Coronary Artery Bypass Surgery (CABG) Off or On Pump Revascularization Study
Coronary Artery Bypass Surgery (CABG) Off or On Pump Revascularization Study
I. Main Research Question:

 -  To compare the risks and benefits of Off-pump Coronary artery bypass surgery (CABG) to
 On-pump CABG and to determine if one is better than the other.

 -  The purpose of this pilot study is also to see the rate of recruitment with
 expertise-based randomization across different hospital settings.

 II. Small RCT studies and meta-analyses done so far have not been able to conclusively say
 which of the procedure is better. A large randomized study is required to establish the risks
 and benefits associated with both the off-pump and on-pump CABG surgical procedures.

 III. The study will look at which of the two techniques reduce major risks associated with
 CABG.
Rationale and purpose of the study:

 Coronary artery bypass grafting (CABG) surgery prolongs life-expectancy in patients with
 severe ischemic heart disease, especially those with left main, triple vessel disease or
 single/double vessel disease with stenosis of the proximal left anterior descending (LAD)
 artery. The perioperative mortality is about 2% with an additional 5% to 7% suffering
 complications such as myocardial infarction, stroke, renal failure, etc. The technique of
 operating on a beating heart (off-pump) for coronary artery bypass grafting surgery has been
 recently developed in the past few years in an effort to decrease the above perioperative
 complications typically related to cardiopulmonary bypass associated with on-pump CABG. While
 registries suggest that off-pump CABG may be superior, these data cannot fully control for
 differences in patient characteristics, which influence patient selection for specific
 procedures. The benefits of off-pump CABG compared with conventional on-pump CABG are
 unclear. The investigators therefore propose a large simple, international multicentre
 randomized controlled trial to definitively evaluate the efficacy and safety of off-pump CABG
 in the treatment of patients undergoing coronary artery surgery funded by CIHR, this pilot
 study will be a preliminary step towards a full trial.

 Sample size:

 The investigators examined the outcomes in the Canadian off-pump CABG Registry to identify a
 group of patients who represent a higher risk of cardiovascular events. Utilizing the
 inclusion criteria described below, this group of patients has accumulated the vast majority
 of outcomes in the Registry and represent more than 50% of patients in the Registry,
 therefore minimizing the sample size but still being representative. The cumulative event
 rate at 30 days (first co-primary outcome) for on-pump CABG is estimated as being 8.6% and
 the investigators expect a 33% relative risk reduction (RRR) for the off-pump CABG group. The
 sample calculated for the whole trial is 4700 patients.

 Design/Methodology:

 Trial design: This is a pilot randomized controlled trial comparing off-pump CABG versus
 on-pump CABG in 60 patients who will be undergoing isolated CABG.

 Interventions: Patients eligible for CABG will be randomized to receive either an Off-pump
 CABG surgery or On-pump CABG surgery.

 Randomization: After obtaining informed written consent patients will be allocated to either
 off-pump CABG or on-pump CABG by calling a 24-hour randomization telephone number. An
 expertise-based randomization will be used wherein a surgeon who is an expert in Off-pump
 surgery will operate on patients randomized to receive Off-pump surgery. Patients randomized
 to receive On-pump CABG will be operated on by a surgeon who is an expert in on-pump CABG
 surgery. To minimize bias stratified block randomization will used. For this pilot study
 randomization will be stratified to 3 centres and random block of 4 or 6.

 The data adjudicators will be blinded to the study. Due to the nature of intervention, the
 operating surgeon, anesthetist, perfusionist, other operation room staff, intensive-care unit
 staff will not be blinded in this study.

 Setting:

 Patients will have either been seen in the emergency, outpatient or ICU and diagnosed with
 having single, double or triple coronary artery occlusion requiring an isolated CABG.

 Study interventions:

 Interventions: Patients eligible for CABG will be randomized to receive either an Off-pump
 CABG surgery or On-pump CABG surgery. A surgeon who is an expert in the assigned technique
 will perform the procedure.

 Primary outcomes:

 -  The occurrence of the composite of total mortality, stroke, nonfatal MI, or new renal
 failure at 30 days post CABG surgery AND

 -  The occurrence of the composite of total mortality, stroke, nonfatal MI, new renal
 failure, or repeat coronary revascularization (i.e. coronary artery bypass surgery or
 percutaneous coronary intervention) over 5 years after randomization.

 The secondary outcomes

 -  The assessment of total costs and resources consumption at 30 days after CABG surgery
 AND

 -  The assessment of total costs and resources consumption at 5 years after CABG surgery

 Measurements:

 The investigators will ascertain all events of interest through periodic and regular
 follow-up utilizing standardized definitions for all events, appropriate supporting documents
 will be obtained centrally.

 -  CV death: all deaths are considered cardiovascular unless a specific non-cardiovascular
 cause is evident (e.g. malignancy).

 -  Stroke: new acute focal neurological deficit (except for subarachnoid hemorrhage which
 may not be focal) thought to be of vascular origin with signs or symptoms lasting
 greater than 24 hours.

 -  MI perioperative (within 24 hours of surgery): new pathologic Q waves with documented
 new wall motion abnormalities other than septal OR cardiac markers ³ 10 x ULN.

 -  MI non-perioperative (later than 24 hours after surgery): ECG changes consistent with
 infarction (new significant Q waves in two contiguous leads in the absence of previous
 LVH or conduction abnormalities) or evolving ST-segment to T-wave changes in two
 contiguous leads or new left bundle branch block or ST segment elevation requiring
 thrombolysis or PCI AND cardiac markers (troponins or CKMB) in the necrosis range.
 Post-PCI MI are included into non-perioperative MI group but are defined as new
 pathologic Q waves with documented new wall motion abnormalities other than septal OR
 cardiac markers ³ 3 x ULN within 24 hours of PCI.

 -  Renal failure: doubling of serum creatinine from pre-op baseline or requirement for
 renal replacement therapy (eg, dialysis, continuous hemofiltration, renal transplant).
 Hemofiltration or dialysis only during cardio-pulmonary bypass does not constitute a
 requirement for renal replacement therapy. Patients who receive dialysis within 1 month
 of the surgery are not eligible for this endpoint.

 -  Repeated coronary revascularization: new CABG procedure or PCI associated with
 documented ischemia by stress testing (ECG, ECHO, or nuclear) AND graft failure or new
 culprit lesion (³ 70% luminal stenosis).

 For other endpoints, the investigators have defined:

 -  Recurrence of angina: new or chronic onset of typical chest pain with documented
 ischemia by stress testing (ECG, ECHO, or nuclear).

 -  Blood transfusions: all blood bank products transfused within 24 hours of the CABG
 surgery.

 -  Total mortality: all causes of mortality

 Plan for data analysis:

 The intention to treat principle, in which all participants will be included in their
 assigned treatment groups regardless of adherence, will guide all analyses. In the principle
 analysis, the time to the first occurrence of one of the components of the cluster of
 (cardiac death, stroke, nonfatal MI, new renal failure) will be presented by Kaplan-Meier
 survival curves and the comparisons between the two treatment groups will be performed by a
 log-rank test. The treatment effect as measured by the hazard ratio and 95% confidence
 interval will be derived by the Cox proportional hazards model. The investigators will also
 calculate the absolute risk reductions and the associated 95% confidence intervals, as well
 as the number needed to treat (NNT) with off-pump CABG to prevent one major cardiovascular
 event. Participants who prematurely discontinue follow-up before a major cardiovascular event
 will be censored as to their last follow-up data; this number is expected to be <1% given the
 relatively short period of follow-up after surgery.

 In secondary analyses the investigators will determine and compare the incidence of major
 cardiovascular events (cardiac death, stroke, nonfatal MI, new renal dialysis) and
 revascularization procedures (i.e. coronary artery bypass surgery and percutaneous coronary
 intervention) using the same strategy. The effect of the two operative techniques on
 different sub-groups (i.e. patients with diabetes, renal failure, congestive heart failure,
 cerebrovascular disease, as well as patient left ventricular function, gender and ages will
 be conducted by stratified analysis through a Cox proportional hazards model. The test of
 interaction between each subgroup factor and the treatment group will be done by including a
 product term in the model already containing treatment and the subgroup factor. The length of
 hospital stay and length of ICU/CCU stay will be compared using a student's t-test. An events
 adjudication committee (blind to surgical allocation) will centrally review all suspected
 major outcomes listed above.

 The investigators will also do subgroup analysis on different sub-groups (i.e. patients with
 diabetes, renal failure, congestive heart failure, cerebrovascular disease, as well as
 patient left ventricular function, gender and ages will be examined for consistency and
 coherence)
Inclusion Criteria:

 Patients who have been diagnosed with coronary artery disease (single, double or triple
 disease) will be eligible if they:

 1. require isolated CABG with median sternotomy

 2. are able to give their informed written consent

 3. are> 21 years of age and

 4. have one or more of the following risk factors:

 -  ≥ 70 years

 -  peripheral vascular disease (previous peripheral bypass or amputation or ABI
 <0.80)

 -  Cerebrovascular disease (history of stroke, TIA)

 -  Renal insufficiency (creatinine above upper limit of normal)

 -  >60 years of age and one of the following:

 -  diabetes (oral hypoglycemic agent and/or insulin)

 -  urgent revascularization (waiting in hospital)

 -  LV ejection fraction <35%

 -  current or recent smoker.

 -  55-59 years of age and two of the following:

 -  diabetes (oral hypoglycemic agent and/or insulin)

 -  urgent revascularization (waiting in hospital)

 -  LV ejection fraction <35%

 -  current or recent smoker.

 Exclusion Criteria:

 Patients will be excluded if they have one of the following:

 1. concomitant cardiac procedure associated with CABG,

 2. contra-indications to off-pump CABG or on-pump CABG (calcified aorta, intramuscular
 LAD, calcified coronaries, small target vessels)

 3. concomitant life-threatening disease likely to limit life expectancy to less than 2
 years,

 4. prior enrollment in this trial

 5. emergency CABG surgery (immediate revascularization for hemodynamic instability) OR

 6. redo CABG.