Randomized control trial study design
Given the paucity of randomized evidence available to guide surgeons in choosing the best grafting strategy for their patients, the present study was designed as a pilot prospective randomized controlled trial comparing total arterial grafting (TAG) to conventional grafting using a LIMA to the LAD and saphenous vein grafts for the other territories (LIMA+SVG) in patients undergoing non-redo isolated CABG.
Patients were excluded from enrolment if they were scheduled to undergo emergent surgery, single vessel bypass surgery, had received a prior CABG or displayed evidence of varicose veins on pre-operative physical examination. In addition, patients with a documented history of chest radiotherapy, allergy to contrast media and renal insufficiency (defined by serum creatinine > 176 μmol/L), were also excluded.
Informed consent was obtained from all patients in accordance with our institutional research ethics review board guidelines (Randomized Controlled Trial number: ISRCTN80270323). Once the patient had consented, he or she was randomized prior to entering the operating room. The randomization process was performed using random permuted blocks with varying block sizes of 4, 6 and 8. Numbered index cards were placed in sealed, opaque envelopes and stored safely with the research coordinator. Consented patients were randomized prior to surgery, and the surgeon opened the envelope in the operating room before starting the case. The index card indicated whether the patient was to be randomized to TAG or LIMA+SVG. If the surgeon decided intra-operatively that the patient could not undergo the procedure to which he or she was randomized, the patient was offered the revascularization strategy most likely to afford the patient the best possible outcome. If the patient required a concomitant cardiac procedure (e.g. valve replacement or repair) or could not undergo a revascularization procedure with a minimum of two distal bypasses, the patient was excluded from the study.
The primary objectives of our pilot study were to evaluate the feasibility of a larger randomized trial in current cardiac surgical practice in which individual surgeon preferences have been suggested to play a large role in choosing grafting strategies . Feasibility was defined as our ability to recruit more than 20% of eligible patients and assess completion of CT-coronary angiography in greater than 80% of patients at 6 month follow-up.
The secondary objectives of the study were to compare postoperative graft patency and in-hospital mortality and morbidity. In addition the quality of graft imaging was also examined. All analysis was performed on an intent-to-treat basis. The treating team and patients were not blinded to the treatment allocation. However, CT-coronary angiograms were reviewed in a blinded manner by a single radiologist.
All interventions were performed via a midline sternotomy, and cardiopulmonary bypass was utilized in a standardized manner for all cases. Body temperature during the procedure was allowed to drift briefly to 32°C. Intermittent cold blood cardioplegia solution was delivered anterograde via the aortic root unless otherwise indicated. Arterial conduits were harvested with minimal trauma (LIMA and RIMA were not skeletonized) and were treated with either a papaverine solution or a nitroglycerine/calcium channel blocker (verapamil) solution prior to their use. TAG was defined as the use of any arterial conduit (LIMA, RIMA or radial artery), either alone or in combination, without concomitant use of SVG. The choice of conduit and the manner in which the grafts were constructed, including composite T- or Y-grafts, proximal aorto-coronary anastomoses or sequential anastomoses, was based entirely on surgeon preference rather than on any fixed criteria such as territory to graft or degree of target vessel stenosis. LIMA+SVG was defined as any case in which the LIMA was used for a single bypass to the LAD and SVGs were used for the remaining bypasses, constructed as either a series of sequential anastomoses or as single bypasses and were anastomosed proximally to the aorta.
Post- operative management
All study patients received postoperative intravenous nitroglycerine infusions for the first 24 hours upon return from the operating room unless hypotensive (systolic blood pressure < 90 mm Hg). Other routine post-operative medications included daily aspirin as well as resumption of cholesterol lowering agents, B-blockers and angiotensin converting enzyme inhibitors as appropriate.
All study patients received CT angiography 6 months post CABG. This was performed on a 64 slice multi-detector CT scanner (Siemens Sensation 64, Erlangen, Germany), using the following scan parameters: 330 ms gantry rotation, detector collimation 32 × 0.6 mm (with a rapidly alternating focal spot resulting the acquisition of 64 slices per gantry rotation with effective special resolution of 0.4 mm), tube voltage 120 kV, maximum obtainable tube current (800 – 900 mAs) scanning in a caudo-cranial direction. Retrospecive ECG gating was used with ECG pulsing such that full tube current was applied between 50% and 80% of the cardiac cycle, and reduced to 40% during the remainder. One hundred mL of contrast agent (Isovue 370, Bracco, Italy) was injected into a right antecubital vein via an 18-guage cannula at a flow rate of 5 mL/s, followed by 40 mL of normal saline bolus chaser at a rate of 5 mL/s. All patients with heart rate >65 beats per minute, unless contra-indicated, received beta blocker in the form of 50 mg oral metoprolol, 0.2 micrograms of sublingual glycerol trinitrate, plus or minus 1–2 mg oral lorazepam prior to being scanned in order to reduce heart rate and maximize the lumen diameter of the coronary artery bypass grafts. Axial data sets with a slice thickness 0.75 mm and slice interval 0.6 mm, were reconstructed using a medium smooth reconstruction kernel (B30f) at the following intervals during the cardiac cycle (20%, 55%, 60%, 65%, 70%, 75%). Further datasets from different time intervals or at a sharper reconstruction kernel (B46f) were reconstructed at the interpreting radiologist’s discretion. Interpretation of all CT angiograms was performed by a single level 3 trained cardiac radiologist who was blinded to the treatment allocation.
Each bypass graft was assessed for image quality with graft visualization determined as excellent, diagnostic or non-diagnostic. The presence or absence of artifact was noted with the following categories: none, clip, rhythm, respiratory motion and other. Heart rate and heart rhythm during the CTA acquisition were recorded.
Each bypass graft for which visualization was determined not to be non-diagnostic was visually assessed using axial data, multi-planar reformats and curved planar reformats as per Society of Cardiovascular Computed Tomography guidelines and assigned to one of three categories: Occluded (defined as any focus where there was complete lack of luminal contrast), luminal stenosis of greater than 50%, or patent (no luminal stenosis greater than 50%) .
The Maritime Heart Center (MHC) Cardiac Surgery Registry captures pre-operative, intra-operative and in-hospital post-operative clinical variables including mortality and morbidity for all patients undergoing cardiac surgery at the QEII Health Sciences Centre in Nova Scotia, Canada. Pre-operative variables included age, sex, body mass index (BMI), smoking history, diabetes, hypercholesterolemia, hypertension, peripheral and/or cerebrovascular disease, chronic obstructive pulmonary disease, left ventricular ejection fraction (EF), myocardial infarction within 21 days prior to surgery, urgency of surgery (urgent patients required surgery within 24 hours, in-house patients were waiting in-hospital, elective patients were waiting at home), prior percutaneous coronary intervention, left main stenosis >50%, and number of diseased vessels. In-hospital outcomes included all-cause mortality, stroke (neurological deficit persisting at time of hospital discharge), peak troponin T, deep sternal wound infection, mechanical ventilation >24 hours, and postoperative length of stay in hospital >9 days. Aortic cross-clamp time was also reported.
The TAG and LIMA+SVG groups were compared using Chi-square or Fisher’s exact tests for categorical variables, two-tailed t-tests for continuous variables that were normally distributed, and Wilcoxon rank sum tests for continuous variables that did not have a normal distribution.
One of the primary objectives was > 20% recruitment of patients into the randomized trial. Patient eligibility was based on inclusion and exclusion criteria and assignment to participating surgeons. This allowed for the creation of a predictive model capable to identify factors that predicted use of TAG. Design variables were created for reference level coding of categorical variables with more than two levels. For the multivariable analysis, candidate variables were selected based on clinical relevance or a significance of bivariate association with p value <0.2. A non-parsimonious logistic regression model was developed to identify the predictors of receiving TAG. The area under the receiver operating characteristic (ROC) curve was used to assess predictive accuracy of the model. A bootstrap procedure was used to obtain 1000 subsamples with replacement. The 2.5th and 97.5th percentiles of the bootstrap distribution were then used to determine the 95% Confidence Interval (CI) of the ROC.
All statistical analyses were performed using the SAS software package version 9.2 (SAS, Cary, North Carolina).