the study and adjudicate them to ensure the events comply with the pre-specified definitions. All events will be independently adjudicated by two members of CES. Discrepancies in event judgement will be reviewed by a third committee member and resolved by consensus. CEC members will be blind to the knowledge of which arm of the trial the vein segments are in.
Frequency and plans for auditing trial conduct {23}
Not applicable.
Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}
Not applicable.
Who will take informed consent? {26a}
Study investigators will take informed consent from patients after individual discussion about the nature of the procedure to be conducted.
Additional consent provisions for collection and use of participant data and biological specimens {26b}
Not applicable.
Confidentiality {27}
Only study investigators, coordinators and network technicians have access to the patient information. Exported records will use encryption to avoid unauthorized reading.
Availability of data and materials {29}
Not applicable.
Provisions for post-trial care {30}
The investigators will touch with participants regularly through telephones, and continue to follow-up these patients at 5 years and 10 years postoperatively.
Dissemination plans {31a}
Not applicable.