DEPOSITION: Pilot Study Decreasing Postoperative Blood Loss by Topical vs. Intravenous Tranexamic Acid in Open Cardiac Surgery
Phase: PHASE4
Conditions: Bleeding, Surgical Blood Loss
Sponsor: Population Health Research Institute

DEPOSITION: Pilot Study 
Decreasing Postoperative Blood Loss by Topical vs. Intravenous Tranexamic Acid in Open Cardiac Surgery 
 
Protocol Final Version 3.0 
2018-03-16 
 
 
Sponsor and Study Coordinating Group: 
Population Health Research Institute 
Hamilton General Hospital, DBCVSRI 
237 Barton Street East 
Hamilton, Ontario, Canada L8L 2X2 
 
Principal Investigator: 
Dr. Andre Lamy, MD MHSc, 
Cardiac Surgeon 
Scientist, Population Health Research Institute  
Professor, Dept of Surgery, Division Head of Cardiac Surgery 
Associate Member, Dept Clinical Epidemiology & Statistics McMaster University 
 
Hamilton General Hospital, DBCVSRI 
237 Barton Street East 
Hamilton, Ontario, Canada L8L 2X2 
 
Dr. Andre Lamy  
Principal Investigator 
PHRI 
 
____________________________ 
Signature 
 
_______________________ 
Date (YYYY-MM-DD) 
 
Co-Investigators: 
Dr. P.J Devereaux, MD, PhD, FRCPC  
 
Population Health Research Institute 
Hamilton General Hospital, DBCVSRI 
237 Barton Street East 
Hamilton, Ontario, Canada L8L 2X2 
Dr. Louay Habbab (Cardiac Surgery Resident) 
Population Health Research Institute 
Hamilton General Hospital, DBCVSRI 
237 Barton Street East 
Hamilton, Ontario, Canada L8L 2X2 
Dr. Lloyd Semelhago, BSc, MD, MSc, FRCS(C), FACS 
Hamilton General Hospital, Room 726 
McMaster Clinic 
237 Barton Street East 
Hamilton, Ontario, Canada L8L 2X2 
Dr. Yannick LeManach, MD, MsC, PhD 
 
Population Health Research Institute 
Hamilton General Hospital, DBCVSRI 
237 Barton Street East 
Hamilton, Ontario, Canada L8L 2X2 
Dr. Murray Potter, MD, FRCPC, FCCMG 
Professor and Acting Chair – Department of Pathology 
and Molecular Medicine 
McMaster University – Health Science Centre 
1280 Main St. W. 
Hamilton, ON, L8S 4K1 
Dr. Josko Ivica, PhD 
Clinical Chemistry Fellow 
Department of Pathology and Molecular Medicine 
McMaster University 
1280 Main St. W. 
Hamilton, ON, L8S 4K1 
 

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DEPOSITION Protocol V3.0 
 
2018-03-16 
 
 
 
 
 
STUDY CONTACTS 
Investigator 
Name: 
Dr. Andre Lamy 
Address: 
Population Health Research Institute 
237 Barton Street East, Hamilton, ON, L8L 2X2 
Tel: 
(905) 527-4322 ext. 40324 
Email: 
alamy1@mac.com 
 
Project Officers 
Name: 
Dr. Louay Habbab 
Address: 
Population Health Research Institute 
237 Barton Street East, Hamilton, ON, L8L 2X2 
Email: 
louay@habbab.com 
 
Project Manager 
Name: 
Ms. Shirley Pettit 
Address: 
Population Health Research Institute 
237 Barton Street East, Hamilton, ON, L8L 2X2 
Tel: 
(905) 527 4322 ext. 40526 
Email: 
shirley.pettit@phri.ca 
 
Study Coordinator 
Name: 
Ms. Ingrid Copland 
Address: 
Population Health Research Institute 
237 Barton Street East, Hamilton, ON, L8L 2X2 
Tel: 
(905) 527 4322 ext. 40368 
Email: 
ingrid.copland@phri.ca 
 
Project Office 
cogency@phri.ca 
 

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TABLE OF CONTENTS  
1.0 STUDY SUMMARY ................................................................................................................................... 7 
2.0 BACKGROUND ......................................................................................................................................... 7 
2.1 Postoperative bleeding ....................................................................................................................... 7 
2.2 Why is this study needed now? .......................................................................................................... 7 
2.3 Conclusions/future direction .............................................................................................................. 8 
3.0 PLAN OF INVESTIGATION ........................................................................................................................ 8 
3.1 Objectives............................................................................................................................................ 8 
3.2 Study Setting and Design .................................................................................................................... 8 
3.3 Sample size .......................................................................................................................................... 8 
3.4 Intervention ........................................................................................................................................ 9 
3.5 Timeline ............................................................................................................................................... 9 
4.0 ELIGIBILITY CRITERIA ............................................................................................................................. 10 
4.1 Inclusion Criteria ............................................................................................................................... 10 
4.2 Exclusion Criteria ............................................................................................................................... 10 
5.0 STUDY PHASES ...................................................................................................................................... 10 
5.1 Phase I: Baseline ............................................................................................................................... 10 
5.2 Phase II: In-hospital ........................................................................................................................... 11 
5.3 Phase III: Follow-up ........................................................................................................................... 11 
6.0 STUDY OUTCOMES ................................................................................................................................ 11 
6.1 Primary Outcomes ............................................................................................................................ 11 
6.2 Secondary Outcomes ........................................................................................................................ 11 
6.3 Reporting and Adjudication of Outcomes ........................................................................................ 11 
7.0 STATISTICAL ANALYSIS .......................................................................................................................... 12 
7.1 General Considerations ..................................................................................................................... 12 
7.2 Analysis of the primary objective...................................................................................................... 12 
7.3 Analysis of Secondary Objectives ...................................................................................................... 12 
8.0 PROJECT MANAGEMENT....................................................................................................................... 13 
9.0 ETHICAL STANDARDS ............................................................................................................................ 13 
9.1 Good Clinical Practice (GCP) ............................................................................................................. 13 
9.2 Informed consent of the patient ....................................................................................................... 13 
9.3 Approval of study protocol ............................................................................................................... 13 

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9.4 Maintenance of records .................................................................................................................... 13 
9.5 Confidentiality ................................................................................................................................... 13 
10.0 REFERENCES ........................................................................................................................................ 14 
11.0 EVENT DEFINITIONS ............................................................................................................................ 17 
 

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List of Abbreviations 
 
CCU: Coronary Care Unit 
CPB: Cardiopulmonary Bypass 
HHS: Hamilton Health Sciences 
ICU: Intensive Care Unit 
I.P.: Intra-Pericardial 
I.V.: Intravenous 
OR: Operating Room 
PHRI: Population Health Research Institute 
RCT: Randomized Controlled Trial 
TA: Tranexamic Acid 

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DEPOSITION Protocol V3.0 
 
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Study Synopsis 
Title 
DEPOSITION: Pilot Study 
Project Office 
Population Health Research Institute 
237 Barton Street East, Hamilton, Ontario Canada L8L 2X2 
Study Size 
115 patients 
Study Design 
Single-center randomized controlled clinical trial 
Primary 
Objectives 
We hypothesize that topical intra-pericardial (i.p.) application of Tranexamic 
Acid (TA) vs. intravenous (i.v.) will reduce postoperative bleeding in patients 
who have undergone cardiac surgery using cardiopulmonary bypass (CPB) 
and decrease or eliminate the risk of seizures. 
Secondary 
Objectives 
Determine the systemic absorption of topical TA 
Primary 
Outcomes 
Postoperative chest tube production 24 hours after surgical procedure 
Secondary 
Outcomes 
1. Postoperative Number of Participants developing seizure 
2. Number of Participants Requiring Surgical Re-exploration 
3. Total Blood Transfusions 
4. Length of ICU stay  
5. All-cause death 
6. Plasma level of TA on arrival in ICU 
Inclusion 
Criteria 
1. Male or female ≥ 18 years old 
2. Undergoing cardiac surgical procedure with the use of 
cardiopulmonary bypass and median sternotomy. 
3. Provide written informed consent 
Exclusion 
Criteria 
1. Poor (English) language comprehension  
2. Minimally invasive surgery  
3. Off-pump procedures 
4. Emergency operations 
5. Known history of increased bleeding disorder 
6. Thromboembolic disease 
7. Allergy to tranexamic acid 
8. Severe renal impairment (eGFR <30 mL/min/1.73m2 ) 
9. Expected circulatory arrest 
Interventions 
This is a double-blinded trial. Anesthetists and surgeons will deliver TA (i.v. 
or i.p.) or matching placebo.  
The interventions are TA i.v. + placebo i.p.  versus placebo i.v. + TA i.p. 
TA and matching placebo will be prepared and blinded in the pharmacy. 
 
TA topical (i.p.): 5 g (diluted in 50 ml normal saline) are poured into the 
pericardial cavity in 2 equal doses, 25 ml when the patient comes off-pump 
(after protamine) and the other 25 ml before sternotomy is closed. 
Placebo topical: as above without TA. 
TA intravenous (i.v.) : as per usual care from anesthetist. The anesthetist will 
give the dose that he/she usually give (usual care). The dose usually varies 
from 3 to 6 g per patient. 
Placebo (i.v.): same as above but without TA. 
Study follow up 
In-hospital,  30-day  

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DEPOSITION Protocol V3.0 
 
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1.0 STUDY SUMMARY 
 
 
We aim 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. 
 
2.0 BACKGROUND 
 
2.1 Postoperative bleeding  
 
Postoperative bleeding related to open cardiac surgery increases the rates of complications and 
mortality, representing a serious problem. It can result from many factors like acquired platelet 
dysfunction, thrombocytopenia, free heparin, clotting factors loss, and increased fibrinolysis [1-
3]. Extracorporeal circulation can result in significant fibrinolysis, reflected by increased 
concentrations of plasmin and fibrin degradation products, both of which have deleterious 
effects on platelet function [4]. Antifibrinolytic therapy has become a mainstay in cardiac 
surgical procedures for decreasing bleeding and minimizing transfusion requirements [5,6]. 
Current guidelines make a class I recommendation for intravenous tranexamic acid (TA) use as a 
blood-conservation strategy during cardiac operations to reduce bleeding [7].  
 
Although intravenous TA is usually well tolerated, its antifibrinolytic effect can theoretically 
increase the risk of thromboembolic events (e.g. early graft closure in coronary artery bypass 
grafting, deep vein thrombosis, pulmonary embolism, myocardial and cerebral infarctions), but 
in practice these adverse events were reported quite rarely [8, 9]. The most significant adverse 
effect recently reported in small and large studies of cardiac surgery is the risk of postoperative 
convulsive seizures after administration of different intravenous doses of TA, particularly with 
high-dose regimens [9-11]. This effect is possibly due to the similarity between TA molecules 
and the molecules of g-aminobutyric acid, which leads to the occupancy of g-aminobutyric A 
brain receptors [12].   
 
2.2 Why is this study needed now?   
 
When used topically, TA is effective in controlling bleeding in patients with hemorrhagic 
diathesis and in patients who are treated with anticoagulants pre-operatively. It is also effective 
in controlling bleeding in oral, orthopedic, gynaecologic, and otolaryngeal surgeries [13-15]. In 
addition, the fibrinolytic activity in the pericardial cavity exceeds that in the systemic circulation 
as human pericardium contains high levels of tissue plasminogen activator, which under 
normal/physiological conditions prevents the formation of adhesions and maintains the fluidity 
of the pericardial [16,17]. Furthermore, surgical tissue manipulations may enhance this local 
fibrinolytic activity. All these findings lead to the rationale for the topical application of TA into 
the pericardial cavity during cardiac surgery.  

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Between 2000 to 2016, seven small randomized controlled trials comparing the topical 
application of TA vs. placebo were reported [18–24]. In all of these trials the topical application 
of TA significantly reduced the 24-hour postoperative blood loss. We performed a meta-
analysis (Appendix 1) of these 7 trials and confirmed the substantial reduction in 24-hour blood 
loss with topical application of TA [25]. In two other reports, the addition of topical application 
to intravenous TA vs. intravenous TA alone did not added benefit in reducing postoperative 24-
hour blood loss compared with intravenous drug alone [26,27] but significantly less products 
were used [26] or significantly less seizures were seen with intravenous TA plus topical TA 
[27]due to lower of intravenous TA used. No studies comparing the effectiveness of topical 
application vs. intravenous administration of TA are reported. We hypothesize that topical 
application of TA can reduce postoperative bleeding in patients who have undergone cardiac 
surgery without the risk of seizures associated with systemic (intravenous) infusion of TA.  
 
2.3 Conclusions/future direction  
 
This is a 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 trial 
using a cluster crossover design with blinding of drugs in pharmacy.  
3.0 PLAN OF INVESTIGATION 
3.1 Objectives 
3.1.1. Primary objectives are:  
We hypothesize that topical intra-pericardial (i.p.) application of TA vs. intravenous (i.v.) 
will reduce postoperative bleeding in patients who have undergone cardiac surgery 
using cardiopulmonary bypass (CPB) and decrease or eliminate the risk of seizures.  
 
3.1.2 Secondary objectives are: 
• Postoperative Number of Participants developing seizure 
• Number of Participants Requiring Surgical Re-exploration (bleeding/tamponade) 
• Total Blood Transfusions and components 
• Length of ICU stay  
• All-cause death 
• Plasma level of TA on arrival in ICU 
 
3.2 Study Setting and Design 
This study is a single-center randomized controlled clinical (RCT) trial at the Hamilton 
General Hospital site. Patients will be recruited before surgery by the research staff.   
3.3 Sample size 

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We will recruit a sample of 115 patients for this pilot study. 
 
3.4 Intervention 
 
The TA comes in bottle of 1g per 10 ml of normal saline or in 5g per 50ml of normal 
saline. For topical applications, we have selected a dose of 5 g of TA (or matching placebo) for 
simplicity as it comes in a reasonable volume of saline to allow distribution everywhere in the 
mediastinum.  The topical will be poured into the pericardial mediastinal cavities in 2 equal 
doses, 25 ml when the patient comes off-pump (after protamine) and the other 25 ml before 
sternotomy is closed.  
The intravenous dose is not standardized at all across the country. Every 
anesthesiologist has his/her own concoction and a standardization of the dose is very difficult. 
The ATACAS trial had a lot of difficulty with this and had to cut the dose in half during the trial 
in order to improve participation and recruitment. Therefore, we will let each anesthesiologist 
give their usual dose. We will collect the dose on induction and subsequent per-infusion. We 
will analyze the results according to the dose per kg. 
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. 
 
We will collect blood at arrival in ICU to measure the serum level of TA in both groups. 
 
3.5 Timeline 
Cardiac surgery is performed on approximately 125-140 patients per month.  We plan 
on recruiting the 115 patients in a 4 month period.   
Consented patients will undergo the intervention during the surgery.  Blood tests are 
done in ICU-West within 3 hours.  Patients will be seen by research staff daily in hospital until 
discharge and will be followed up at 30 days as per chart below.   

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a Primary and secondary outcome events.  
  
 
4.0 ELIGIBILITY CRITERIA  
4.1 Inclusion Criteria 
1. Male or female ≥ 18 years old 
2. Undergoing cardiac surgical procedure with the use of cardiopulmonary bypass and 
median sternotomy. 
3. Provide written informed consent 
 
4.2 Exclusion Criteria 
1. Poor (English) language comprehension  
2. Minimally invasive surgery  
3. Off-pump procedures 
4. Emergency operations 
5. Known history of increased bleeding disorder 
6. Thromboembolic disease 
7. Allergy to tranexamic acid 
8. Severe renal impairment (eGFR <30 mL/min/1.73m2 ) 
9. Expected circulatory arrest 
 
5.0 STUDY PHASES  
5.1 Phase I: Baseline  
 
Time period 
Screening 
Baseline 
OR 
Post-op 
Clinical or Phone Visit  
(30 days) 
Eligibility 
X 
 
 
 
 
Informed Consent  
X 
 
 
 
 
Medical History 
 
X 
 
 
 
Demographics 
 
X 
 
 
 
Medications  
 
X 
 
X 
X 
Operative Details 
 
 
X 
 
 
Eventsa 
 
 
 
X 
X 

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Eligible patients will be approached by a trained member of the research team before 
surgery to obtain consent to participate in the study. When the consent is signed, the 
randomization will be done at PHRI. The ratio is 1:1 with blocks of 2 and 4 patients.   
Upon obtaining written informed consent, research staff will collect baseline risk data 
from the patient’s chart including demographics, relevant information from medical history and 
physical examination, and medication.   
5.2 Phase II: In-hospital  
 
Research staff will prospectively collect relevant intra-operative details from 
observations in the OR and referring to the anesthesia and OR documentation.  
5.3 Phase III: Follow-up 
 
Participants will complete a follow-up (surgeon’s office or by phone) that will be 
scheduled at 30 days post-op.   
6.0 STUDY OUTCOMES 
6.1 Primary Outcomes 
1. Postoperative chest tube production 24 hours after surgical procedure  
2. Rate of crossover (need to use both approaches or supplementary dose of TA) 
3. Recruitment rate per week 
4. Proportion of patients lost to follow-up at 30 days post-operatively 
 
6.2 Secondary Outcomes 
1. Postoperative Number of Participants developing seizure 
2. Number of Participants Requiring Surgical Re-exploration (bleeding/tamponade) 
3. Total Blood Transfusions 
4. Length of ICU stay  
5. All-cause death 
6. Level of TA on arrival in ICU 
 
6.3 Reporting and Adjudication of Outcomes 
If it becomes evident from the clinic visit or telephone follow-up that the participant 
suffered from any event of interest or a hospital-readmission, the institution where the patient 
was admitted will be contacted by members of the research team to request the patient’s chart 
around this episode.  
If the patient is deceased, the death certificate will be requested from the institution 
where the death took place or from the patient’s family physician if the death occurred outside 
of hospital. This will allow us to collect information about the cause of death.  
 

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Available source documents will be adjudicated by two independent reviewers at the 
central project office. We will adjudicate the following outcomes:  mortality, surgical re-
exploration and seizures.  
All adjudication will be performed by a committee of clinicians independent of the study 
design and conduct. The clinicians on this committee will be individuals with experience in 
perioperative outcomes.  
7.0 STATISTICAL ANALYSIS 
 
7.1 General Considerations 
 
Standard methods will be used to provide tabular and graphical summaries as 
appropriate for continuous and categorical variables. Summaries of continuous variables will 
include the number of subjects (N), mean, standard deviation, median, quartiles 1 and 3, 
minimum and maximum. Frequency distributions (N and %) will be given for categorical data. 
Descriptive summaries will be provided overall, and by surgical technique. Baseline 
characteristics will be compared between patients with and without covert stroke with chi-
square tests for categorical variables, and analysis of variance for numerical variables (or 
Kruskal-Wallis [non-parametric] test, if the assumption of normality of the residuals and/or 
homoscedasticity do not hold). Analyses will be conducted with SAS version 9.4 or higher, and 
the significance level will be 0.05. 
 
7.2 Analysis of the primary objective 
 
The primary outcome (blood loss) will be analyzed with a t-test as it is a continuous variable.  
7.3 Analysis of Secondary Objectives 
 
The secondary outcomes (death, surgical re-exploration, seizures) will be compared via a 
Fisher’s exact test as their frequency will be low. Transfusions will be analyzed by chi-square. 
Plasma levels and length of stay will be analyzed with a t-test.  
Method Development and Measurement of Tranexamic Acid in Blood - The proposed study 
aims at developing a method for measurement of antifibrinolytic agent, tranexamic acid, in 
blood for potential therapeutic monitoring of this drug. The specific objectives of this study are 
1) to develop, optimize, and validate an analytical method for measurement of tranexamic acid 
levels in human plasma and serum; 2) use the in-house developed method for measuring 
tranexamic acid in patients treated the drug during the open heart surgery, who have been 
enrolled in the DEPOSITION Study.  
The Biochemical Genetics Laboratory, Hamilton Regional Laboratory Medicine Program at 
McMaster University Medical Centre will be developing and validating the method using liquid 

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chromatography-mass spectrometry technology.   This will be led by Dr. Murray Potter and Dr. 
Josko Ivica.   
8.0 PROJECT MANAGEMENT 
The study will be centrally co-ordinated by the Peri-operative and Cardiac Surgery 
division of the Population Health Research Institute (PHRI) at McMaster University, Hamilton, 
Canada. The NeuroVISION Cardiac Project Office will be responsible for the day-to-day study 
management of this pilot.   
9.0 ETHICAL STANDARDS 
9.1 Good Clinical Practice (GCP) 
The procedures set out in this protocol are designed to ensure that the investigator abide 
by the principles of the Declaration of Helsinki and Good Clinical Practice Guidelines (ICH-GCP) in 
the latest version, in conduct, evaluation and documentation of the study.  
9.2 Informed consent of the patient 
Patients who meet all inclusion criteria and none of the exclusion criteria are deemed 
eligible. Before being registered into the clinical study, all patients, or their proxy decision-makers, 
will be explained the details of this study protocol, and be asked to sign a consent form for 
participation after the nature, scope and possible consequences of the study have been explained 
both orally and in writing.  
 
9.3 Approval of study protocol 
Before the start of the study, the study protocol and the informed consent form used at 
the site and other appropriate documents must be submitted to and approved by Hamilton Health 
Sciences Research Ethics Board (HIREB) before sites are activated to enroll patients. 
9.4 Maintenance of records 
The Investigator agrees to obtain a correctly completed informed consent form for each 
patient included in the study. The investigator will maintain a personal list of patient numbers and 
patient names to enable records to be found at a later date. The Investigator must maintain all 
study records, patient files and other source data for the maximum period of time permitted by 
the hospital, institution or private practice.  
9.5 Confidentiality 
 
All patient names will be kept confidential. Patients will be identified by the patient ID 
number allotted to them by the study. The patients will be assured that all findings will be stored 
on computer and handled in the strictest confidence. The Investigator agrees to maintain the 
confidentiality of the study protocol. 

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10.0 REFERENCES 
1-Kucuk O, Kwaan HC, Frederickson J, Wade L, Green D: Increased fibrinolytic activity in 
patients undergoing cardiopulmonary bypass operation.Am J Hematol1986; 23:223-9. 
2-Harker LA, Malpass TW, Branson HE, Hessel EA II, Slichter SJ: Mechanism of abnormal 
bleeding in patients undergoing cardiopulmonary bypass: acquired transient platelet 
dysfunction associated with selective alpha-granule release. Blood 1980; 56:824-34. 
3-Depotis GJ, Santoro SA, Spitznagel E, Kater KM, Cox JL, Barnes P: Prospective evaluation and 
clinical utility of on-site monitoring of coagulation in patients undergoing cardiac operation. J 
Thorac Cardiovasc Surg. 1994; 107:271-279. 
4-Lemmer JH Jr, Stanford W, Bonney SL, Breen JF, Chomka EV, Elderge WJ: Aprotonin for 
coronary bypass operations: efficacy, safety, and influence on early saphenous graft patency-a 
multicenter, randomized, double blind, placebo-controlled study. J Thorac Cardiovasc Surg 
1994, 107:543-53. 
5-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 bypass grafting. Braz J Med Biol Res 2006; 39:63–69. 
6-Pleym H, Stenseth R, Wahba A, Bjella L, Karevold A, Dale O. Single dose tranexamic acid 
reduces post-operative bleeding after coronary surgery in patients treated with aspirin until 
surgery. Anesth Analg 2003; 96:923–92 8. 
7-Ferraris VA, Brown JR, Despotis GJ, et al. 2011 update to the Society of Thoracic Surgeons and 
the Society of Cardiovascular Anesthesiologists blood conservation clinical practice guidelines. 
Ann Thorac Surg 2011; 91:944–98 2. 
8-Ross J., Al-Shahi S.R. The frequency of thrombotic events among adults given antifibrinolytic 
drugs for spontaneous bleeding: systematic review and meta-analysis of observational studies 
and randomized trials, Current Drug Safety 2012;7: 44–54. 
9-Myles PS, Smith JA, Forbes A, et al. Tranexamic acid in patients undergoing coronary-artery 
surgery. N Engl J Med. 2017;376:136-148. 
10-Martin K., Wiesner G., Breuer T., et al., The risks of aprotinin and tranexamic acid in cardiac 
surgery: a one-year follow-up of 1188 consecutive patients, Anesthesia and Analgesia 2008; 
107:1783–1790. 
11-Kalavrouziotis D., Voisine P., Mohammadi S., et al. High-dose tranexamic acid is an 
independent predictor of early seizure after cardiopulmonary bypass, Annals of Thoracic 
Surgery 2012;93:148–153. 
12-Furtmu¨ller R., Schlag M.G., Berger M., et al., Tranexamic acid, antifibrinolytic agent, causes 
convulsions by g-aminobutyric acid A receptor antagonistic effect, Journal of Pharmacology and 
Experimental Therapeutics 2002; 301:168–173. 

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13-Versraette M: Clinical application of fibrionolysis. Drugs 1985; 29:236-61. 
14-Valsecchi A: Further notes on the topical use of Tranexamic acid in the treatment of 
gynaecological haemorrhage. Minerva Ginecol 1980; 32:825-30. 
15-Sindet-Pedersen S, Ramtro G, Bernvil S, Blomback M: Haemostatic effect of tranexamic acid 
mouthwash in anticoagulanttreated patients undergoing oral surgery. N Engl J Med 1989; 
320:840-3. 
16-Henry D, Carless P, Fergusson D, Laupacis A: The safety of aprotinin and lysine-derived 
antifibrinolytic drugs in cardiac surgery: a meta-analysis. CMAJ 2009; 180(2):183-93. 
17-Alderman EL, Levy JH, Rich JB: Analyses of coronary graft patency after Aprotinin use: results 
from the International Multicenter Aprotinin Graft Patency Experience study (IMAGE) trial. J 
Thorac Cardiovasc Surg 1998; 116:716-730. 
18-De Bonis M., Cavaliere F., Alessandrini F., et al., Topical use of tranexamic acid in coronary 
artery bypass operations: a double-blind, prospective, randomized, placebo-controlled study, 
Journal of Thoracic and Cardiovascular Surgery 2000;119:575–580. 
19-Abul-Azm A., Abdullah K.M., Effect of topical tranexamic acid in open heart surgery, 
European Journal of Anaesthesiolgy 23 (2006) 380–384. 
20-Baric D., Biocina B., Unic D., et al., Topical use of antifibrinolytic agents reduces 
postoperative bleeding: a double-blind, prospective, randomized study, European Journal of 
Cardiothoracic Surgery 2007;31:366–371. 
21-Fawzy H., Elmistekawy E., Bonneau D., et al., Can local application of tranexamic acid reduce 
post-coronary bypass surgery blood loss? A randomized controlled trial, Journal of 
Cardiothoracic Surgery 2009;4:25. 
22-Aoki M, Okawa Y, Goto Y, Ogawa S, Baba H. Local administration of tranexamic acid in off-
pump coronary artery bypass. Asian Cardiovasc Thorac Ann. 2012; 20:658-62. 
23-Hosseini H, Rahimianfar AA, Abdollahi MH, Moshtaghiyoon MH, Haddadzadeh M, Fekri A, 
Barzegar K, Rahimianfar F. Evaluations of topical application of tranexamic acid on post-
operative blood loss in off-pump coronary artery bypass surgery. Saudi J Anaesth. 2014; 8:224-
8.  
24-Ali Shah MU, Asghar MI, Siddiqi R, Chaudhri MS, Janjua AM, Iqbal A. Topical application of 
tranexamic acid reduces postoperative bleeding in open-heart surgery: myth or fact? J Coll 
Physicians Surg Pak. 2015; 25:161-5. 
25-Habbab LM, Semelhago L, Lamy A. Intrapericardial Use of Tranexamic Acid in Cardiac 
Surgery:  a meta-analysis of seven RCT. (in process). 

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26-Spegar J., Vanek T., Snircova J., et al., Local and systemic application of tranexamic acid in 
heart valve surgery: a prospective, randomized, double blind LOST study, Journal of Thrombosis 
and Thrombolysis 32 (2011) 303–310. 
27-Taman HI., Amer GF., Amera SA. Can topical administration of tranexamic acid be a good 
adjuvant to the intravenous route for decreasing postoperative seizure incidence? A double 
blinded randomized study. Ain-Shams Journal of Anesthesiology 2015; 08:36–42 

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11.0 EVENT DEFINITIONS 
 
Chest tube bleeding 
The bleeding will be collected from the nurses’ charts at 24 hours after arrival in ICU 
 
Seizure 
All causes of seizures will be recorded as the secondary outcome. We will define further these 
seizures as related to a stroke (including acute cerebral ischemia, TIA, covert stroke) or as 
unknown 
 
Surgical exploration 
All causes of return to the operating room for bleeding, tamponade, surgical ischemia or shock. 
Pacemaker insertion, tracheostomy are sternal dehiscence/mediatinitis are excluded. 
 
Transfusions 
All blood products (except albumin) will be recorded and analyzed as a total but also 
individually by type. Usage of factor VII will be also recorded 
 
Death 
Any death regardless of cause. Death will be stratified as cardiac and non-cardiac. All deaths in 
the first 30 days or before hospital discharge will be considered cardiac deaths. 
Cardiac Death - All death related to cardiovascular system or of sudden or unknown cause. 
Non-Cardiac Death – Defined as clearly documented death unrelated to cardiovascular system 
(e.g. trauma, malignancy, suicide).  
 
Clinical stroke  
Stroke that is clinically apparent and confirmed by a neurologist and imaging (CT scan or MRI) 
 
Acute cerebral ischemia  
Acute cerebral ischemia will be defined as a hyper intense lesion on diffusion-weighted/T2 
magnetic resonance imaging  
 
Covert stroke  
Covert stroke is defined as acute cerebral ischemia detected on MR testing, but without any 
new clinical findings of focal neurological deficits.  
 
Overt Stroke  
Overt stroke is defined as a new focal neurological deficit thought to be vascular in origin with 
signs and symptoms lasting more than 24 hours, as diagnosed by a physician involved in the 
patient’s care.  
 

Page 18 of 18 
DEPOSITION Protocol V3.0 
 
2018-03-16 
Transient Ischemic Attack  
Transient ischemic attack is defined as a new focal neurological deficit thought to be vascular in 
origin with signs and symptoms lasting less than 24 hours, as diagnosed by a physician involved 
in the patient’s care.  
 
Myocardial infarction (MI) 
The diagnosis of myocardial infarction requires any one of the following criteria:  
1. A typical rise of troponin or a typical fall of an elevated troponin detected at its peak post 
surgery in a patient without a documented alternative explanation for an elevated troponin 
(e.g., pulmonary embolism). This criterion also requires that 1 of the following must also exist:  
a. ischemic signs or symptoms (i.e., chest, arm, neck, or jaw discomfort; shortness 
of breath, pulmonary edema)  
b. development of pathologic Q waves present in any two contiguous leads that are 
> 30 milliseconds  
c. ECG changes indicative of ischemia (i.e., ST segment elevation [> 2 mm in leads 
V1, V2, or V3 OR > 1 mm in the other leads], ST segment depression [> 1 mm], or 
symmetric inversion of T waves > 1 mm) in at least two contiguous leads  
d. coronary artery intervention (i.e., PCI or CABG surgery)  
e. new or presumed new cardiac wall motion abnormality on echocardiography or 
new or presumed new fixed defect on radionuclide imaging  
2. Pathologic findings of an acute or healing myocardial infarction  
3. Development of new pathological Q waves on an ECG if troponin levels were not obtained or 
were obtained at times that could have missed the clinical event  
 
Renal failure 
Patients who require dialysis after surgery (not including peri-operative dialysis) 
 
New delirium 
Defined as acute onset of confusion fulfilling the diagnostic criteria of the Cognitive Assessment Method 
(CAM) for delirium.  
1) Acute onset of fluctuating cognitive impairment;  
2) Deficits of attention; AND  
3) One of:  
a. altered level of consciousness; OR  
b. disorganized thought processes.