Trial design
The study was a prospective, randomized, double-blinded and controlled trial. It was sponsored by National Center for Cardiovascular Diseases and was conducted at Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. The study was approved by the Ethical Review Board of Fuwai Hospital. (Ethical approval No. 2008-366). And written informed consent was provided by all participants.
Study population
The inclusion criteria were patients between 18 and 79 years old undergoing elective heart surgery with cardiopulmonary bypass, including the coronary artery bypass graft, valvular repair or replacement, or repair of congenital heart deformities. The exclusion criteria included previous cardiac surgery, hematocrit level less than 33%, platelet count less than 100 000×103/L, allergy to tranexamic acid, and being recruited in other studies.
Randomization and blinding
The surgical procedures and peri-operative care followed the institutional routine. Aspirin and clopidogrel, if any, were discontinued at least five days before the operation. In patients using warfarin, it was required that prothrombin time (PT) was normal before the operation. Patients were randomly assigned into three groups for the use of ulinastatin (group U), tranexamic acid (group T) or placebo (group C). The randomization sequence was generated by computer in permuted blocks by a 1:1:1 ratio and was masked in sealed, sequentially numbered and opaque envelopes. Patient enrollment, randomization, and blinding were conducted and supervised by an independent committee. The participants, medical staff, and investigators were unaware of the treatment allocation until the end of the study.
Primary and secondary outcomes
The primary outcome of this study was the total volume of post-operative blood loss. The secondary outcomes included stroke, post-operative myocardial infarction, renal failure, respiratory failure, in-hospital adverse outcomes and long-term morbidities and mortalities. Stroke was stated as new focal neurologic deficit lasting more than 24 hours confirmed by a cerebral computed tomography scan and an attending neurologic consultant. Post-operative myocardial infarction was diagnosed by two of the following: prolonged (>20 minutes) chest pain not relieved by rest or nitrates, new pathologic Q waves in more than two contiguous electrocardiograph leads, elevated enzyme levels (creatine kinase-MB >5% of total creatinine phosphokinase or troponin T >0.5 ng/mL), new wall motion abnormalities, or the need for revascularization. Renal failure was stated as first-time dependency on renal dialysis, an increase of post-operative creatinine of at least 2 mg/dL, or a difference of at least 0.7 mg/dL between baseline value and the maximal post-operative plasma creatinine concentration. Respiratory failure was defined as prolonged mechanical ventilation (>48 hours), the need for continuous positive airway pressure therapy, reintubation, or tracheostomy. The in-hospital adverse outcomes were evaluated and defined as seizure, sudden cardiac arrest, readmission to intensive care unit (ICU), re-operation for surgical cause, using intra-aortic balloon pulsation (IABP) or extracorporeal membrane oxygenation (ECMO) and deep sternal infection. The long-term morbidities included stroke, myocardial infarction, renal failure, respiratory failure, seizure and sudden cardiac arrest.
Interventions
Study and placebo medication were prepared by the hospital pharmacy. Identical syringes of 50 mL labeled with the randomization number contained transparent solution, 30 mg/Kg body weight of tranexamic acid (Jie Ning®; Changchun Tiancheng Pharmaceutical Co., Changchun, China), 1,000,000 U ulinastatin (Tian Pu Luo An®; Guangdong Tianpu Biochemistry Pharmaceutical Co., Guangzhou, China) or normal saline. There were two syringes prepared for each patient labeled ‘#1’ and ‘#2’. In the tranexamic acid group, both the syringes contained 15 mg/kg tranexamic acid to fulfill a total dosage of 30 mg/kg. In the ulinastatin group, the syringe #1 contained 1,000,000 U ulinastatin and the syringe #2 contained normal saline. In the control group, both the syringes contained normal saline. The syringe #1 and #2 were pumped intravenously after anaesthetic induction and after the administration of protamine respectively.
Post-operative blood loss
Postoperative blood loss was assessed via chest drain tubes every 8 hour for the first 24 hours after admittance to the ICU, and then was assessed every day beyond the first 24 hours until the chest drain tubes were withdrawn. Post-operative blood loss was defined as the total volume of drainage from the end of the operation until the removal of the chest tubes. Chest tube drainage more than 300 ml within the first post-operative hour, more than 5 ml/kg per hour consecutively for 3 hours, or any signs of pericardial tamponade justified surgical re-exploration to control bleeding.
Transfusion criteria
The criteria for the transfusion of packed red blood cells (RBC) were:
(1) bleeding caused hemodynamic instability or
(2) hemoglobin concentrations below 8.0 g/dL in the early postoperative period.
In all other situations the decision to transfuse was left to the discretion of the treating physician. The criteria for transfusion of platelet concentrates and fresh frozen plasma were:
- excessive bleeding and a platelet count < 50000/L or
(2) PT and/or aPTT of > 1.5 times the upper limit of normal (after heparin reversal), respectively.
Additional protamine was administered in cases of prolonged ACT (the preoperatively measured ACT served as reference).
Follow-up
All patients were followed up for ten years via reviewing outpatient records and questionnaires by mail/telephone 30 days post-operatively and annually.
Statistical analysis
The sample size was calculated based on the volume of post-operative bleeding using one-way ANOVA at an alpha level of 0.05 and effect size of 0.2 with 95% power. Assuming a dropout rate of 10%, the estimated total sample size was 426 patients (142 patients for each group). For continuous variables, normal distribution assumption was assessed. Equal variance assumption was assessed. The differences of these characteristics between groups were performed using independent two-sample t-tests and one-way ANOVA. Mean difference (MD) and its 95% confidence interval (CI) was calculated. Categorical variables were summarized using frequency and percentage and compared using Chi-square test or Fisher’s exact test. The estimated effect size and its precision were presented by the absolute risk difference (RD) and relative risk (RR) with their associated 95% CIs. The Mantel- Haenszel method was applied in the calculation of RR. Survival analysis was performed using the Kaplan-Meier method and log-rank test. All the analyses were performed using SPSS (Version 18.0, SPSS Inc.) software. All tests were two-sided, and a probability value less than 0.05 was considered to be statistically significant. The authors had full access to the data and take responsibility for its integrity.