Coronary Artery Disease
Conditions
Keywords
coronary artery bypass grafting, tranexamic acid, antifibrinolytic, administration, topical, operative blood salvage
Brief summary
The goal of this project is to determine whether the use of tranexamic acid, a clot-promoting drug, applied topically over the heart in coronary artery bypass graft surgery (CABG) will reduce post operative blood loss. The investigators' hypothesis is that the use of a tranexamic acid-containing cardiac bath prior to chest closure will result in a statistically significant reduction in blood loss and transfusion requirements in patients who undergo CABG.
Detailed description
Bleeding is expected during major surgeries. In patients who undergo CABG, the risk for bleeding is increased because of the need for intra-operative anticoagulation, or thinning, of patient blood. This anticoagulation is necessary to reduce the risk of thrombosis potentially precipitated by the cardiopulmonary bypass machine, which pumps blood throughout the body while the surgeon operates on the heart. Strategies are currently used in the operating room to minimize blood loss and the need for allogenic blood transfusion during and after cardiac surgeries. These strategies include the use of intravenous antifibrinolytic agents, intra-operative red blood cell salvage devices, and topical fibrin sealants. Although the risk of infection from a blood transfusion is very small with modern methods of blood screening, the risk of developing a transfusion reaction is possible and not predictable. Therefore, it is preferred to avoid administering a blood transfusion unless absolutely necessary. The use of topical antifibrinolytic agents has been explored to further reduce blood loss in cardiac surgery. Several trials have been published in the literature since 1993 evaluating the efficacy of various antifibrinolytic medications applied topically, as a cardiac bath, prior to chest closure in CABG patients to reduce post-operative blood loss and potential need for blood transfusion. The applicability of the methodology utilized in these studies, however, is limited in the context of the current Canadian practices of cardiac surgery. Considerable differences in the perioperative strategies of these trials are seen, in comparison to current North American practices of cardiac surgery. These trials also compared use of topically applied antifibrinolytic agents, including the lysine analogue tranexamic acid, to a control in the absence of intravenous antifibrinolytic agents. The use of intravenous lysine analogues to reduce peri-operative bleeding has now become a near-standard of care in CABG patients. Currently, the only available antifibrinolytic agent in Canada is the lysine analogue tranexamic acid. This drug is widely used administered as an intravenous preparation in cardiac surgery because its safety profile and reduction in blood loss and frequency of blood transfusion. There is presently no published randomized controlled trial evaluating blood loss in CABG patients who have received intravenous tranexamic acid, plus topical tranexamic acid or placebo.
Interventions
DRUGTranexamic Acid
Solution containing 2 grams (20mL) tranexamic acid + normal saline (50mL), for a total volume of 70mL poured over the heart as a 'cardiac bath' prior to sternotomy closure near the end of surgery. Total duration of immersion is approximately 10 minutes, until mediastinal chest tubes are connected to suction.
DRUGnormal saline
A total volume of 70mL of normal saline poured over the heart as a 'cardiac bath' prior to sternotomy closure near the end of surgery. Total duration of immersion is approximately 10 minutes, until mediastinal chest tubes are connected to suction. Identical in appearance to the trial drug, and is visually indistinguishable.
Sponsors
Saskatoon Health Region
University of Saskatchewan
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
Inclusion Criterion: * Patients scheduled for elective or urgent CABG of two to six vessels
Exclusion criteria
Preoperative: * Hemoglobin of less than 110g/L * Under 18 years of age * Body mass less than 75kg * Presence of an intra-aortic balloon pump * Emergency surgery, requiring operative intervention within 24 hours of consultation to the cardiac surgery team * Need for cardiac surgical intervention in addition to planned CABG (with the exception of patent foramen ovale closure) * Ejection fraction (EF) of less than 50%, as determined by echocardiogram or angiography * Pulmonary hypertension with pulmonary artery pressures greater than 60mmHg (as estimated by right ventricular systolic pressure (RVSP)) * Presence of infectious endocarditis * Hepatic failure with impaired liver function, including International Normalized Ratio (INR) greater than 1.5 * Known diagnosed bleeding disorder * History of heparin induced thrombocytopenia and thrombosis (HITT) * Renal failure with pre-operative creatinine greater than 200ml/min or oliguria with urine output less than 10ml/hour * Allergy to tranexamic acid * Pregnancy Intraoperative: * Discovery of infectious endocarditis * Need for cardiac surgical intervention in addition to planned coronary CABG * Development of allergic reaction to tranexamic acid following intravenous infusion
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total Volume of Blood Loss From Mediastinal Chest Tubes at Time of Removal (Assuming the Total Volume of Loss is Blood). | From ICU admission post-operatively to mediastinal chest tube removal (placebo group = 20.6 hours; trial group = 19.8 hours) | According to standard practice, research participants were be transferred to the intensive care unit (ICU) for post-operative monitoring. Measurement of chest tube output began immediately on arrival to the ICU. Hourly measurements were recorded. Data collection ended upon chest tube removal, or return to the operating room for exploratory surgery due to massive blood loss. As per ICU protocol, chest tubes were be removed when blood loss was recorded to be less than 200mL after six consecutive hours. |
| Number of Units of Packed Red Blood Cells (PRBC) Transfused Following Coronary Artery Bypass Graft Surgery | From ICU admission to transfer to the Cardiology Ward (placebo group = 24.4 hours; trial group = 24.7 hours) | Research participants were to receive a blood transfusion in the Intensive Care Unit (ICU) post-operatively if hemoglobin reached a nadir of 80g/L, or at the discretion of the intensivist or cardiac surgeon according to patient clinical status. Transfusion was quantified based on the number of units of PRBC received. (1 unit = 1 bag of blood, as prepared by Canadian Blood Services). Clinical status of research participants was followed throughout their duration in the ICU only. Participation in this study ended upon transfer out of the ICU, to the Cardiology Ward. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Volume of Blood Loss at 6 Hours | 6 hours following admission to the Intensive Care Unit | Volume of chest tube loss at 6 hours (assuming the total volume of loss is blood). |
| Volume of Blood Loss After 12 Hours | 12 hours following admission to the Intensive Care Unit | Volume of chest tube loss at 12 hours (assuming the total volume of loss is blood). |
Participant flow
Recruitment details
All patients scheduled to undergo elective or urgent CABG at Royal University Hospital between December 1, 2011 and April 30, 2012 were screened for participation. Patients meeting inclusion criteria were approached by a study team member at the time of pre-admission clinic attendance or on the in-patient ward with an invitation to participate.
Pre-assignment details
Patients meeting inclusion criteria were eligible for study participation. Randomization of consented participants took place by the Clinical Trials Pharmacy on the day of surgery, following confirmation of surgical procedure. The study team could withdraw consented patients prior to randomization and surgery if exclusion criteria were identified.
Participants by arm
| Arm | Count |
|---|---|
| Trial Drug Total 70mL solution containing 2 grams tranexamic acid (20mL) + normal saline (50mL) | 23 |
| Placebo Normal saline (70mL) | 18 |
| Total | 41 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Met exclusion criteria, not analysed | 1 | 2 |
Baseline characteristics
| Characteristic | Total | Trial Drug | Placebo |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 15 Participants | 8 Participants | 7 Participants |
| Age, Categorical Between 18 and 65 years | 26 Participants | 15 Participants | 11 Participants |
| Age Continuous | 62 years STANDARD_DEVIATION 9.4 | 62 years STANDARD_DEVIATION 8.7 | 62 years STANDARD_DEVIATION 10.4 |
| Angina No | 1 participants | 1 participants | 0 participants |
| Angina Yes | 40 participants | 22 participants | 18 participants |
| Atrial Fibrillation No | 41 participants | 23 participants | 18 participants |
| Atrial Fibrillation Yes | 0 participants | 0 participants | 0 participants |
| Body Mass Index | 31.1 kg/m^2 STANDARD_DEVIATION 4.6 | 31.1 kg/m^2 STANDARD_DEVIATION 4.2 | 31.2 kg/m^2 STANDARD_DEVIATION 5.1 |
| Diabetes No | 25 participants | 14 participants | 11 participants |
| Diabetes Yes | 16 participants | 9 participants | 7 participants |
| Dyslipidemia No | 11 participants | 6 participants | 5 participants |
| Dyslipidemia Yes | 30 participants | 17 participants | 13 participants |
| Height | 1.7 meters STANDARD_DEVIATION 0.1 | 1.7 meters STANDARD_DEVIATION 0.1 | 1.7 meters STANDARD_DEVIATION 0.1 |
| History of Myocardial Infarction No | 23 participants | 14 participants | 9 participants |
| History of Myocardial Infarction Yes | 18 participants | 9 participants | 9 participants |
| Hypertension No | 9 participants | 5 participants | 4 participants |
| Hypertension Yes | 32 participants | 18 participants | 14 participants |
| Mass | 92.2 kilograms STANDARD_DEVIATION 11.6 | 92.7 kilograms STANDARD_DEVIATION 10.5 | 91.3 kilograms STANDARD_DEVIATION 13.2 |
| Number of Bypasses | 4.2 Number of vessels STANDARD_DEVIATION 1.1 | 4.1 Number of vessels STANDARD_DEVIATION 1 | 4.3 Number of vessels STANDARD_DEVIATION 1.1 |
| Pre-operative Antiplatelet Use Off 7 days or less | 40 participants | 22 participants | 18 participants |
| Pre-operative Antiplatelet Use Off more than 7 days | 1 participants | 1 participants | 0 participants |
| Pre-operative Creatinine | 81 umol/L STANDARD_DEVIATION 23 | 84 umol/L STANDARD_DEVIATION 25 | 76 umol/L STANDARD_DEVIATION 18 |
| Pre-operative Hemoglobin | 145 g/L STANDARD_DEVIATION 14 | 147 g/L STANDARD_DEVIATION 13 | 142 g/L STANDARD_DEVIATION 14 |
| Pre-operative International Normalized Ratio (INR) | 1.0 International Normalized Ratio STANDARD_DEVIATION 0.1 | 1.0 International Normalized Ratio STANDARD_DEVIATION 0.1 | 1.0 International Normalized Ratio STANDARD_DEVIATION 0.1 |
| Pre-operative platelet count | 239 platelets x 10^9/L STANDARD_DEVIATION 66 | 242 platelets x 10^9/L STANDARD_DEVIATION 70 | 234 platelets x 10^9/L STANDARD_DEVIATION 62 |
| Pre-operative white blood cell (WBC) count | 7.8 WBC x 10^9/L STANDARD_DEVIATION 2.5 | 7.7 WBC x 10^9/L STANDARD_DEVIATION 1.9 | 7.9 WBC x 10^9/L STANDARD_DEVIATION 3.2 |
| Region of Enrollment Canada | 41 participants | 23 participants | 18 participants |
| Sex: Female, Male Female | 12 Participants | 6 Participants | 6 Participants |
| Sex: Female, Male Male | 29 Participants | 17 Participants | 12 Participants |
| Stent in situ No | 34 participants | 20 participants | 14 participants |
| Stent in situ Yes | 7 participants | 3 participants | 4 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 23 | 0 / 18 |
| serious Total, serious adverse events | 0 / 23 | 0 / 18 |
Outcome results
Primary
Number of Units of Packed Red Blood Cells (PRBC) Transfused Following Coronary Artery Bypass Graft Surgery
Research participants were to receive a blood transfusion in the Intensive Care Unit (ICU) post-operatively if hemoglobin reached a nadir of 80g/L, or at the discretion of the intensivist or cardiac surgeon according to patient clinical status. Transfusion was quantified based on the number of units of PRBC received. (1 unit = 1 bag of blood, as prepared by Canadian Blood Services). Clinical status of research participants was followed throughout their duration in the ICU only. Participation in this study ended upon transfer out of the ICU, to the Cardiology Ward.
Time frame: From ICU admission to transfer to the Cardiology Ward (placebo group = 24.4 hours; trial group = 24.7 hours)
Population: None of the research participants received PRBC transfusion postoperatively in the ICU.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Trial Drug | Number of Units of Packed Red Blood Cells (PRBC) Transfused Following Coronary Artery Bypass Graft Surgery | 0 Unit(s) of PRBC |
| Placebo | Number of Units of Packed Red Blood Cells (PRBC) Transfused Following Coronary Artery Bypass Graft Surgery | 0 Unit(s) of PRBC |
Primary
Total Volume of Blood Loss From Mediastinal Chest Tubes at Time of Removal (Assuming the Total Volume of Loss is Blood).
According to standard practice, research participants were be transferred to the intensive care unit (ICU) for post-operative monitoring. Measurement of chest tube output began immediately on arrival to the ICU. Hourly measurements were recorded. Data collection ended upon chest tube removal, or return to the operating room for exploratory surgery due to massive blood loss. As per ICU protocol, chest tubes were be removed when blood loss was recorded to be less than 200mL after six consecutive hours.
Time frame: From ICU admission post-operatively to mediastinal chest tube removal (placebo group = 20.6 hours; trial group = 19.8 hours)
Population: A total of 44 consented participants were randomized. Prior to unblinding, 3 of the randomized participants were withdrawn from the study due to discovery of ineligibility criteria (1 EF \<50%, 1 weight \<75kg, 1 CABG x 7). Therefore, a total 41 patients were included in final analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Trial Drug | Total Volume of Blood Loss From Mediastinal Chest Tubes at Time of Removal (Assuming the Total Volume of Loss is Blood). | 632 mL | Standard Deviation 265 |
| Placebo | Total Volume of Blood Loss From Mediastinal Chest Tubes at Time of Removal (Assuming the Total Volume of Loss is Blood). | 789 mL | Standard Deviation 216 |
Comparison: Intention to Treat principles of data analysis were applied. The two-sided T-test (95% confidence interval) was used for statistical calculation of primary outcomes. The null hypothesis was that no difference in chest tube losses would be found between the topical tranexamic acid and placebo groups in low-risk cardiac patients undergoing CABG.p-value: 0.0493t-test, 2 sided
Secondary
Volume of Blood Loss After 12 Hours
Volume of chest tube loss at 12 hours (assuming the total volume of loss is blood).
Time frame: 12 hours following admission to the Intensive Care Unit
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Trial Drug | Volume of Blood Loss After 12 Hours | 464 mL | Standard Deviation 222 |
| Placebo | Volume of Blood Loss After 12 Hours | 570 mL | Standard Deviation 157 |
Comparison: Intention to Treat principles of data analysis were applied. The two-sided T-test (95% confidence interval) was used for statistical calculation of secondary outcomes. The null hypothesis was that no difference in chest tube losses would be found between the topical tranexamic acid and placebo groups in low-risk cardiac patients undergoing CABG.p-value: 0.093t-test, 2 sided
Secondary
Volume of Blood Loss at 6 Hours
Volume of chest tube loss at 6 hours (assuming the total volume of loss is blood).
Time frame: 6 hours following admission to the Intensive Care Unit
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Trial Drug | Volume of Blood Loss at 6 Hours | 342 mL | Standard Deviation 191 |
| Placebo | Volume of Blood Loss at 6 Hours | 417 mL | Standard Deviation 163 |
Comparison: Intention to Treat principles of data analysis were applied. The two-sided T-test (95% confidence interval) was used for statistical calculation of secondary outcomes. The null hypothesis was that no difference in chest tube losses would be found between the topical tranexamic acid and placebo groups in low-risk cardiac patients undergoing CABG.p-value: 0.1876t-test, 2 sided