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Study Aims
The main objective is to assess whether the use of both IMA during CABG (BIMA) improves survival and reduces the need for further interventions over that observed with a single IMA (SIMA).
Study Design
Two-arm, randomised multi-centre trial. Patients will be randomised to SIMA or BIMA to the left side of the heart with supplemental vein or radial artery grafts as required.
Eligibility
Patients may be enrolled if they fulfil the following eligibility criteria:
Inclusion criteria
1. CABG patients with multi-vessel coronary artery disease (including urgent and off-pump CABG patients)
Exclusion criteria
1. IMA placed to right coronary artery
2. Single graft
3. Redo CABG
4. Evolving myocardial infarction
5. Concomitant valve surgery
Randomisation and Enrolment Process
All patients requiring CABG should be considered for entry into the study. Centres should keep a screening log and record if the patient is entered into the study and if not the reason why not. Patients who meet the eligibility criteria and give written informed consent should be randomised.
Each investigator is requested to randomise 54 patients (27 per annum or 2-3 patients per month) over a 2 year period.
Randomisation will be performed by telephone contact with the trial co-ordinating centre (the Clinical Trials and Evaluation Unit (CTEU) based at the Royal Brompton Hospital in London). The randomisation service will be available 09:00-17:00 (UK time). Centres will be asked for a few simple details about the patient including initials, date of birth and eligibility criteria. The caller will be given the procedure allocation (SIMA or BIMA) and a fax will be sent to the centre confirming this.
Eligible patients will be randomised in equal proportions between the two surgical strategies SIMA or BIMA. The allocated procedure will be performed by a trial nominated surgeon who has been approved by the Trial Steering Committee as being sufficiently experienced (ie. performed >50 BIMA procedures).
Randomisation will be stratified by centre with specific tables using block allocation to provide treatment distribution in equal proportions. The block size will itself be subject to random variation.
To reduce the possibility of outcome measure events occurring after randomisation and before revascularisation, surgery should be performed within 6 weeks of randomisation.
Follow Up
Patients will be followed up 6 weeks post surgery and annually thereafter up to 10 years. Patients will also be flagged at the Office of National Statistics (ONS) for long term follow-up for death and other major adverse events.
Outcome Measures
Primary
Death from any cause (cardiovascular and non-cardiovascular mortality).
Secondary
Secondary clinical outcome measures will be assessed in a blinded fashion by the Clinical Events Review Committee. These outcomes will be measured in hospital, at routine 6 week clinical follow-up and from telephone questionnaires. Outcomes are as follows:-
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Cause-specific death
Death will be classified into cardiac, other vascular and non-cardiovascular, where possible, using autopsy reports and death certificates. Death will also be classified by ICD code:
Death due to cardiac causes: Cardiac causes of death such as congestive heart failure, arrhythmia or myocardial infarction.
Other vascular causes of death: Vascular causes of death such as pulmonary embolus, dissection, cerebrovascular accident or bleeding event.
Non-cardiovascular causes of death: This includes any other cause of death
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30 day mortality
Death from any cause by 30 days post surgery
Cause-specific death by 30 days post surgery
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Need for re-intervention
ie percutaneous coronary intervention or redo surgery
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Other clinical events
Recurrent angina, unstable angina, myocardial infarction, wound dehiscence, major bleeding, cerebrovascular accident and other serious adverse events will be captured.
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Quality of Life and Cost effectiveness evaluation
These outcomes will be measured from questionnaires (Rose -shortened form, EuroQol-5D, SF36 and Health Services Resource use). These outcomes will be assessed blind to the knowledge of which arm the trial the patient is in.
Statistical Issues
Number of Patients
To achieve an absolute 5% reduction in 10-year mortality (ie from 25% to 20%), with 90% power at 5% alpha requires 2928 patients. The mortality data is taken from a summary of previous studies. The aim is to enrol at least 3000 patients (1500 in each arm) over a 2-year recruitment period in 19 centres in the UK, Italy and Australia.As the intervention is the operation, compliance is likely to be 100% except in the unusual situation where the planned operation is not possible for technical reasons.
Assumptions
Fifty-six surgeons are participating from 19 centres, each performing >150 CABG per annum so there should be over 16800 potentially eligible patients in 2 years (56 x 150 x 2). Screening logs show that around 80% of all CABG patients are eligible for ART. There would, therefore, be approximately 13440 potentially eligible patients over a two-year recruitment period. Based on 3000 patients, ART aims to recruit 22% of these patients. Each surgeon would therefore, need to recruit 54 patients (27 per annum). As most surgeons have 120 (80% of 150) eligible patients per annum, inclusion of even a low proportion (<1 patient per week) should still ensure successful recruitment.
Loss to Follow-up
For the primary outcome (ie death of trial patients) there should be minimal loss as patient death will be automatically flagged via the Office of National Statistics. For secondary outcome measures around 5% of patients may be lost to follow-up due to non-compliance with questionnaires or movement to other areas. Study co-ordinators at each centre will maintain telephone contact with participants to record Health Service Resource Use, to record adverse events, to alert them of the questionnaires' arrival, to ensure addresses are current and to follow-up any non-responders.
Type of Analyses
The trial data will be analysed on an intention-to-treat basis with patients included in the groups assigned at randomisation, irrespective of future management and events. Outcome measure event tracking will begin at randomisation and continue until death or the end of follow-up. Analysis of time to event data will use log rank tests and possibly other methods suitable for survival data, in particular to take account of known prognostic variables.
Frequency of Analyses
A limited number of interim analyses will be performed by the trial statistician as specified by the Data Monitoring Committee (DMC). The accumulating results will not be available to the trialists or other principal investigators. The final, definitive analysis of the trial data will be conducted 120 months after the date of commencement of the trial.
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