Comparison of the Risk of Stroke With On- Versus Off-Pump Coronary Artery Bypass Grafting

Objective - Off-pump coronary artery bypass grafting (CABG) is hypothesized to be a safer alternative to conventional on-pump CABG, but the comparative risks and benefits of the procedures for neurological outcomes have not been established by prospective randomized testing. The primary objective of this study is to assess the difference in frequency of new ischemic brain lesions in patients randomized to either on- or off-pump CABG. We will test the hypothesis that off-pump CABG is associated with a smaller proportion of patients with new lesions on MRI post-operatively. Secondary objectives will explore the relationship of other imaging markers, blood markers, and results of cognitive testing to the occurrence of new ischemic lesions, and estimate the relative risk of pre-operative factors. We will also conduct an observational substudy of non-randomized heart surgery patients acquiring complementary data to estimate the relative risk of pre-operative and operative factors for the occurrence of new ischemic lesions.

Study population - A total of 140 patients (70 per each group) will be randomized. Subjects will be neurologically independent adult patients undergoing non-emergency CABG who are appropriate for either on- or off-pump surgery. In the observational study we will also assemble a cohort of 100 consecutive patients that will have CABG and 100 consecutive patients that will have valve replacement surgery. Total accrual across both studies will be 340 patients.

Design - The study has a prospective randomized single blinded design. Patients will be randomized to on- or off-pump surgical technique if they meet all eligibility criteria. Analyses will be performed blinded to the surgical group assignment and based on intention-to-treat principle. MRI evaluation will be performed prior to surgery, 48 hours after surgery, 30 days and 6 months after surgery. Biomarkers will be quantified in blood drawn before and immediately after surgery and 6, 24, 48 and 72 hours post-operatively. Cognitive testing will also be performed 30 days and 6 months after surgery. Interim analysis after each 20 patients will be performed up to the first 100 patients, with stopping rules if a highly significant difference is observed on the primary outcome variable. Patients randomized but who have no post-operative scan and have no clinical evidence of post-operative stroke will not be included in the sample for the primary analysis. Patients in the observational substudy will undergo the same pre- and post-operative evaluations as patients in the RCT.

Outcome measures - The primary outcome measures are evidence of new ischemic lesions on 48-hour DWI or 30-day DWI or FLAIR, or clinical evidence of new stroke if protocol required scans are not performed, determined at 30 days after surgery. The proportion of patients in each group with primary outcome variable will be tested by a chi-square for proportions. Secondary imaging outcome variables will include the number of new lesions, and the total volume of new ischemic lesions. Secondary outcome measure include all cause mortality, encephalopathy, 30-day and 6-month cognitive decline, evidence of reperfusion injury on 48-hour post-gadolinium FLAIR, new ischemic lesions on 6-month DWI or FLAIR, and changes in values of blood markers. The relationships among new ischemic lesions, cognitive decline, and changes in blood markers will be explored. The association of baseline variables to the prediction of new lesions will be explored using multivariate logistic regression procedures.