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The aim is to conduct a double-blinded single-centre randomized controlled clinical trial of application of topical dose of tranexamic acid (TA) versus the usual intravenous TA in patients undergoing cardiac surgery at the Hamilton General Hospital. This pilot study will assess the feasibility to perform a large randomized international trial exploring this objective.
Postoperative bleeding related to open cardiac surgery increases the rates of complications and mortality. It results from the blood thinners that are needed for use. Intravenous tranexamic acid (TA) has become a mainstay in cardiac surgical procedures for decreasing bleeding and minimizing transfusion requirements. Although intravenous TA is usually well tolerated, there is a well-known risk (1 to 4%) of postoperative seizures. This is due to the similarity between TA and the brain tissues. The aim is to eliminate the risk of seizures but to maintain the protection against bleeding. When TA is used directly on the tissues (topically) for other type of surgeries (joints), TA is effective to reduce blood loss and transfusions. The aim is to prove that direct application of TA on the heart can eliminate postoperative seizures and reduce the amount of blood transfusions in patients who have cardiac surgery.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| TA Topical | Active Comparator | 1 syringe of 50ml of topical Tranexamic Acid (5g) or placebo. The topical will be poured into the pericardial mediastinal cavities in 2 equal doses, 25ml when the pt comes off-pump and the other 25ml before sternotomy is closed. |
|
| TA Intravenous | Active Comparator | 2 syringes of 50ml (5mg) Tranexamic Acid for intravenous injection or placebo. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Tranexamic Acid | Drug | Tranexamic Acid is a medication used to treat or prevent excessive blood loss from major trauma, post partum, surgery, tooth removal, nose bleeds, and heavy menstruation. |
| Measure | Description | Time Frame |
|---|---|---|
| Median Volume of Mediastinal Fluid Collected From Participants | Cumulative volume (mL) of fluid collected from mediastinal drainage tubes 24 hours after the surgical procedure | Fluid collected in the first 24 hours after the surgical procedure |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Seizures | Patients experiencing a post-operative seizure | Patients will be followed post-operatively until hospital discharge |
| Number of Participants With Mortality |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Andre Lamy, MD MHSc | Population Health Research Institute | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Hamilton General Hospital | Hamilton | Ontario | L8L 2X2 | Canada |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 3766524 | Background | Kucuk O, Kwaan HC, Frederickson J, Wade L, Green D. Increased fibrinolytic activity in patients undergoing cardiopulmonary bypass operation. Am J Hematol. 1986 Nov;23(3):223-9. doi: 10.1002/ajh.2830230306. | |
| 6448643 | Background | Harker LA, Malpass TW, Branson HE, Hessel EA 2nd, Slichter SJ. Mechanism of abnormal bleeding in patients undergoing cardiopulmonary bypass: acquired transient platelet dysfunction associated with selective alpha-granule release. Blood. 1980 Nov;56(5):824-34. No abstract available. |
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Between December 2017 and April 2018 a total of 97 patients were randomized to the topical (n = 49) and intravenous (n = 48) groups.
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| ID | Title | Description |
|---|---|---|
| FG000 | Topical TxA (Intervention) | 50 mL of topical tranexamic acid (equivalent to 5 g TxA) poured into the pericardial and mediastinal cavities in 2 equal doses: 25 mL when the patient comes off-pump and the remaining 25 mL before sternotomy closure. In addition, patients received intravenous placebo (saline) administered as per anesthetist standard of care. |
| FG001 | Intravenous TxA (Control) | Up to 100 mL of intravenous tranexamic acid (equivalent to 10 g TxA) administered as per anesthetist standard of care. In addition, patients will receive topical placebo (saline) poured into the pericardial and mediastinal cavities in 2 equal doses: 25 mL when the patient comes off-pump and the remaining 25 mL before sternotomy closure. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Topical TxA (Intervention) | 50 mL of topical tranexamic acid (equivalent to 5 g TxA) poured into the pericardial and mediastinal cavities in 2 equal doses: 25 mL when the patient comes off-pump and the remaining 25 mL before sternotomy closure. In addition, patients will receive intravenous placebo (saline) administered as per anesthetist standard of care. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Median Volume of Mediastinal Fluid Collected From Participants | Cumulative volume (mL) of fluid collected from mediastinal drainage tubes 24 hours after the surgical procedure | Posted | Median | Inter-Quartile Range | mL | Fluid collected in the first 24 hours after the surgical procedure |
|
30 days post-operatively
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Topical TxA (Intervention) | 50 mL of topical tranexamic acid (equivalent to 5 g TxA) poured into the pericardial and mediastinal cavities in 2 equal doses: 25 mL when the patient comes off-pump and the remaining 25 mL before sternotomy closure. In addition, patients received intravenous placebo (saline) administered as per anesthetist standard of care. |
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Due to the small sample size (N<100 patients) the DEPOSITION pilot trial is not sufficiently powered to detect statistically significant differences between topical and intravenous TxA groups.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Research assistant | Population Health Research Institute | 19055212100 | 40582 | Austin.Browne@phri.ca |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Mar 16, 2018 | May 27, 2019 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D006470 | Hemorrhage |
| D016063 | Blood Loss, Surgical |
| ID | Term |
|---|---|
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D007431 | Intraoperative Complications |
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| ID | Term |
|---|---|
| D014148 | Tranexamic Acid |
| ID | Term |
|---|---|
| D003509 | Cyclohexanecarboxylic Acids |
| D000146 | Acids, Carbocyclic |
| D002264 | Carboxylic Acids |
| D009930 | Organic Chemicals |
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Tranexamic Acid intravenous + Placebo topical versus Placebo intravenous + Tranexamic Acid topical
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The pharmacy will prepare 1 syringe of 50 ml of topical TA (5 g) or placebo. They will also prepare for the same patient 2 syringes of 50 ml (5 g) for intravenous (i.v.) injection or placebo. TA is similar in all aspects to normal saline. Blinding of both teams will be easy. The syringes will be prepared and randomized in pharmacy before the surgery.
|
The occurrence of death due to any cause
| Patients will be followed post-operatively until hospital discharge |
| Number of Participants With RBC Transfusion | Patients requiring a red blood cell transfusion | Intra-operative and post-operative RBC transfusions |
| Number of Participants With Re-operation for Bleeding or Tamponade | Occurrence of re-operation for the purpose of bleeding or cardiac tamponade | Patients will be followed post-operatively until hospital discharge |
| Median Number of Hours Participants Spent in ICU | Number of hours participants spent in the intensive care unit (ICU) | Number of hours spent in ICU from arrival to exit (collected at the Post-Operative Visit). |
| Mean Concentration of TxA in Plasma Collected From Participants | Plasma TxA concentrations measured from blood samples taken upon arrival in the ICU | on arrival in ICU within 3 hours |
| 8283896 | Background | Despotis GJ, Santoro SA, Spitznagel E, Kater KM, Cox JL, Barnes P, Lappas DG. Prospective evaluation and clinical utility of on-site monitoring of coagulation in patients undergoing cardiac operation. J Thorac Cardiovasc Surg. 1994 Jan;107(1):271-9. |
| 7508070 | Background | Lemmer JH Jr, Stanford W, Bonney SL, Breen JF, Chomka EV, Eldredge WJ, Holt WW, Karp RB, Laub GW, Lipton MJ, et al. Aprotinin for coronary bypass operations: efficacy, safety, and influence on early saphenous vein graft patency. A multicenter, randomized, double-blind, placebo-controlled study. J Thorac Cardiovasc Surg. 1994 Feb;107(2):543-51; discussion 551-3. |
| 16400465 | Background | Santos AT, Kalil RA, Bauemann C, Pereira JB, Nesralla IA. A randomized, double-blind, and placebo-controlled study with tranexamic acid of bleeding and fibrinolytic activity after primary coronary artery bypass grafting. Braz J Med Biol Res. 2006 Jan;39(1):63-9. doi: 10.1590/s0100-879x2006000100007. Epub 2005 Dec 15. |
| 12651635 | Background | Pleym H, Stenseth R, Wahba A, Bjella L, Karevold A, Dale O. Single-dose tranexamic acid reduces postoperative bleeding after coronary surgery in patients treated with aspirin until surgery. Anesth Analg. 2003 Apr;96(4):923-928. doi: 10.1213/01.ANE.0000054001.37346.03. |
| 27774838 | Background | Myles PS, Smith JA, Forbes A, Silbert B, Jayarajah M, Painter T, Cooper DJ, Marasco S, McNeil J, Bussieres JS, McGuinness S, Byrne K, Chan MT, Landoni G, Wallace S; ATACAS Investigators of the ANZCA Clinical Trials Network. Tranexamic Acid in Patients Undergoing Coronary-Artery Surgery. N Engl J Med. 2017 Jan 12;376(2):136-148. doi: 10.1056/NEJMoa1606424. Epub 2016 Oct 23. |
| 19020118 | Background | Martin K, Wiesner G, Breuer T, Lange R, Tassani P. The risks of aprotinin and tranexamic acid in cardiac surgery: a one-year follow-up of 1188 consecutive patients. Anesth Analg. 2008 Dec;107(6):1783-90. doi: 10.1213/ane.0b013e318184bc20. |
| 22054656 | Background | Kalavrouziotis D, Voisine P, Mohammadi S, Dionne S, Dagenais F. High-dose tranexamic acid is an independent predictor of early seizure after cardiopulmonary bypass. Ann Thorac Surg. 2012 Jan;93(1):148-54. doi: 10.1016/j.athoracsur.2011.07.085. Epub 2011 Nov 4. |
| BG001 |
| Intravenous TxA (Control) |
Up to 100 mL of intravenous tranexamic acid (equivalent to 10 g TxA) administered as per anesthetist standard of care. In addition, patients will receive topical placebo (saline) poured into the pericardial and mediastinal cavities in 2 equal doses: 25 mL when the patient comes off-pump and the remaining 25 mL before sternotomy closure. |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Diabetes mellitus | Count of Participants | Participants |
|
| Stroke | Count of Participants | Participants |
|
| Transient ischemic attack | Count of Participants | Participants |
|
| Carotid endarterectomy/stent | Count of Participants | Participants |
|
| History of seizures | Count of Participants | Participants |
|
| New oral anticoagulants (NOAC) | Count of Participants | Participants |
|
| Aspirin | Count of Participants | Participants |
|
| Clopidogrel (Plavix) | Count of Participants | Participants |
|
| Ticagrelor | Count of Participants | Participants |
|
Up to 100 mL of intravenous tranexamic acid (equivalent to 10 g TxA) administered as per anesthetist standard of care. In addition, patients will receive topical placebo (saline) poured into the pericardial and mediastinal cavities in 2 equal doses: 25 mL when the patient comes off-pump and the remaining 25 mL before sternotomy closure.
|
|
| Secondary | Number of Participants With Seizures | Patients experiencing a post-operative seizure | Posted | Count of Participants | Participants | Patients will be followed post-operatively until hospital discharge |
|
|
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| Secondary | Number of Participants With Mortality | The occurrence of death due to any cause | Posted | Count of Participants | Participants | Patients will be followed post-operatively until hospital discharge |
|
|
|
| Secondary | Number of Participants With RBC Transfusion | Patients requiring a red blood cell transfusion | Posted | Count of Participants | Participants | Intra-operative and post-operative RBC transfusions |
|
|
|
| Secondary | Number of Participants With Re-operation for Bleeding or Tamponade | Occurrence of re-operation for the purpose of bleeding or cardiac tamponade | Posted | Count of Participants | Participants | Patients will be followed post-operatively until hospital discharge |
|
|
|
| Secondary | Median Number of Hours Participants Spent in ICU | Number of hours participants spent in the intensive care unit (ICU) | Posted | Median | Inter-Quartile Range | hours | Number of hours spent in ICU from arrival to exit (collected at the Post-Operative Visit). |
|
|
|
| Secondary | Mean Concentration of TxA in Plasma Collected From Participants | Plasma TxA concentrations measured from blood samples taken upon arrival in the ICU | 4 patients from the topical TxA group and 3 patients from the intravenous TxA group were excluded because they either did not receive a TxA dose or received an incomplete TxA dose. | Posted | Mean | Standard Deviation | microgram per milliliter per kilogram | on arrival in ICU within 3 hours |
|
|
|
| 1 |
| 49 |
| 0 |
| 49 |
| 0 |
| 49 |
| EG001 | Intravenous TxA (Control) | Up to 100 mL of intravenous tranexamic acid (equivalent to 10 g TxA) administered as per anesthetist standard of care. In addition, patients will receive topical placebo (saline) poured into the pericardial and mediastinal cavities in 2 equal doses: 25 mL when the patient comes off-pump and the remaining 25 mL before sternotomy closure. | 1 | 48 | 0 | 48 | 0 | 48 |
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