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.

- 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