Comparison of the Risk of Stroke With On- Versus Off-Pump Coronary Artery Bypass Grafting
Comparison of the Risk of Stroke With On- Versus Off-Pump Coronary Artery Bypass Grafting
This study will compare the safety of coronary artery bypass grafting (CABG) with and without
 the use of heart-lung bypass during surgery (on- versus off-pump surgery). CABG carries a
 risk of stroke and of cognition problems (problems with thought processes) that may be caused
 by small strokes. This study will use magnetic resonance imaging (MRI) to determine whether
 the newer technique of off-pump CABG carries a lower risk of stroke than on-pump CABG. The
 study will also evaluate the relative risk (the risk of stroke in CABG patients exposed to
 the following factors compared to CABG patients who are not exposed to the following factors)
 of other factors for stroke and cognitive problems, such as atherosclerosis (hardening of the
 arteries), age, sex, pre-surgery intellectual function and performance, previous stroke,
 chronic kidney failure, diabetes, high blood pressure, carotid artery disease (narrowing of
 the neck arteries to the brain), peripheral blood vessel disease, and micro embolism (tiny
 blood clots that travel to the brain).

 Patients 18 years of age and older with chest pain or narrowing of the coronary arteries who
 are scheduled to undergo CABG surgery may be eligible for this study.

 Participants will be randomly assigned to have CABG either on-pump or off-pump. They will
 undergo the following tests and procedures:

 -  Tests of cognitive and neurological function before surgery and 6 months after surgery

 -  Blood tests to look for cytokines (substances that indicate inflammation) before
 surgery, immediately after surgery and 1 day after surgery

 -  MRI scans to detect stroke before surgery, 1 day after surgery and 1 month after
 surgery.

 MRI is a diagnostic test that uses a strong magnetic field and radio waves to show structural
 and chemical changes in tissue. For the procedure, the patient lies on a table that slides
 into the scanner-a metal cylinder surrounded by a magnetic field. Earplugs are worn to muffle
 the loud knocking sounds that occur when the pictures are being taken. The scan, taken before
 surgery, will last about 20 minutes; the two after surgery take about 10 minutes to perform.
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.
-  INCLUSION CRITERIA:

 1. Age 18 years or greater

 2. Neurologically and cognitively independent prior to surgery (mRS less than 2)

 3. Patients with stable or unstable angina pectoris (Braunwald Class I-II, B) and/or
 documented ischemia due to single or multivessel disease and a normal, mild or
 moderately impaired global left ventricular function

 4. Patients who are a candidate for CABG

 5. Patients who are eligible for on-pump and off-pump CABG: Patients with single or
 multi-vessel disease in which one or more significant stenosis(es) in at least
 one major epicardial coronary artery (left anterior descending artery, left
 circumflex artery, right coronary artery, or the combination of one of the former
 and a side branch providing different myocardial territories).

 EXCLUSION CRITERIA:

 1. History of CABG

 2. Need for concomitant major surgery (e.g., valve replacement, resection ventricular
 aneurysm, congenital heart disease, vascular surgery of the carotid artery or
 thoracic-abdominal aorta) or salvage or emergency CABG

 3. Concomitant medical disorders making clinical follow-up of at least 6 months unlikely
 or impossible (e.g., neoplastic disease, hepatic failure)

 4. Q-wave myocardial infarction in the previous 6 weeks

 5. Overt congestive heart failure

 6. Hemorrhagic diathesis or hypercoagulability

 7. Any contraindication for off-pump CABG (i.e., thoracic deformities)

 8. Patients whose procedure requires no clamps (i.e., LIMA to LAD)

 9. Patients with hemodynamic instability, severe left ventricular dysfunction (ejection
 fraction less than 25%), significant cardiac enlargement, frequent arrhythmia or
 respiratory instability

 10. Carotid stenosis (greater than or equal to 60%) by magnetic resonance angiography or
 carotid Doppler

 11. Patients with a history of dementia, cognitive dysfunction (MMSE score less than 24)
 or psychiatric disorder

 12. Any MRI contraindication (cardiac pacemaker or defibrillator, insulin pump, aneurysmal
 clip, implanted neural stimulator, cochlear implant, metal shrapnel or bullet, etc)

 13. Unable to give informed consent

 14. Patients with the following intraoperative findings such as 1) hemodynamic instability
 with positioning, 2) inadequate visualization, 3) inappropriate vessels (i.e., small,
 intramyocardial), or 4) heavily calcified aorta by palpation

 INCLUSION CRITERIA FOR THE OBSERVATIONAL STUDY

 1. Age 65 years or greater

 2. Neurologically and cognitively independent prior to surgery (mRS less than 2)

 3. Patient scheduled for CABG or aortic or mitral valve replacement within one week

 EXCLUSION CRITERIA FOR THE OBSERVATIONAL STUDY

 1. Need for concomitant carotid endarterectomy

 2. Concomitant medical disorders making clinical follow-up of at least 6 months unlikely
 or impossible (e.g., neoplastic disease, hepatic failure)

 3. Patients with a history of dementia, cognitive dysfunction (MMSE score less than 24)
 or psychiatric disorder

 4. Any MRI contraindication (cardiac pacemaker or defibrillator, insulin pump, aneurysmal
 clip, implanted neural stimulator, cochlear implant, metal shrapnel or bullet, etc)

 5. Patient unable to give informed consent

 6. Participation in other research studies