Trial Summary
Background Synopsis
There are more than 20,000 cardiac surgery cases done each year in Australia. About 5% (1,000 patients) have a serious complication or die; this adds substantially to healthcare costs (>$15 billion/yr in the USA alone). Cardiac surgery activates platelets and coagulation factors, and the fibrinolytic pathway. Excessive bleeding is common. This may require surgical re-exploration and increases morbidity and mortality. Recent aspirin exposure increases surgical bleeding. It is routine practice in most cardiac surgical centres for aspirin to be ceased 1 wk before elective cardiac surgery. But a recent landmark study found that aspirin had a lower mortality, as well as less stroke, renal failure and bowel infarction (all P<0.01), presumably because of its anti-thrombogenic effects.
Another drug, TA, is sometimes used to reduce bleeding after cardiac surgery. It works by blocking the activation fibrinolysis ("clot breakdown") that often occurs during bypass and surgery. It can block the bleeding risk associate with aspirin, and does not increase thrombotic risk. Meta-analyses of trials have shown that antifibrinolytic therapy reduces blood loss, need for blood transfusion and re-operation for bleeding in cardiac surgery. Such therapy may also reduce mortality. Large outcome trial data are lacking.
Research Plan Synopsis
Design: Large, multi-centre, prospective,randomised, double blind, factorial trial. Patients will be randomly allocated to aspirin, TA, aspirin + TA, or placebo.
Primary End Point: Composite: 30-day mortality or major morbidity (myocardial infarction, cardiogenic shock, stroke, pulmonary embolism, cardiac tamponade).
Secondary End Points: Each of the above, plus blood transfusion, re-operation, respiratory failure, renal failure, serious wound infection, prolonged hospitalisation.
Sample size: 4600 patients (alpha 0.05, beta 0.10), to detect a 30% (or greater) reduction in major complications or death.
Outcomes & Significance: There are some compelling reasons to question the routine stopping of aspirin before elective CABG surgery. Although preoperative aspirin may increase bleeding, it may also reduce MI, other complications and death. TA prevents excessive bleeding and is likely to have other benefits. On the basis of cost and safety, the best antifibrinolytic agent to evaluate is TA.
When considering the cost and extent of CABG surgery in Australia and around the world, small differences in outcome would have major implications for healthcare delivery.
Randomisation
On the morning of surgery patients are randomised to one of 4 groups:
Group 1 = Aspirin
Group 2 = Tranexamic acid
Group 3 = Aspirin plus tranexamic acid
Group 4 = Placebo
Treatment of the patient postoperatively
1. Preoperative period
All patients will receive their usual preoperative care. After providing informed consent, they will be ordered premedication (if required) as per their anaesthetist's usual practice.
2. Intraoperative period
Appropriate patient and equipment monitoring will be established before induction of anaesthesia (usual practice). Choice of anaesthetic agents, muscle relaxants and perioperative analgesia will be left to the discretion of the anaesthetist. Operative characteristics will be recorded: adverse intraoperative events, duration of anaesthesia, additional surgery. Surgery will be according to local practices.
3. Postoperative period.
Early postoperative care in the ICU will be jointly determined by the cardiac surgical and ICU staff, as per usual local practice. In general, the intensive care physician is primarily responsible for decisions regarding management in the ICU and the cardiac surgical staff are primarily responsible for most aspects of later postoperative care. Local hospital practices will vary and are allowable in this trial.
Blood will be collected postoperatively day 1 for troponin levels, and a 12-lead ECG will be performed on the 3 days following surgery to detect MI.
Additional tests will be ordered if clinically indicated (eg, chest pain, dyspnoea, circulatory instability). Additionally, patients will be contacted by phone at 30 days and their medical record reviewed to ascertain if they have experienced any adverse outcomes.