TRANEXAMIC ACID IN THE TREATMENT OF RESIDUAL CHRONIC SUBDURAL HEMATOMA: A SINGLE-CENTRE,

OBSERVER-BLINDED, RANDOMIZED CONTROLLED TRIAL (TRACE)

by

Adriana Micheline Workewych

A thesis submitted in conformity with the requirements for the degree of Master of Science

Institute of Medical Science

University of Toronto

© Copyright by Adriana Micheline Workewych 2018

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TRANEXAMIC ACID IN THE TREATMENT OF RESIDUAL CHRONIC SUBDURAL HEMATOMA: A SINGLE-CENTRE,

OBSERVER-BLINDED, RANDOMIZED CONTROLLED TRIAL (TRACE)

Adriana Micheline Workewych

Master of Science

Institute of Medical Science University of Toronto

2018

ABSTRACT

Chronic subdural hematoma (CSDH) is a frequent consequence of head trauma, particularly

in older individuals. Given the aging of populations globally, its incidence is projected to

increase substantially. Hyperfibrinolysis may be central to CSDH enlargement by causing

excessive clot degradation and liquefaction, impeding resorption. The only current standard

treatment for CSDH is surgery, however, up to 31% of residual hematomas enlarge,

requiring reoperation. Tranexamic acid (TXA), an antifibrinolytic medication that prevents

excessively rapid clot breakdown, may help prevent CSDH enlargement, potentially

eliminating the need for repeat surgery. To evaluate the feasibility of conducting a trial

investigating TXA efficacy in residual CSDH, we conducted an observer-blinded, pilot

randomized controlled trial (RCT). We showed this trial was feasible and safe, reporting only

minor to moderate AEs, and an attrition rate of 4%. The results from this study will inform

the conduct of a double-blinded RCT investigating TXA efficacy in post-operative CSDH

management.

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ACKNOWLEDGEMENTS

First, I would like to thank my supervisor Dr. Michael Cusimano, my mentor for nearly six

years. You have always given me more opportunity than I could have ever hoped for – I

could not ask for a more dedicated teacher. Learning from you has been an absolute

privilege.

Thank you to my Program Advisory Committee members, Dr. Jeannie Callum and Dr. Olli

Saarela. It has been an honor to learn from you these past two years, and I am greatly

indebted to you for the time and effort you have put into guiding me through this trial and

thesis.

Thank you to Dr. Michael Meier, who enthusiastically contributed to the initial study idea.

Thank you to Dr. Irene Vanek – you have been the greatest support these past six years, and I

am grateful to learn from you every day.

Thank you to Dr. Walter Montanera for your guidance in reading CT imaging and your

expertise in designing the trials imaging protocol, and the substantial time and effort you put

into teaching me over the years.

Thank you to all the neurosurgeons at St. Michael’s Hospital – Dr. Julian Spears, Dr.

Jefferson Wilson, Dr. Sunit Das, Dr. Howard Ginsberg, and Dr. Richard Perrin – for

allowing your patients to be enrolled in the trial, and for your time in evaluating participant

eligibility.

Thank you to all the neurosurgery residents and fellows who took the time to screen and

speak to eligible patients: Dr. Farshad Nassiri, Dr. Benjamin Davidson, Dr. Arthur Dalton,

Dr, Allan Martin, Dr. Matthew Voisin, Dr. Justin Wang, and Dr. Ali Moghaddamjou.

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Thank you to all the registered nurses, pharmacists, and staff on the 9CC Neurosurgery

Ward, without whom conducting this trial would not have been possible: Tom Willis,

Theresa Cooke, Martine Andrews, Linda Lo, April Sienes, Jenny Pak, Elyse Kalpage, Renee

Ng, and Winnie Chan. Thank you to Judy Pararajasingham and Sanam Shinde for your help

organizing the study on the ward, and training staff in study procedures.

Thank you to all the members of the Research Pharmacy, namely Laura Parsons, Ann

Dowbenka and Gitana Ramonas, for your instrumental roles in randomizing our study

patients and dispensing the study drug so meticulously. Thank you to the pharmacists – Mae

Yuen, Emily Wong, Kevin Curley, and Mark Naccarato – who came in on evenings and

weekends to randomize patients and dispense the study drug.

Thank you to Cristina Lucarini, Lee-Ann Graham, Umberta Bottoni, Chris Northrup,

Shamim Sumar, Ann Augello, Barb Chamczuk, Brianna Richard-Gallant and Kacper

Michalak for helping me coordinate clinical study visits.

Thank you to all the members of the CT imaging department, including Shadi Mossaed and

Cristhian Moran, without whom we would not have been able to obtain our hematoma

volume measurements.

Thank you to Marlene Santos and Velma Marzinotto, who patiently guided me through the

many procedures of coordinating a clinical trial.

Thank you also for the academic and moral support of the members of the Injury Prevention

Research Office Team, both past and present: Stanley Zhang, Ling Chen, Karen Delina, Dr.

Zsolt Zador, Dr. Kenny Yu, Dr. Omar Pathmanaban, Dr. Cesar Hincapie, Dr. Rowan Xing

and Julia Casey.

This work was supported by the AFP Innovation Funds. Thank you also to the Institute of

Medical science for awarding me with the Institute of Medical Science Admissions Awards

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and Open Fellowship Award, which have supported me in my academic pursuits, and for

which I am sincerely grateful.

Finally, thank you to the participants of this study, who, in a moment of great personal

stress, selflessly dedicated their time to the pursuit of science, in a mission to improve the

care of future patients suffering this affliction.

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This work is dedicated to Natalie, my better half – I will never be able to thank you enough for everything you have done for me.

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CONTRIBUTIONS

PAC members: intellectual contributions to the study design, protocol, and thesis revisions.

Research pharmacy department: study randomization and study drug dispensation.

Registered nurses: in-patient study drug administration.

Shadi Mossaed: coordinating the CT imaging department.

Dr. Rowan Xing: exploratory power calculation.

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TABLE OF CONTENTS

ACKNOWLEDGEMENTS………………………………………………………………...iii

CONTRIBUTIONS………………………………………………………………………...vii

TABLE OF CONTENTS………………………………………………………………….viii

ABBREVIATIONS………………………………………………………………………...xiv

LIST OF TABLES…………………………………………………………………………xvi

LIST OF FIGURES……………………………………………………………………….xvii

LIST OF APPENDICES…………………………………………………………………xviii

1. INTRODUCTION AND LITERATURE REVIEW

1.1 CHRONIC SUBDURAL HEMATOMA: THE CLINICAL PICTURE AND

CURRENT STANDARD OF CARE………………………………………………1

1.1.1 WHAT IS A CHRONIC SUBDURAL HEMATOMA?...………………………1

1.1.2 RELEVANT NEUROANATOMY AND FORMATION OF A CHRONIC

SUBDURAL HEMATOMA…….………………………………………………1

1.1.3 ETIOLOGY, DEMOGRAPHICS AND CLINICAL PRESENTATION………3

1.1.4 RISK FACTORS FOR DEVELOPMENT………………………………………3

1.1.5 SUBDURAL HEMATOMA APPEARANCE ON AND SUBTYPE

CLASSIFICATION WITH DIAGNOSTIC IMAGING…………………………4

1.1.6 SURGICAL EVACUATION IS THE STANDARD TREATMENT FOR

CSDH…………………………………………………………………………….7

1.1.7 SURGICAL AND MEDICAL COMPLICATIONS AFTER SURGICAL

EVACUATION………………………………………………………………….8

1.2 THE CLINICAL PROBLEM: POST-OPERATIVE HEMATOMA

RECURRENCE…………………………………………………………………….9

1.2.1 DEMOGRAPHIC, CLINICAL, OPERATIVE, AND RADIOLOGIC

PREDICTORS OF POST-OPERATIVE CSDH RECURRENCE………………9

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1.2.2 RADIOLOGIC HEMATOMA SUBTYPES AS PREDICTORS OF

RECURRENCE………………………………………………………………...13

1.3 PATHOGENESIS AND THE MECHANISM OF CSDH ENLARGEMENT…14

1.3.1 OSMOLARITY………………………………………………………………....14

1.3.2 INFLAMMATION……………………………………………………………...14

1.3.3 ANGIOGENESIS…………………………………………………………….…17

1.3.4 HYPERFIBRINOLYSIS…………………………………………………….….18

1.3.5 MECHANICAL MECHANISMS………………………………………………22

1.4 NON-SURGICAL TREATMENT OF CSDH……………………………………22

1.5 TRANEXAMIC ACID…………………………………………………………….24

1.5.1 CURRENT THERAPEUTIC INDICATIONS…………………………………25

1.5.2 PHARMACOLOGY……………………………………………………………26

1.5.3 SAFETY………………………………………………………………………...27

1.5.4 CONTRAINDICATIONS……………………………………………………....27

1.5.5 WARNINGS AND PRECAUTIONS…………………………………………...28

1.5.6 DRUG INTERACTIONS……………………………………………………….30

1.5.7 SIDE EFFECTS AND ADVERSE EVENTS…………………………………..30

1.6 DOSING REGIMENS IN TRANEXAMIC ACID TREATMENT…………….30

1.7 TRANEXAMIC ACID TREATMENT IN TRAUMA AND NEUROSURGICAL

CONDITIONS………………………………………………………………….….31

2. STUDY RATIONALE AND DESIGN……………………………………………34

2.1 STUDY DESCRIPTION AND OBJECTIVES…………………………………...36

2.1.1 PRIMARY STUDY OBJECTIVE………………………………………………36

2.1.1.1 Feasibility………………………………………………………………………..36

2.1.2 SECONDARY STUDY OBJECTIVES…………………………………………36

2.1.2.1 Hematoma volume change………………………………………………………36

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2.1.2.2 Neurological status………………………………………………………………37

2.1.2.3 Quality of life…………………………………………………………………….37

2.1.2.4 TXA safety………………………………………………………………………..37

2.2 STUDY DESIGN…………………………………………………………………...38

2.2.1 STUDY DURATION AND TIMELINE………………………………………..38

2.2.2 RESEARCH ETHICS BOARD AND HEALTH CANADA APPROVAL…….41

2.3 PARTICIPANT ELIGIBILITY AND RECRUITMENT………………………..41

2.3.1 INCLUSION CRITERIA………………………………………………………..41

2.3.2 EXCLUSION CRITERIA……………………………………………………….42

2.3.3 PATIENT SCREENING AND DETERMINING PATIENT ELIGIBILITY…..43

2.3.4 PARTICIPANT RECRUITMENT………………………………………………43

2.3.5 PARTICIPANT RANDOMIZATION…………………………………………..44

2.4 STUDY DRUG……………………………………………………………………...44

2.4.1 TXA DOSING REGIMEN………………………………………………………44

2.4.2 TXA DISPENSING PROCEDURES…………………………………………....46

2.4.3 MONITORING STUDY DRUG COMPLIANCE………………………………46

3. STUDY METHODS………………………………………………………………..47

3.1 DATA COLLECTION……………………………………………………………..47

3.1.1 STUDY FEASIBILITY DATA………………………………………………….47

3.1.2 RADIOLOGIC DATA…………………………………………………………..47

3.1.2.1 Hematoma volume calculation…………………………………………………..47

3.1.2.2 Other radiologic variables………………………………………………………51

3.1.3 NEUROLOGICAL TESTS AND ASSESSMENTS…………………………….53

3.1.3.1 Glasgow Coma Scale…………………………………………………………….53

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3.1.3.2 Glasgow Outcome Scale-Extended………………………………………………53

3.1.3.3 Markwalder Grading Score……………………………………………………...54

3.1.3.4 modified Rankin Scale…………………………………………………………...54

3.1.3.5 National Institutes of Health Stroke Scale……………………………………….54

3.1.4 QUALITY OF LIFE (QOL) MEASURES………………………………………55

3.1.4.1 SF-36…………………………………………………………………………….55

3.1.4.1.1 SF-36 questionnaire overview……………………………………………….55

3.1.4.1.2 Scoring of the SF-36…………………………………………………………56

3.1.4.2 HUI……………………………………………………………………………....56

3.1.4.2.1 HUI questionnaire overview…………………………………………………56

3.1.4.2.2 Scoring of the HUI questionnaire……………………………………………57

3.2 CASE REPORT FORM AND DATA COLLECTION MONITORING………59

3.3 SAFETY MONITORING…………………………………………………………60

3.3.1 LABORATORY TESTS………………………………………………………...60

3.3.2 OPHTHALMOLOGICAL EVALUATIONS…………………………………...60

3.3.3 MONITORING AND MANAGING ADVERSE EVENTS AND ADVERSE

DRUG REACTIONS……………………………………………………………61

3.4 STUDY ENDPOINTS, PARTICIPANT DISCONTINUATION, AND

PARTICIPANT WITHDRAWAL………………………………………………...61

3.5 DATA ANALYSIS…………………………………………………………………62

3.5.1 STATISTICAL TESTS…………………………………………………………62

3.5.2 SAMPLE SIZE CALCULATION………………………………………………62

4. RESULTS……………………………………………………………………….….63

4.1 CONSORT FLOW DIAGRAM…………………………………………………..63

4.2 PARTICIPANT RECRUITMENT AND STUDY FEASIBILITY……………...64

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4.3 BASELINE DEMOGRAPHICS AND CLINICAL CHARACTERISTICS……67

4.4 RADIOLOGIC SUBDURAL HEMATOMA FEATURES……………………...69

4.4.1 BASELINE RADIOLOGIC CHARACTERISTICS……………………………69

4.4.2 HEMATOMA VOLUME CHANGE OVER STUDY COURSE……………….71

4.4.3 HEMATOMA RECURRENCE RATE AND NEED FOR REOPERATION…..74

4.5 NEUROLOGICAL STATUS ASSESSMENTS AT BASELINE AND 4-8 WEEK

FOLLOW-UP………………………………………………………………………75

4.6 QUALITY OF LIFE ASSESSMENT SCORES AT BASELINE AND

FOLLOW-UP………………………………………………………………………78

4.6.1 SF-36 QUESTIONNAIRE SCORES AT BASELINE AND 4-8 WEEK

FOLLOW-UP……………………………………………………………………79

4.6.2 HUI QUESTIONNAIRE SCORES AT BASELINE AND 4-8 WEEK

FOLLOW-UP……………………………………………………………………80

4.6.2.1 HUI Mark 3……………………………………………………………………...80

4.6.2.2 HUI Mark 2……………………………………………………………………...85

4.7 ADVERSE EVENTS AND TXA SAFETY……………………………………….89

5. DISCUSSION…………………………………………………………………….....91

5.1 BASELINE DEMOGRAPHIC AND CLINICAL CHARACTERISTICS……..91

5.2 RADIOLOGIC SUBDURAL HEMATOMA CHARACTERISTICS…………..92

5.3 PRIMARY OUTCOME……………………………………………………………92

5.3.1 STUDY FEASIBILITY AND RECRUITMENT RATE………………………..92

5.3.2 STUDY DRUG COMPLIANCE AND OUTCOME MEASURE

COMPLETION………………………………………………………………….98

5.4 SECONDARY OUTCOMES……………………………………………………..100

5.4.1 HEMATOMA VOLUME CHANGE FROM BASELINE TO FOLLOW-UP..100

5.4.2 HEMATOMA RECURRENCE AND REOPERATION RATE………………101

5.4.3 NEUROLOGICAL STATUS FROM BASELINE TO FOLLOW-UP………..102

5.4.4 QUALITY OF LIFE FROM BASELINE TO FOLLOW-UP…………………104

5.4.4.1 SF-36…………………………………………………………………………...104

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5.4.4.2 HUI……………………………………………………………………………..104

5.4.5 TXA SAFETY: ADVERSE EVENTS AND SAFETY OF TXA DOSING

REGIMEN……………………………………………………………………...106

5.5 STUDY LIMITATIONS………………………………………………………….109

6. CONCLUSIONS…………………………………………………………………..113

7. FUTURE DIRECTIONS…………………………………………………………114

7.1 DOUBLE-BLINDED EFFICACY TRIAL……………………………………...114

7.2 SCOPING REVIEW OF CSDH PATHOGENESIS……………………………115

7.3 DEVELOPING A PROGNOSTIC MODEL TO ESTIMATE RISK OF CSDH

RECURRENCE…………………………………………………………………..118

7.4 INVESTIGATING CSDH PATHOGENESIS………………………………….119

8. REFERENCES…………………………………………………………………...120

9. APPENDICES…………………………………………………………………….137

xiv

ABBREVIATIONS ACE angiotensin converting enzyme ADR adverse drug reactions AE adverse event ANCOVA analysis of covariance APTT activated partial thromboplastin time ASA acetylsalicylic acid BBB blood-brain barrier bFGF basic fibroblast growth factor BHC burr-hole craniostomy BID bis in die (twice a day) bCSDH bilateral chronic subdural hematoma CAD coronary artery disease CD31 Cluster of differentiation 31 protein COX-1 cyclooxygenase-1 COX-2 cyclooxygenase-2 CRF case report form CSDH chronic subdural hematoma CSF cerebrospinal fluid CT computed tomography eGFR estimated glomerular filtration rate ELISA enzyme-linked immunosorbent assay FDP fibrin degradation product FEIBA factor eight inhibitor bypassing activity GCS Glasgow Coma Scale GFR glomerular filtration rate GOS Glasgow Outcome Score GOSE Glasgow Outcome Scale-Extended H&E hematoxylin and eosin HGF hepatocyte growth factor HRQL health-related quality of life HUI2 Health Utilities Index Mark 2 HUI3 Health Utilities Index Mark 3 ICH intracranial hemorrhage IFA intravenous fluid administration IL-1E interleukin 1 beta IL-2R interleukin 2R IL-4 interleukin 4 IL-5 interleukin 5 IL-6 interleukin 6 IL-7 interleukin 7 IL-8 interleukin 8 IL-10 interleukin 10 IL-13 interleukin 13

xv

INR International Normalized Ratio IP investigational product MeSH medical subject heading MGS Markwalder Grading Score MMP matrix metalloproteinase mRS modified Rankin Scale MVD microvessel density NIHSS National Institutes of Health Stroke Scale PAF platelet activating factor PCC prothrombin complex concentrate PECAM-1 Platelet endothelial cell adhesion molecule PGE2 prostaglandin-E2 PI Principal Investigator POA power of attorney PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses PT prothrombin time QOL quality of life RCT randomized controlled trial REB Research Ethics Board SAE serious adverse event SAH subarachnoid hemorrhage SDH subdural hematoma SDM substitute decision maker SF-36 RAND 36-Item Short Form Health Survey 1.0 SMD standardized mean difference RN registered nurse SOP Standard Operating Procedures STD standard deviation TID ter in die (three times a day) TNF-D tumor necrosis factor alpha tPA tissue plasminogen activator VEGF vascular endothelial growth factor VP ventroperitoneal

xvi

LIST OF TABLES

Table 1. Variables collected at each in-hospital and telephone follow-up for study duration

Table 2. TXA dose administration schedule according to bodyweight

Table 3. Subdural hematoma radiologic sub-classification system

Table 4. Baseline demographic and clinical characteristics

Table 5. Radiologic hematoma characteristics at baseline

Table 6. Procedure type and hematoma volume change over study course

Table 7. Neurological status at baseline and 4-8 week follow-up

Table 8. Neurological status change from baseline to 4-8-week follow-up

Table 9. SF-36 scores at baseline and 4-8 week follow-up

Table 10. Change in SF-36 scores from baseline to 4-8-week follow-up

Table 11. Frequency distribution of HUI3 single-attribute levels

Table 12. Mean overall HUI3 multi-attribute HRQL utility scores

Table 13. Change in overall HUI3 multi-attribute HRQL utility scores

Table 14. Frequency distribution of disability category based on overall HUI3 Multi-

attribute (HRQL) Utility Scores at baseline

Table 15. Frequency distribution of HUI2 single-attribute levels

Table 16. Mean overall HUI2 multi-attribute HRQL utility scores

Table 17. Change in overall HUI2 multi-attribute HRQL utility scores

Table 18. Frequency distribution of disability category based on overall HUI2 Multi-

attribute (HRQL) Utility Scores at baseline

Table 19. Frequency of adverse events and serious adverse events

xvii

LIST OF FIGURES

Figure 1. Illustration of chronic subdural hematoma (CSDH)

Figure 2. Subdural hematomas on CT imaging

Figure 3. The coagulation cascade

Figure 4. The fibrinolytic cascade

Figure 5. Mechanism of action of Tranexamic Acid (TXA)

Figure 6. Timeline of study follow-up visits and phone calls

Figure 7. Hematoma tracing technique and measurement of other radiologic features using

the Carestream PACS viewer

Figure 8. CONSORT flow diagram

Figure 9. Most common reasons for patient ineligibility

Figure 10. Cumulative participant recruitment

Figure 11. Recruitment per month

Figure 12. Proportion of eligible patients per month

Figure 13. Mean hematoma volume over time

Figure 14. Frequency distribution of overall HUI3 Multi-attribute (HRQL) Utility Scores

Figure 15. Frequency distribution of overall HUI2 Multi-attribute (HRQL) Utility Scores

Figure 16. PRISMA Flowchart

xviii

LIST OF APPENDICES

APPENDIX A: Glasgow Coma Scale

APPENDIX B: Glasgow Coma Scale-Extended

APPENDIX C: Markwalder Grading Score

APPENDIX D: modified Rankin Scale

APPENDIX E: HUI Mark 3 (HUI3) and HUI Mark 2 (HUI2) Classification Systems

1

1. INTRODUCTION AND LITERATURE REVIEW

1.1 CHRONIC SUBDURAL HEMATOMA: THE CLINICAL PICTURE AND

CURRENT STANDARD OF CARE

1.1.1 WHAT IS A CHRONIC SUBDURAL HEMATOMA?

Chronic subdural hematoma (CSDH) is one of the most frequently encountered

neurosurgical conditions, with an incidence of 13.5 persons per 100,000 (Almenawer et al.,

2014). This condition predominantly affects older individuals, with the average patient age at

time of occurrence reported to range between 63-81 years old (Asghar, Adhiyaman,

Greenway, Bhowmick, & Bates, 2002; Lee, Ebel, Ernestus, & Klug, 2004). In individuals

over the age of 65, the incidence is much higher, at 58.1 per 100,000 (Almenawer et al.,

2014). Due to the unprecedentedly rapid rate of aging of our population, this incidence is

projected to more than double in the next decade (Santarius, Kirkpatrick, Kolias, &

Hutchinson, 2010).

1.1.2 RELEVANT NEUROANATOMY AND FORMATION OF A CHRONIC

SUBDURAL HEMATOMA

In order to understand the clinical presentation and health implications of CSDH, as well as

risk factors for its occurrence, it is important to first understand the pertinent neuroanatomy.

The brain is surrounded by three tissue coverings called meninges. Directly attached to the

brain tissue is the thinnest covering, called the pia mater. Above the pia is a second, thicker

meningeal layer, called the arachnoid mater. There is a space between the pia and arachnoid

mater, called the subarachnoid space, where cerebrospinal fluid (CSF) collects and from

which its constituents are absorbed into the venous circulation for recycling. Finally, the

third and thickest meningeal covering, the dura mater, is above and directly adjacent to the

2

arachnoid mater. Unlike the subarachnoid space between the pia and arachnoid, no space

exists between the arachnoid and dura unless a space-occupying mass grows or fluid

collection occurs. It is therefore termed a potential space, as there exists a possibility of a

space forming.

The dura mater – Latin for hard mother – is a thick, fibrous tissue composed of two layers:

the meningeal dura mater, which is adjacent to the arachnoid mater, and the periosteal dura

mater, which is adjacent to the skull. In some areas of the cranial cavity, these layers separate

to form dural venous sinuses, where deoxygenated venous blood from the brain is collected

and returned to the venous circulation for reoxygenation. In order to drain the brain of

deoxygenated blood, blood vessels called bridging veins carry blood from the brain tissue to

these dural sinuses, and traverse the meninges in order to do so. Given their position, a tear in

a bridging vein can result in a slow accumulation of venous blood into the potential subdural

space between the meningeal dura and arachnoid mater, forming a collection of blood called

a hematoma (Figure 1).

Figure 1. Illustration of chronic subdural hematoma (CSDH). When trauma causes bridging veins to tear, venous blood accumulates between the meningeal dura and arachnoid mater, forming a subdural hematoma. Illustration by Adriana M. Workewych.

3

Subdural hematomas are typically traumatic in nature, resulting usually from a minor form of

head trauma. The hematoma begins as an acute bleed. Usually, fibrinolytic processes lead to

the resorption of the clot in this acute, post-traumatic phase. For unclear reasons however,

this process sometimes fails (particularly in senior populations), and the clot is not always

resorbed. Instead, over the course of weeks to months the clot breaks down, leading to a

liquefied or partially liquefied collection of blood in the subdural space, and what is

clinically and radiographically classified as a chronic subdural hematoma.

1.1.3 ETIOLOGY, DEMOGRAPHICS AND CLINICAL PRESENTATION

The presentation of patients with CSDH varies in symptoms reported and severity of those

symptoms. Most patients report having experienced headache for several days to weeks prior

to presenting to the emergency room. Other presenting symptoms include confusion,

memory problems, speech and word-finding difficulties, behavioural changes (pseudo-

dementia), lethargy, gait instability and balance problems, and hemiparesis (Liu, Bakker, &

Groen, 2014a). In rare cases, patients may present with seizure or coma. These symptoms

arise from mass-effects of the enlarging hematoma on the brain.

1.1.4 RISK FACTORS FOR DEVELOPMENT

The major risk factor for CSDH development is age. As we age, brain tissue atrophies,

resulting in an overall shrinkage of brain volume. This shrinkage creates tension on bridging

veins. An accelerating force to the head, or even to the body that causes a rapid acceleration

of the head, causes these blood vessels to tear, leading to the formation of the hematoma.

A history of previous head trauma is present in more than 60% of CSDH cases (Sousa et al.,

2013). Including unreported cases of mild head injury, head trauma is considered one of the

major risk factors for CSDH. Senior populations also have increased susceptibility to falls

4

due to balance and gait instabilities, increasing the risk of a minor head trauma event that

leads to a subdural bleed.

However, they may also develop spontaneously, with either an idiopathic origin, or as a

result of an existing medical condition. Patients who develop spontaneous intracranial

hypotension as a result of a cerebrospinal fluid leak are at increased risk of developing a

CSDH (Xia et al., 2015). Patients with a pressure-adjustable ventroperitoneal (VP) shunt

placed for hydrocephalus are likewise susceptible to intracranial hypotension and therefore at

increased risk for developing a CSDH.

Coagulation disorders or the use of anticoagulant or antiplatelet medications are significant

risk factors for CSDH (Sim, Min, Lee, Kim, & Kim, 2012). Seniors in particular are more

likely to be taking anticoagulant and antiplatelet medications for other comorbidities, such as

atrial fibrillation, coronary artery disease, or hypertension. The incidence of CSDH in

chronic renal-dialysis patients, for instance, is about ten-times higher than the general

population (Sood, Sinson, & Cohen, 2007). These patients are more likely to experience

venous hypertension, which, in addition to the anticoagulation therapy administered during

the dialysis procedure, increases the risk of subdural hematoma formation.

Another risk factor is prolonged alcohol abuse, not only because it induces brain atrophy,

liver cirrhosis with associated impairment of coagulation, but because it is more likely to

lead to unrecognized head trauma events (Sim et al., 2012). Seizures and epilepsy are also

recognized risk factors for CSDH (Balser et al., 2013; Sim et al., 2012).

1.1.5 SUBDURAL HEMATOMA APPEARANCE ON AND SUBTYPE

CLASSIFICATION WITH DIAGNOSTIC IMAGING

The standard imaging technique for radiologically investigating a subdural hematoma is

computed tomography (CT) scan. On CT imaging, a subdural hematoma appears as an extra-

axial, crescent-shaped collection of blood between the dura mater and arachnoid mater

5

(Figure 2). An acute subdural hematoma appears hyperdense on CT imaging. After several

days to weeks of clot liquefaction, the hematoma begins to appear isodense (Figure 2A)

compared to the surrounding brain tissue. Clinically, this is referred to as a subacute

hematoma. After several weeks to months of continued clot liquefaction, the hematoma

appears hypodense with respect to the brain parenchyma (Figure 2A). The fibrous outer

membrane appears hyperdense, and depending on its thickness, may or may not be visible on

imaging. Calcifications may also form within the outer membrane, appearing as

hyperdensities on a CT scan.

Depending on the age of the hematoma, degree of clot breakdown, and presence of one or

more fibrous membranes, the hematoma can appear homogenous (that is, uniform in

density), or heterogenous (mixed-density) (Figure 2B). If acute bleeds, perhaps resulting

from a second traumatic event or microbleeds from the surrounding membrane, contribute to

the existing liquefied hematoma, both hypodense and hyperdense components would appear

on CT imaging. Clinically, this is referred to as an acute-on-chronic hematoma. Mixed

density hematomas often appear as separated with fluid-fluid levels, with a hypodense

component sitting above a hyperdense component.

6

A. B.

Figure 2. Subdural hematomas on CT imaging (from left to right) A. Bilateral, homogenous chronic subdural hematomas: right hematoma appears hypodense relative to brain tissue, and left hematoma appears isodense relative to brain tissue on CT scan. B. Heterogenous (mixed-density) left-sided subdural hematoma, with hypodense, hyperdense, and isodense fluid components, traversed by loculations and septations.

Hematomas can also appear septated, or loculated, as a result of the formation of several

membranes traversing the hematoma, separating the hematoma into several compartments

rather than one uniform bleed.

Due to the mass effect of the hematoma on the surrounding brain tissue, several radiologic

features can also be noted on imaging. Often, mass effects of the hematoma cause effacement

of the surrounding sulci. Unilateral hematomas in particular often result in a midline shift as

a result of increasing intracranial pressure. Finally, while most hematomas are unilateral, up

to 25% of cases are bilateral (Y.-H. Huang, Yang, Lee, & Liao, 2013), which do not always

cause a large midline shift. The degree of midline shift is a useful indicator of patient

prognosis, and may be associated with other symptoms of intracranial hypertension, such as

7

brain tissue herniation and hydrocephalus.

1.1.6 SURGICAL EVACUATION IS THE STANDARD TREATMENT FOR CSDH

On occasion, spontaneous resolution of CSDHs has been reported (Rohde, Graf, & Hassler,

2002). However, due to the fact that an enlarging hematoma places increasing pressure on

surrounding brain tissue, surgical evacuation is the preferred treatment, particularly for

symptomatic hematomas. Medical interventions, while previously explored, were quickly

considered inferior to surgical intervention.

The current standard treatment for CSDH is surgical evacuation (Regan, Worley, Shelburne,

Pullarkat, & Watson, 2015). At most neurosurgical institutions, the preferred approach is

burr-hole craniostomy (BHC) to evacuate the hematoma. This technique is minimally-

invasive compared to a larger craniotomy, thereby substantially mitigating the risk of

morbidity and mortality from a more extensive neurosurgical procedure. A retrospective

review of 119 patients who underwent surgical evacuation of at least one CSDH – 58 by

craniotomy and 61 by burr-hole craniostomy – reported better clinical outcome in patients

who underwent burr-hole drainage (Regan, Worley, Shelburne, Pullarkat, Watson, et al.,

2015). Performed either under general or local anesthesia, the surgeon creates a burr-hole in

the skull overlying the hematoma, opening the dura mater, draining the hematoma and

flushing out the space with saline solution. Before closure, a closed-system drain is placed in

the subdural space to continue drainage for typically up to 24 hours after surgery, and is then

removed. Depending on the size and laterality of the hematoma, more than one burr-hole is

made, though there are inconsistent findings as to the ideal number of burr-holes (Kansal,

Nadkarni, & Goel, 2010; Taussky, Fandino, & Landolt, 2008). Further, depending on the

nature and density of the hematoma, a mini-craniotomy may be fashioned by expanding the

size of the burr-hole with a craniotome. This larger cranial opening is usually preferred when

the hematoma is septated by fibrous membranes, which need to be removed to evacuate the

entire hematoma (membranectomy) (Rohde et al., 2002).

8

Patients typically remain in hospital for several days following the procedure. The symptoms

experienced prior to surgery are usually relieved by surgery. However, symptoms may

persist as a result of incomplete hematoma evacuation and persisting mass effects. Post-

operative care includes an assessment by physiotherapy and occupational therapy to assess

patient mobility, as some patients may require rehabilitation to return to their previous level

of functionality. In a large prospective cohort study of 823 surgically-treated CSDH patients,

47% were transferred to an outside institution for ongoing care and 49% were discharged

home (Brennan et al., 2017). They also reported a 2% mortality rate.

1.1.7 SURGICAL AND MEDICAL COMPLICATIONS AFTER SURGICAL

EVACUATION

In neurosurgical terms, burr-hole evacuation is a minor procedure, and surgery-related

complications are rarely reported (Mori & Maeda, 2001). Complications do occur, however,

and given their contribution to overall mortality, their clinical significance cannot be

neglected. Seizures are one of the most common minor complications experienced after BHC

with closed-system drainage, and in some cases may persist for some time (Rohde et al.,

2002). Major complications include subdural empyema and intracranial hemorrhage (Rohde

et al., 2002).

Due to the advanced age of this patient population, many have concurrent medical

conditions, which increase their susceptibility to medical complications after surgery.

Complications often include infection and seizures (Rohde et al., 2002). Mortality from

medical complications after burr-hole evacuation is higher than from surgical complications

(Rohde et al., 2002).

Patients are typically discharged home, or referred to a rehabilitation center if they are

experiencing physical, cognitive, or speech impairment that requires the services of a

physical therapist or speech pathologist. Several weeks after surgery, patients undergo a

9

repeat CT scan and clinical examination with their neurosurgeon to evaluate the resolution of

the hematoma and their subsequent clinical status.

1.2 THE CLINICAL PROBLEM: POST-OPERATIVE HEMATOMA

RECURRENCE

After hematoma evacuation, the brain does not immediately re-expand to fill the space left

by the hematoma. Consequentially, hematoma remnants – both liquid and fibrous – typically

remain in this space, presenting the potential for re-accumulation of the hematoma. The rate

of recurrence reported in the literature is somewhat variable; 3-31% of patients experience a

re-accumulation of their CSDH after initial surgical evacuation, requiring reoperation (Rohde

et al., 2002). Repeated surgery is associated with increased risk of morbidity and mortality,

including pneumonia or other infection, stroke, intracerebral hemorrhage, and seizure (Mori

& Maeda, 2001). This is particularly concerning in elderly patients, who are more susceptible

to medical complications after surgery (Rohde et al., 2002). The potential risks associated

with repeated surgical intervention therefore cannot be discounted as insignificant (Nayil et

al., 2012).

1.2.1 DEMOGRAPHIC, CLINICAL, OPERATIVE, AND RADIOLOGIC

PREDICTORS OF POST-OPERATIVE CSDH RECURRENCE

Research with regards to identifying predictors of recurrence has been largely inconclusive,

with focus placed primarily on the type of surgical intervention (specifically, the size of the

cranial opening, either a burr-hole or mini-craniotomy), the duration of post-operative drain

placement, the use of anticoagulants, age and gender. Previously reported causative factors

include advanced age (Han et al., 2016), preoperative antiplatelet therapy (Wada et al., 2014)

(though this evidence is inconsistent (Aspegren, Åstrand, Lundgren, & Romner, 2013)),

shorter duration of post-operative drainage (Song et al., 2014), bilateral vs unilateral

hematoma site (Q. Huang et al., 2009; C.-C. Lin et al., 2014; Song et al., 2014), larger post-

10

operative hematoma volume (F.-F. Xu et al., 2014), and separated/layered type hematomas

(Y.-H. Huang, Lin, Lu, & Chen, 2014; C.-C. Lin et al., 2014). Pre-operative volume has not

been significantly associated with recurrence (Y.-H. Huang et al., 2014). No significant

correlation between operative factors (operation type, drain used, anesthetic) and post-op

recurrence has been found (Phang, Sivakumaran, & Papadopoulos, 2015). A meta-analysis of

13 studies suggested decreased risk of recurrence in burr-hole surgery with closed-system

drainage compared to other surgical procedures (C. Xu, Chen, Yuan, & Jing, 2016). No

difference in recurrence rates was identified between burr-hole vs twist drill (Escosa Baé,

Wessling, Salca, & de las Heras Echeverría, 2011; Liu, Bakker, & Groen, 2014b) evacuation,

and inconsistent evidence exists as to whether or not the use of saline irrigation effects post-

operative recurrence (Liu et al., 2014b; C. Xu et al., 2016).

The use of post-operative drainage has fairly consistently been correlated with decreased

recurrence rates (Wada et al., 2014). A systematic review of 297 studies, including 19 RCTs,

reported a decreased risk of recurrence with the use of post-operative drainage (Liu et al.,

2014b). A prospective randomized study of 200 patients surgically treated for CSDH

reported decreased recurrence rate in patients assigned to post-operative drainage compared

to patients without drainage (Singh et al., 2014). Drains were placed for 48-hours in the

drainage group. Nine patients in the drainage group required reoperation for postoperative

hematoma recurrence compared to 26 in the no-drainage group.

A study retrospectively reviewed 209 cases of CSDH admitted to their institution (Miranda,

Braxton, Hobbs, & Quigley, 2011). They primarily investigated the relationship of several

factors – including neurological status upon admission, type of intervention, hematoma size

and anticoagulant use – to survival. The overall mortality rate was 26.3% at six months, and

32% at one-year. They identified neurological status upon hospital admission as the only

predictive factor of in-hospital mortality. The group also reported a 3.6% recurrence rate in

their cohort, and saw no correlation between premorbid anticoagulant use or hematoma

laterality with hematoma recurrence.

11

Berghauser Pont et al (Berghauser Pont, Dammers, Schouten, Lingsma, & Dirven, 2012)

performed a retrospective review of 496 consecutive SDH patients treated with burr hole

craniostomy over 18 years (1990-2008) at a single institution. All patients were treated

preoperatively with 4 mg dexamethasone 4 times daily for at least 2 days. Prolonged

preoperative corticosteroid use, and Glasgow Coma Scale (GCS) motor score were identified

as independent predictors of recurrence.

Janowski et al (Janowski & Kunert, 2012) focused on investigating post-operative

interventions with potential to prevent recurrence. They investigated post-operative

intravenous fluid administration (IFA), and performed a univariate regression analysis

demonstrated that IFA independently influenced hematoma recurrence rate and Glasgow

Outcome Score (GOS), a measure of cognitive status.

Chon et al, 2012 (Chon, Lee, Koh, & Choi, 2012a) also aimed to investigate individual

predictors of recurrence. They retrospectively evaluated 420 patients and identified a 21.9%

recurrence rate. The authors identified independent radiologic and clinical predictors of

recurrence, including postoperative midline shifting (≥5 mm), diabetes mellitus,

preoperative seizure, preoperative width of hematoma (≥20 mm), and use of anticoagulant

therapy.

Stanisic et al, (Stanišić et al., 2013b) retrospectively reviewed 107 patients, finding a 15.9%

recurrence rate. They identified several radiological predictors of recurrence, including:

preoperative hematoma volume and the residual total hematoma cavity volume on the first

postoperative day after drain removal.

Tugcu et al, (Tugcu et al., 2013) aimed to determine predictors of recurrence after single

burr-hole for hematoma evacuation. In their retrospective review of 292 CSDH patients, they

identified a 14.7% recurrence rate. They identified a single predictor of recurrence: bilateral

subdural hematoma. They also looked at age, gender, hypertension, diabetes mellitus,

preceding head trauma, the time interval between trauma and the operation, and previous

12

anticoagulant and anti-platelet therapy, but saw no association with these factors and

hematoma recurrence.

Xu et al (F.-F. Xu et al., 2014) prospectively studied 54 SDH patients, and focused on

association between CT features and recurrence. They identified that a higher recurrence rate

was associated with greater pre-operative (over 120 ml) and/or pre-discharge subdural fluid

volumes (over 22 ml), and larger pre-operative (over 15.1 mm) and/or residual (over

11.7 mm) SDH widths. Changes in residual volume during the acute resolution period were

also identified as radiological predictors of recurrence.

Jung et al (Jung, Jung, & Kim, 2015) aimed to determine predictors of recurrence after burr-

hole trephination. In their retrospective chart and CT review of 182 patients, they saw a

13.7% recurrence rate. They found that recurrence correlated with midline displacement of

more than 10 mm and clinical presentation of hemiparesis.

Leroy et al (Leroy et al., 2015) retrospectively reviewed 140 consecutive cases of SDH.

Multivariate analyses showed an association between increased risk of poor functional

outcome and advanced age, residual hematoma thickness >14 mm, and GCS < 15. They

identified a 17% recurrence rate. Independent predictors of recurrence were preoperative

anticoagulant therapy and persistent mass effect on postoperative CT imaging.

Schwarz et al (Schwarz et al., 2015) retrospectively reviewed 193 patients who underwent

burr-hole trephination for SDH evacuation. They identified an 18.1% recurrence rate.

Midline shift, arterial hypertension, and bilateral hematomas were identified as risk factors

for recurrence. While no correlation was found, the authors also looked at demographic

factors, comorbidities, medications, symptom presentation, trauma, and some features on CT

(midline shift, size, bleeding, membranes, density).

Andersen-Ranberg et al (Andersen-Ranberg, Poulsen, Bergholt, Hundsholt, & Fugleholm,

2017) looked at independent predictors of recurrence specifically for bilateral CSDH

(bCSDH). They performed a retrospective review of 291 patients with bCSDH who

13

underwent either unilateral or bilateral burr holes. Overall there was a 21.6% recurrence rate,

and absence of post-operative drainage, and unilateral burr-hole for bilateral hematoma were

identified as predictors of recurrence.

1.2.2 RADIOLOGIC HEMATOMA SUBTYPES AS PREDICTORS OF

RECURRENCE

Nakaguchi et al (2001) proposed a classification system for CSDH based on hematoma

density and radiographic characteristics, as seen on CT imaging. They classified CSDH into

four subtypes: Homogenous (uniform density); Laminar (uniform density with a thin hyper-

density along inner membrane); Separated (two densities with a clear separation, with the

hypodense component above the hyperdense component); and Trabecular (heterogenous

densities, with hyperdense septation traversing from the outer to the inner membrane). They

further went on to classify the progression of hematoma development through these subtype

classifications, proposing that a CSDH may originate as a homogenous type, progress into

the laminar type, mature into the separated stage, and finally undergo absorption during the

trabecular stage (Nakaguchi, Tanishima, & Yoshimasu, 2001).

Several studies have proceeded to use the Nakaguchi classification system to identify

radiologic hematoma features that may predict recurrence. Chon et al. saw significantly

lower recurrence rates in homogenous and trabecular subtypes, compared to laminar and

separated subtypes (Chon, Lee, Koh, & Choi, 2012b). Ohba et al. later reported that the

separated hematoma type was significantly more closely related to recurrence when

compared to the laminar subtype (Ohba, Kinoshita, Nakagawa, & Murakami, 2013).

Stanisic et al. (Stanišić & Pripp, 2017) and Jack et al. (Jack, O’Kelly, McDougall, & Max

Findlay, 2015)created grading systems using radiologic hematoma features as predictors of

recurrence requiring reoperation, though more work is needed in this field to arrive at an

accurate prediction of recurrence.

14

1.3 PATHOGENESIS AND THE MECHANISM OF CSDH ENLARGEMENT

The exact mechanism of CSDH development and enlargement is not entirely clear, though it

is likely that several mechanisms work in tandem to cause the chronification of the initially

acute bleed. Elucidating the pathogenic mechanism is crucial for determining biomarkers that

may predict hematoma recurrence or clinical outcome, but also for identifying potential

therapeutic targets. The most well supported theories for CSDH development and

enlargement emphasize osmolarity, inflammation, angiogenesis, and hyperfibrinolysis as

central mechanisms.

1.3.1 OSMOLARITY

Bradykinin, an inflammatory factor that causes blood vessel dilation, was found to be

significantly elevated in hematoma fluid compared to blood plasma (Fujisawa, Ito,

Kashiwagi, Nomura, & Toyosawa, 1995). There was also a higher blood protein content in

hematoma fluid. It is possible that these elevated factors together contribute to increased

exudation from capillaries into the hematoma, contributing to its evolution.

1.3.2 INFLAMMATION

In 1657, pathologist Johann Wepfer first identified what he termed a “bloody cyst” in the

subdural space while performing an autopsy on an elderly man who at his time of death was

experiencing aphasia and hemiplegia (Putnam & Cushing, 1925). In 1857, Rudolph Virchow

described a similar case which he termed pachymeningitis hemmorhagica interna, and was

the first to attribute its cause to inflammation (Virchow, 1857). In the following years, the

idea that inflammation was a cause of CSDH development was contested, with emphasis

placed on trauma as a singular cause. However, the role of inflammation was revisited and

today is ubiquitously accepted as a key underlying pathogenic mechanism.

15

Inflammatory responses are necessary for tissue repair, however in CSDH it is believed there

is a pathological and sustained inflammatory response to the presence of blood in the

subdural space (Hong et al., 2009). This likely encourages the formation of a fibrous

membrane, which grows to encapsulate the hematoma. Radiographically and pathologically

the membrane is usually identified as an outer, thicker membrane adjacent to the dura mater,

and an inner membrane adjacent to the arachnoid mater.

One proposed mechanism for hematoma development is that trauma to endothelial tissue and

the meninges leads to the exudation of high levels of inflammatory cytokines into the

subdural space, triggering the acute hematoma to begin to chronify (Frati et al., 2004).

Several studies suggest that inflammatory cytokines and chemokines are mediators of CSDH

development, and play a crucial role in hematoma enlargement (Stanisic, Aasen, et al., 2012;

Stanisic, Lyngstadaas, et al., 2012). This has been additionally corroborated in several

studies that identified elevated levels of pro-inflammatory cytokines, as are discussed below.

Interleukins 6 and 8 (IL-6 and IL-8) were found in greater levels within the hematoma fluid

compared to venous blood (K.-S. Park, Park, Hwang, Kim, & Hwang, 2015). While

investigating the role of cytokines in development of CSDH, another group also found higher

levels of IL-6, as well as IL-10, thrombomodulin and tumor necrosis factor (TNF)- in

hematoma fluid relative to blood serum (Kitazono et al., 2012). Additional studies saw the

same increase in IL-6 and IL-10, in addition to IL-2R, IL-5, and IL-7, IL-13, in the

hematoma fluid compared to systemic blood levels, while significantly lower levels of TNF-

, IL-1, and IL-4 were present in hematoma fluid (Stanisic, Aasen, et al., 2012; Stanisic,

Lyngstadaas, et al., 2012). Importantly, IL-10 levels were found to be lower in layered

hematoma types with visible membranes, suggesting the possibility that IL-10 deactivates the

inflammatory process in CSDH formation (T. Wada et al., 2006). Furthermore, the ratio

between pro- and anti-inflammatory cytokines was also determined to be significantly higher

in the hematoma fluid than in systemic plasma. These elevated levels of inflammatory

cytokines in the subdural fluid relative to serum provides evidence that the inflammatory

processes involved in hematoma progression are localized to the area of the hematoma,

rather than systemic in nature. Suzuki et al proposed that cytokines in the subdural fluid do

16

not permeate from the blood, rather they are likely synthesized and released in situ from cells

adjacent to the subdural space or from immune cells that have infiltrated the subdural space

(Suzuki, Endo, et al., 1998). Finally, high levels of these cytokines, namely IL-6 and IL-8,

may even predict postoperative hematoma recurrence (Frati et al., 2004).

Additional findings suggesting a role for inflammation in CSDH progression include the

measurement of markedly elevated levels of the inflammatory mediator platelet activating

factor (PAF) in the blood plasma of CSDH patients compared to healthy controls. PAF was

subsequently localized via staining to the outer hematoma membrane, but not the dura

(Hirasima et al., 1994). Hirasima et al proposed that after the formation of a small, initially

acute hematoma following some traumatic force, focal production of PAF occurs in the outer

membrane of the hematoma, initiating the infiltration and subsequent degranulation of

eosinophils into the membrane. Several additional studies, as well as routine pathological

staining, have demonstrated eosinophilic infiltrations within the outer membrane of the

hematoma, supporting inflammation as a pathogenic mechanism for CSDH progression

(Miller, 1990). It is likely that the infiltration of eosinophils into the outer membranes of

CSDHs is important for repair and healing, similar to other chronic inflammatory granulation

tissues. Sarkar et al further observed that the outer membrane was composed of vascularized

and hyalinized fibrocollagenous tissue that was infiltrated with eosinophils in more than half

of their study samples (Sarkar et al., 2002). They also noted that the older the hematoma, the

higher the concentration of eosinophils in the outer membrane. They proposed that

chemotactic stimuli secreted by mast cells as well as lymphocytes may recruit eosinophils to

the membrane. Eosinophils may be recruited to the site of the bleed for their phagocytic role

to aid hematoma reabsorption. Compounding this event, tissue plasminogen activator (tPA)

is released from damaged endothelial cells contributing to local fibrinolysis and possibly

even hyperfibrinolysis. These processes occur in tandem to increase vascular permeability,

leading to repeated bleeding into the hematoma.

17

1.3.3 ANGIOGENESIS

Several studies have implicated vascular endothelial growth factor (VEGF) in the

pathogenesis of CSDH (Nanko et al., 2009; R Weigel, Schilling, & Schmiedek, 2001). In

fact, VEGF as well as its receptors are upregulated after CNS injury. Weigel et al proposed

that high VEGF accumulation in hematoma fluid leads to the continuous formation of

immature, fragile microvasculature in the neomembrane. High VEGF levels also increase

vascular permeability, resulting in higher exudation rates from these microcapillaries. New

hemorrhagic events, in addition to the secretion of plasma components into the hematoma,

result in hematoma enlargement (Ralf Weigel, Hohenstein, & Schilling, 2014). More recent

evidence suggests that high levels of matrix metalloproteinases (MMPs), proteins implicated

in angiogenesis, contribute to high levels of VEGF, which stimulates angiogenesis and

contributes to CSDH development through microbleeds (Hua et al., 2016).

Given the potential role of endothelial factors in CSDH pathogenesis, angiogenic markers

could possibly be used as predictors of recurrence. Hong et al performed

immunohistochemical staining of the outer membrane at the time of initial hematoma

evacuation and saw significantly stronger staining of angiogenic mediators VEGF and basic

fibroblast growth factor (bFGF) in the membranes of patients whose hematomas later

recurred. Given their findings, they suggested that higher concentrations of IL-6 in the

subdural fluid, or enhanced expression of VEGF and bFGF in the outer membrane, may

predict postoperative hematoma recurrence (Hong et al., 2009).

Finally, many proposed theories for CSDH formation combine inflammatory and angiogenic

mechanisms. In addition to finding higher levels of IL-6, IL-8 and VEGF in hematoma fluid

relative to serum, Hara et al also found greater levels of the inflammatory mediator

prostaglandin-E2 (PGE2), a product of cyclooxygenase-1 and -2 (COX-1 and COX-2) pro-

inflammatory enzymatic activity (Hara, Tamaki, Aoyagi, & Ohno, 2009). Staining for COX-

2 in the endothelial cells of sinusoids and capillaries, as well as inflammatory cells, was

positive in the outer membrane but not in the adjacent dura mater. Hara et al thus implicated

COX-2 as a potential contributor to CSDH development. As a result of their findings, they

18

proposed that over-expression of COX-2 in the hematoma outer membrane leads to increased

levels of PGE2 and subsequent overexpression of VEGF, promoting angiogenesis in the

outer membrane, ultimately resulting in immature, leaky blood vessels repeatedly bleed into

the existing hematoma and furthering its enlargement. This proposed theory implicated the

administration of COX-2 inhibitors as a potential medical intervention for CSDH.

1.3.4 HYPERFIBRINOLYSIS

In order to introduce hyperfibrinolysis as a potential mechanism in CSDH formation, it is

first important to briefly summarize the coagulation and fibrinolytic cascades. The

coagulation cascade is initiated when there is damage to a blood vessel, such as tearing to

bridging veins as a result of head trauma (Figure 3). The initial stage in repair is the

formation of a temporary platelet plug at the side of vascular endothelial tissue damage.

Prothrombinase (blood clotting factor Xa and Va) catalyzes the activation of prothrombin to

thrombin (factor IIa), which subsequently catalyzes the conversion of fibrinogen to its active

form fibrin (factor Ia). Active fibrin molecules have a high affinity for one another, leading

to polymerization. Factor XIII cross-links thrombin monomers, resulting in the formation of

a stable fibrin clot. This hemostatic seal prevents re-hemorrhaging during tissue repair, and is

maintained through a careful balance between fibrin formation and fibrin breakdown, or

fibrinolysis.

19

Figure 3. The coagulation cascade. Trauma and damage to endothelial cells leads to the release of factors that triggers the coagulation cascade, eventually resulting in the formation of a cross-linked fibrin clot. Illustration by Adriana M. Workewych.

Fibrinolysis is initiated when vascular endothelial cells release tissue plasminogen activator

(tPA) (Figure 4). The inactive molecule plasminogen first binds to fibrin molecules,

followed subsequently by tPA binding to plasminogen and catalyzing its conversion to the

active form plasmin. Plasmin hydrolyzes fibrin polymers, leaving fibrin degradation products

(FDPs) and causing clot breakdown. Plasmin also degrades fibrinogen, the precursor to

fibrin. This contributes to the low levels of fibrinogen seen in patients with subdural

hematoma (Fujisawa et al., 1995; S.-H. Park et al., 2011).

20

Figure 4. The fibrinolytic cascade. Tissue plasminogen activator (tPA) catalyzes the conversion of plasminogen to plasmin, forming a complex that degrades fibrin clots into fibrin degradation products. Illustration by Adriana M. Workewych.

Though the reason remains unclear, should an imbalance occur between coagulation and

fibrinolysis there is a rapidly excessive dissolution of the blood clot, a process called

hyperfibrinolysis. There is substantial evidence to suggest local hyperfibrinolysis is central to

CSDH formation. Several studies have shown that tissue plasminogen activator (tPA) is

elevated in hematoma fluid (Ito, Komai, & Yamamoto, 1978), and was found to be

particularly elevated in layered-type, multi-membrane hematomas (Fujisawa et al., 1991; Ito,

Saito, Yamamoto, & Hasegawa, 1988). While normal tPA production leads to the absorption

of subdural blood and ultimately hematoma resolution, overproduction of tPA over an

extended period of time leads to hyperfibrinolysis, and therefore excessively rapid clot

dissolution. Based on findings involving the fibrinolytic cascade, Ito et al. proposed a

mechanism for hematoma formation: an initially acute hemorrhage in the subdural space

becomes encapsulated by a fibrous membrane, which releases tPA. High levels of tPA,

released from the outer hematoma membrane, diffuse into the hematoma, catalyzing the

conversion of plasminogen to plasmin, thereby increasing the levels of fibrin degradation

products (FDP). Elevated levels of FDP interfere with homeostasis of the blood clotting

21

process, leading to a progressive enlargement of the hematoma, and presumably also

degrading the clot, leading to rebleeding from the original vessel. Another group measured

high levels of plasminogen and low levels of antiplasmin, an inactivator of plasmin, in the

hematoma fluid, contributing to elevated levels of plasmin and therefore overproduction of

FDPs (Weir & Gordon, 1983).

Similarly, Suzuki et al. theorized that following a head injury, both blood and cerebrospinal

fluid collect in the subdural space (Suzuki, Kudo, et al., 1998). Prothrombin is activated to

thrombin and endothelial tissue damage triggers the recruitment of fibroblasts and

inflammatory cells, which lead to the formation of the outer hematoma membrane.

Angiogenesis in this outer membrane leads to the formation of immature capillaries which

repeatedly rupture, releasing tPA from the damaged epithelial cells and subsequently

increasing the rate of fibrinolysis. This process repeats itself through recurrent bleeding from

the capillaries, and in this way, the hematoma increases in size.

In addition to its likely role in hematoma enlargement, elevated levels of tPA have also been

identified as a potential predictor of post-operative hematoma recurrence (Katano, 2006).

Katano et al measured higher levels of tPA, as well as 2-antiplasmin, in hematomas that

later recurred compared to non-recurrent hematomas. Both were also found to be higher in

hematoma fluid than blood serum. This was also true for hepatocyte growth factor (HGF)

and VEGF, though these were not identified as predictors of recurrence. From these findings

they also proposed a mechanism of hematoma development: an initial traumatic injury leads

to bleeding and hematoma formation, which triggers an inflammatory response and initial

hypercoagulation. An increase in tPA, as well as eosinophil infiltration and bradykinin

release, leads to co-occurring hyperfibrinolysis, hyperpermeability, and a storm of cytokine

release, as well as elevated VEGF and HGF levels. These processes working in tandem

promote rebleeding into the hematoma, and therefore continued hematoma enlargement.

22

1.3.5 MECHANICAL MECHANISMS

While inflammatory, angiogenic, and hyperfibrinolytic mechanisms likely contribute most

significantly to CSDH development, other mechanical mechanisms may also play a role.

Murakami et al. suggested that pulsation in the hematoma cavity as a result of the pulsating

brain leads to repeated compression and decompression of the outer membrane, causing the

fragile microvessels present within to repeatedly rupture. Thrombomodulin is released,

preventing the healing of injured outer membrane microvessels. This facilitates the process

of recurrent slow bleeding into the hematoma and prevents coagulation, ultimately

contributing to the expansion in hematoma volume (Murakami et al., 2002).

Song et al (2013) hypothesized that when trauma causes damage to the dural border cell

layer, cerebrospinal fluid as well as blood accumulates in the subdural space as foreign

matter, stimulating the inflammatory response and resulting in the secretion of inflammatory

cytokines, VEGF and angiopoietins (Y. Song, Wang, Liu, Wang, & Zhang, 2013). They

proposed that due to an insufficient number of locally circulating endothelial progenitor

cells, the capillaries in the neomembrane harbor structural deficits. This predisposes them to

tearing during abnormal cerebral pulsations, undermining their structural integrity and

physiological repair. A continuous effusion from these pathologically permeable capillaries

into subdural space ensues, leading to CSDH formation and enlargement.

1.4 NON-SURGICAL TREATMENT OF CSDH

Based on the proposed mechanism of hematoma evolution, several medicinal therapies have

and are currently being investigated as either alternatives to surgical evacuation or adjunctive

therapies. Various attempts have been made in past decades to treat CSDH with medications,

including glucocorticoids, angiotensin converting enzyme (ACE) inhibitors, platelet

activating factor inhibitors and traditional Japanese medicines. Unfortunately, there are still

no results from randomized clinical trials to support superiority of any of these treatments to

surgical therapy or any effectiveness over no treatment.

23

In light of the inflammatory hypothesis for CSDH development and progression,

dexamethasone has been explored as an alternative therapy for CSDH. In a placebo-

controlled clinical trial, 20 participants were randomized to receive 12 mg daily of

dexamethasone for 3 weeks or placebo (Prud’homme, Mathieu, Marcotte, & Cottin, 2016).

There were no statistically significant differences in hematoma thickness or other measurable

changes between the two groups over the study period, however, the dexamethasone-treated

group experienced many more side effects and serious adverse events. The small study

sample size, in addition to the high risks of complications associated with dexamethasone

treatment, were insufficient to demonstrate a benefit of dexamethasone treatment compared

to placebo.

Atorvastatin has also been evaluated in CSDH treatment due to its potential anti-

inflammatory mechanism (Qiu et al., 2017). A clinical trial is currently underway to

investigate its efficacy as a safe alternative to surgery (ClinicalTrials.gov Identifier:

NCT02024373) (Jiang et al., 2015).

Poulsen et al. conducted a double-blind, placebo controlled, randomized controlled trial to

investigate the efficacy of perindopril, an angiotensin-converting enzyme (ACE) inhibitor, in

decreasing the risk of CSDH recurrence after burr-hole evacuation (Poulsen, Munthe, Søe, &

Halle, 2014). Of the 47 patients randomized to the study, none experienced a recurrence of

their hematoma within the first six weeks after surgery. Furthermore, there was no significant

difference in residual CSDH size between perindopril-treated and control patients.

One group retrospectively compared the effects of Gorei-san, a commonly used traditional

Japanese medicine, with the effects of TXA for reducing CSDH recurrence after burr-hole

evacuation (Wakabayashi et al., 2012). A total of 199 consecutively admitted patients were

divided into four treatment arms. The lowest recurrence rate was among the patients who

were treated with Gorei-san and TXA. An 8.3% recurrence rate was seen in the Gorei-san-

only treated group. This was compared to a 10.9% recurrence rate in the TXA group, and

24

5.7% recurrence rate in the group that received surgery alone. The differences in recurrence

rates among the four groups did not reach statistical significance.

Kageyama et al. retrospectively reviewed the medical records of 21 patients that were given

oral TXA at a dose of 750 mg daily for the treatment of CSDH (Kageyama, Toyooka,

Tsuzuki, & Oka, 2013). They used CT and magnetic resonance imaging (MRI) throughout

the course of TXA administration to evaluate hematoma volume change. Three patients had

been treated by burr-hole surgery before receiving TXA therapy. All patients experienced a

decrease in total hematoma volume during follow-up, and none of the patients experienced

hematoma recurrence or progression. They proposed that CSDH could be treated with TXA

alone, and without surgical evacuation.

1.5 TRANEXAMIC ACID

Tranexamic Acid (TXA) is an antifibrinolytic drug. That is, it slows the dissolution of clot.

When plasminogen binds to fibrin to initiate clot breakdown, it does so at a lysine binding

site. As a physical analog of lysine, TXA binds to this site on plasminogen, preventing

plasmin from binding to fibrin, thereby preventing the conversion of fibrin to FDPs,

ultimately preventing clot breakdown (Figure 5).

25

Figure 5. Mechanism of action of Tranexamic Acid (TXA). Tissue plasminogen activator (tPA) binds to plasminogen, catalyzing its conversion to plasmin, and forming a complex that binds to lysine binding sites on fibrin, breaking it down into fibrin degradation products (FDPs). Tranexamic Acid (TXA) competes for the lysine binding site, preventing the conversion of plasmin to plasminogen, and ultimately the breakdown of fibrin into FDPs. Illustration by Adriana M. Workewych.

TXA also has low to moderate effects on other enzymatic activity by competitively

inhibiting the activation of trypsinogen, and non-competitively inhibits trypsin (Dubber et al,

1965).

1.5.1 CURRENT THERAPEUTIC INDICATIONS

TXA is widely used in the treatment of congenital bleeding disorders, perioperatively as a

blood-sparing strategy in cardiac and non-cardiac surgery, and in significant trauma with

hemodynamic instability.

26

It has been shown to reduce blood loss in gynecological bleeding disorders, and is commonly

prescribed for abnormal uterine bleeding, most notably menorrhagia (Nilsson & Rybo, 1967,

1971). It has also been shown to be effective in reducing blood loss from post-partum

hemorrhage, as well as bleeding irregularities arising from complications of contraceptive

implants (Gungorduk et al., 2011; Lukes et al., 2010). In a large, international, randomized

controlled trial, 20,060 women diagnosed with post-partum hemorrhage after delivery were

randomized to receive a 1g intravenous dose of TXA or placebo in addition to the standard of

care (WOMAN Trial Collaborators et al., 2017). The results showed a significant reduction

in death due to bleeding in the TXA group compared to controls. Further, the occurrence of

adverse events did not differ between the two groups.

Several randomized controlled trials have shown a significant reduction in perioperative

blood loss after TXA administration compared to placebo controls, namely in cardiac and

orthopedic surgeries, as well as prostatectomies (Later et al., 2009; Sukeik, Alshryda,

Haddad, & Mason, 2011; Zhang, Chen, Chen, & Que, 2012).

Early administration of TXA after injury or trauma has been show to significantly reduce all-

cause mortality and death due to bleeding (CRASH-2 trial collaborators et al., 2010). It is

most effective in reducing mortality if given within the first 60 minutes of injury, with

effectiveness dropping by 10% for every 15-minute delay in time to treatment (I. Roberts,

2015; Ian Roberts et al., 2017).

TXA has also been shown to be an effective therapy in traumatic hyphema, gastrointestinal

bleeding (Ian Roberts et al., 2014), and for symptom relief in angioedema (Wintenberger et

al., 2014).

1.5.2 PHARMACOLOGY

TXA can be administered topically, intravenously, and orally, and is rapidly absorbed after

oral administration. In order to elicit therapeutic effects, the plasma concentration of TXA

27

must be 5-15mg/L (Fiechtner et al., 2001; Katsaros, Petricevic, Snow, Woodhall, & Van

Bergen, 1996; Std, n.d.).

The bioavailability of oral TXA is 40%, and 50% is likely biotransformed by acetylation or

deamination and subsequent oxidation or reduction, resulting in either a dicarboxylic acid or

acetylated products. TXA is renally cleared, with approximately 1% eliminated one hour

after administration, and 39% eliminated after 24 hours.

The terminal elimination half-life of a single oral dose of 1300 mg TXA is approximately

11.1 hours. Pharmacodynamic properties appear to vary slightly according to the indication

for which the drug is used (Dunn & Goa, 1999).

1.5.3 SAFETY

TXA is generally well tolerated. Most reported adverse events in clinical trials are mild or

moderate in severity. Severe or serious adverse events are rare (Leminen & Hurskainen,

2012; McCormack, 2012). Despite this, however, safety concerns regarding TXA include

gastrointestinal symptoms (which typically subside with dose reduction), risk of seizures,

visual disturbances (including impaired visual acuity and color vision), and dizziness.

Isolated and rare cases of thromboembolic events and hypotension have also been reported.

1.5.4 CONTRAINDICATIONS

TXA treatment is contraindicated in patients who exhibit a hypersensitivity to the drug or

any of its ingredients. It is contraindicated in patients who have had a history or have an

increased risk of thrombosis, unless it is possible to administer TXA with anticoagulants, and

as long as there is a strong medical indication for its use, although this contraindication is not

based on the results of clinical studies. Patients with active thromboembolic disease,

including deep vein thrombosis, pulmonary embolism, cerebral thrombosis, and disseminated

28

intravascular coagulation are listed as contraindications to TXA. In some cases, venous and

arterial thrombosis and thromboembolism has been reported in patients being treated with

TXA – however, results from the CRASH-2 trial, as well as a large meta-analysis and other

reviews, show that there is no causative link between the two (CRASH-2 trial collaborators

et al., 2010; Hunt, 2015; Ker, Edwards, Perel, Shakur, & Roberts, 2012). It is not safe for

patients with subarachnoid hemorrhage to be treated with TXA, as the increased risk of

cerebral ischemia outweighs the reduced risk of re-bleeding, according to the product

monograph, as indicated by the product monograph. Patients with hematuria caused by

diseases of the renal parenchyma should not take TXA because of the increased frequency of

intravascular precipitation of fibrin typically seen in this disease. Moreover, in the event of a

renal hemorrhage, antifibrinolytic therapy may increase the risk of clot retention in the renal

pelvis. In one isolated case, a patient developed an insoluble clot obstruction in the renal

pelvis after the administration of epsilon-aminocaproic acid, an anti-fibrinolytic (Wymenga

& van der Boon, 1998).

As advised by the product monograph, TXA therapy should also be discontinued if a patient

experiences colour vision disturbances, as chromatopsia has been reported as a rare case

adverse event after prolonged TXA use. Due to its rarity, the occurrence rate of this adverse

event is not known, however transient colour vision disturbance has been reported as an

isolated adverse event in the post-marketing period (Cravens, Brown, Brown, & Wass,

2006).

1.5.5 WARNINGS AND PRECAUTIONS

Caution while taking TXA is advised in patients with visual disturbances, such as sudden

impaired visual integrity, colour vision, or blurred vision. Convulsions and seizure activity

has been reported in association with TXA treatment, and therefore precautions should be

taken when considering TXA treatment in patients with a history of seizure, or if high doses

are used during high-risk surgeries as a result of disruption of the blood-brain barrier (BBB)

(Neville, Butterworth, James, Hammon, & Stump, 2001; Schwinn, Mackensen, & Brown,

29

2012). The risk can potentially be mitigated by using a lower-dose TXA dosing regimen

(Schwinn et al., 2012).

Women who experience irregular menstrual bleeding should not take TXA unless the cause

of the irregularity is determined; this is in order to avoid potentially delayed diagnosis of

endometrial cancer, which may cause irregular menstrual bleeding. Women who are taking

combination hormonal contraceptives are at increased risk of a deep-vein thromboembolism

and arterial thromboses, and should therefore only take TXA if there is a strong medical

need, as the addition of TXA treatment can theoretically heighten the risk of a thrombotic

event. Further, women who are pregnant or planning to become pregnant should not take

TXA unless it is strongly indicated, as TXA crosses over to and may affect the fetus. TXA

passes into the breastmilk, and therefore because of the unknown effects of TXA on the

fetus, warning should be given to women who are breastfeeding. Consideration should also

be taken when treating men who may father a child, as TXA passes into the semen, inhibiting

its fibrinolytic activity (Liedholm, 1973).

Due to the excretion of TXA by glomerular filtration, TXA may accumulate in patients with

renal insufficiency. According to the product monograph, the recommended dose reduction

for renal failure is: 15 mg orally per kg body weight, twice daily, in patients with serum

creatine concentrations of 120 to 250 μmol/L; 15 mg orally per kg body weight every 24-

hours in patients with serum creatine levels of 250 to 500 μmol/L, and 15 mg orally per kg

body weight every 48-hours at serum creatine levels of 500 μmol/L or more. Precautions

should be taken when treating patients who experience hematuria from the upper urinary

tract. When prescribing TXA, warning should also be given to patients who are obese or

diabetic, have polycystic ovarian syndrome or a history of endometrial cancer, or women

already being treated with estrogen or tamoxifen.

30

1.5.6 DRUG INTERACTIONS

TXA should be taken with caution and close physician supervision if procoagulants (e.g.,

prothrombin complex concentrates, recombinant factor VIIa) are co-administered. Potential

theoretical drug-drug interactions may lead to myocardial infarction if TXA is co-

administered with hormonal contraceptives, hydrochlorothiazide, desmopressin, sulbactam or

ampicillin, carbazochrome, ranitidine, nitroglycerin, and combination hormonal

contraceptives, according to the product monograph.

1.5.7 SIDE EFFECTS AND ADVERSE EVENTS

Potential side effects of TXA administration may include allergic reaction, obstruction of the

central retinal artery or vein, sudden or unexpected visual disturbances, hypotension, cerebral

infarction or thrombosis, myocardial infarction, deep vein thrombosis or arterial thrombotic

event, and acute renal cortical necrosis leading to unusual bladder or kidney function. TXA

may cause dizziness, and may therefore impair one’s ability to drive or operate heavy

machinery. Seizures are the only truly established serious adverse event (Keyl et al., 2010; Z.

Lin & Xiaoyi, 2016).

Adverse events include nausea, vomiting, diarrhea, allergic contact dermatitis, persistent

dizziness and hypotension, and retinal changes. Rare case adverse events include acute

myocardial infarction, venous or arterial thrombosis, cerebrovascular accident, cerebral

thrombosis, acute renal cortical necrosis, central retinal artery or vein obstruction, impaired

colour vision, visual acuity, or blurred vision, dizziness, and seizure (Std, n.d.).

1.6 DOSING REGIMENS IN TRANEXAMIC ACID TREATMENT

The ideal dosing regimens for TXA in various clinical indications are not well-defined, and

the doses used in clinical studies vary. The recommended dose of 500mg TXA oral tablets

31

for conization of the cervix, epistaxis, and hyphaema is 2-3 tablets every 8-12 hours for 12

days, 10 days, and 7 days, respectively. For menorrhagia, 2-3 tablets should be taken 3-4

times daily for several days upon the onset of very heavy bleeding. In patients with

coagulopathies who are undergoing dental surgery, it is recommended that an oral TXA

should be given at a dose of 25 mg per kilogram of bodyweight 2 hours before dental

surgery, in addition to factor replacement. Post-operatively, oral TXA should be given at a

dose of 25 mg/kg 3-4 times daily for 6-8 days. To treat hereditary angioneurotic oedema,

patients may benefit from intermittent or continuous treatment with 2-3 tablets, 2-3 times

daily for several days. Dose adjustment should be made for patients with impaired renal

function. Patients with serum creatinine concentrations of 120 to 250 μmol/L should be

administered 15 mg orally tranexamic acid per kg body weight, twice daily. At serum

creatinine levels of 250 to 500 μmol/L, the dosage should be 15 mg orally per kg body

weight at 24-hourly intervals. At serum creatinine levels of 500 μmol/L or more, 15 mg

orally per kg body weight should be given at intervals of 48 hours between doses.

In Japan, the recommended usual daily adult dosage for oral is 750–2000 mg, divided into

three or four doses (McCormack, 2012). Thus, doses up to 1500 mg daily, divided into

several administrations, appear to be safe and well tolerated by patients of various clinical

conditions.

1.7 TRANEXAMIC ACID TREATMENT IN TRAUMA AND NEUROSURGICAL

CONDITIONS

Several studies have evaluated the use of TXA in trauma, surgery, and various neurosurgical

conditions. A large, randomized controlled trial investigated the efficacy of early TXA

administration in trauma patients who were experiencing or at risk for significant

hemorrhage. Patients were administered an intravenous loading dose of 1000 mg TXA – or

matching placebo – over 10 minutes, followed by a 1000 mg maintenance dose over 8 hours.

The results showed that TXA significantly reduced all-cause mortality at 4 weeks as well as

the rate of death due to bleeding (CRASH-2 trial collaborators et al., 2010). A sub-study of

this trial in a cohort of patients with traumatic intracranial hemorrhage saw no statistically

32

significant difference in hemorrhage growth in TXA-treated compared to control subjects

(CRASH-2 Collaborators, Intracranial Bleeding Study, 2011).

There have been inconsistent results from studies assessing the efficacy of TXA in reducing

re-bleeding in subarachnoid hemorrhage patients.

In a large, randomized, placebo-controlled trial, patients with subarachnoid hemorrhage were

administered 4–6 g/day of TXA, or placebo, for up to 4 weeks. There was a significant

reduction in the incidence of re-bleeding in TXA-treated patients compared to controls. It is

however important to note that they saw no between-group difference in outcome at 3-

months because of a concurrent increase in ischemic complications in the TXA group

compared with placebo (Vermeulen et al., 1984).

A recently published retrospective study assessed the efficacy of oral 650 mg twice a day

TXA in treating residual CSDH (Tanweer et al., 2016). Fourteen patients with 20 CSDHs

were included. They reported 91.3% reduction in residual hematoma size after TXA therapy.

This study, however, had several limitations. First, and most significantly, it was not a

randomized, controlled trial. There was no concurrent or historical control group, and it

cannot be concluded that TXA was efficacious without comparison to a control group of

CSDH patients. Second, TXA was started after initial treatment with bedside twist-drill

hematoma evacuation and subdural evacuating portal system (SEPS). However, there were

no AEs or SAEs associated with the medication reported in any of the study patients,

supporting the safety of TXA in patients with residual CSDH.

There is currently a phase 2, double-blind, placebo controlled, randomized, parallel-design

study underway assessing tranexamic acid in chronic subdural hematoma (TRACS) (Iorio-

Morin, Blanchard, Richer, & Mathieu, 2016) (ClinicalTrials.gov Identifier: NCT02568124).

This multi-center Canadian trial is assessing the efficacy of TXA in faster resolution of

CSDH in non-surgical patients after conservative management. They plan to recruit 130

patients to be randomly assigned to either the TXA arm or the control arm. The TXA arm

will receive one 750mg dose of TXA daily, while the control group will receive one placebo

33

tablet daily for 20 weeks, at which point they will determine CSDH volume as a measure of

CSDH resolution (their primary outcome measure).

34

2. STUDY RATIONALE

As our population continues to age at an unprecedented rate (Bélanger A, Martel L, &

Caron-Malenfant E, 2005), by 2030 the prevalence of CSDH is expected to surpass that of

brain tumours becoming the most common condition requiring neurosurgery (Balser, Farooq,

Mehmood, Reyes, & Samadani, 2015). With surgery as the only current treatment for CSDH

(Santarius et al., 2009), a low-risk alternative for this sentinel event is strongly desired.

We hypothesize that tranexamic acid treatment can prevent the enlargement of residual

CSDH after surgery, or prevent re-bleeding that may require repeated surgical intervention.

However, no studies to date have prospectively examined whether TXA is effective in

improving the clinical course of residual CSDH after surgical drainage. As described above,

there is currently a multi-center trial (TRACS) for TXA efficacy primarily in non-surgical

CSDH (Iorio-Morin et al., 2016). As of yet, there is no data published from this study.

Therefore, there is still no completed study providing compelling support in favor of TXA as

an efficacious non-surgical intervention in CSDH volume resolution. Moreover, the TRACS

study is recruiting mainly conservatively-managed, non-surgical patients, rather than

primarily investigating the efficacy of TXA in preventing post-operative recurrence. Second,

it is possible that the TXA half-life period is too short to be given only once a day, as is

currently outlined in their protocol.

To verify the potentially therapeutic effects of TXA in CSDH, a randomized controlled trial

would be required to examine its efficacy compared to current medical practice. We therefore

designed the present pilot study to investigate the feasibility of conducting a trial investigating

TXA treatment success in post-surgical, residual chronic subdural hematomas. Our primary

objective of this pilot is to evaluate the feasibility of conducting this trial at St. Michael’s

Hospital. Secondarily, we will be evaluating the efficacy if TXA in preventing post-operative

residual subdural hematoma growth, as well as TXA safety in this study population.

There is also a lack of literature regarding the course of volume changes in CSDH and in

residual hematomas after burr-hole surgery. Our study will facilitate a close patient

35

observation in the beginning of the treatment course and generate source data on the volume

courses of postoperative CSDH and consequently the development of recurrent CSDH.

Our present pilot study is also designed to obtain preliminary data for a future multicenter,

double-blinded, randomized, placebo-controlled in post-operative patients.

Should this larger study demonstrate TXA efficacy in residual CSDH treatment, it could be

implemented as a safe alternative to repeat surgery, lowering repeat-surgery rates, and

sparing patients physical and emotional stress. The high affordability of oral TXA therapy

would also benefit the healthcare system. The mean cost per SDH patient, attributed to

operating time alone, was estimated at $7,588 for burr-holes procedures and $10,416 for

craniotomy procedures (Regan, Worley, Shelburne, Pullarkat, & Watson, 2015). These

estimates did not include other inpatient hospital costs. Further, the national annual cost of

subdural hematomas in the United States has been estimated to be $1.6 billion as of 2007,

and rising with increasing incidence (Frontera, Egorova, & Moskowitz, 2011). In

comparison, 500mg TXA oral tablets cost approximately $140 for 100 tablets. The economic

value of being able to treat CSDH with TXA rather than surgery would not be insignificant.

36

2.1 STUDY DESCRIPTION AND OBJECTIVES

2.1.1 PRIMARY STUDY OBJECTIVE

2.1.1.1 Feasibility

As a pilot study, our primary study objective was to gather preliminary study feasibility data,

and data on the course of hematoma volume changes under current treatment practice. This

would inform the conduct of a future multi-center, double-blind randomized controlled trial

assessing TXA efficacy in post-surgical patients.

Our outcome measures for this objective were participant recruitment and attrition rates

over the study duration, participant eligibility rates, study drug compliance, and

outcome measure completion.

2.1.2 SECONDARY STUDY OBJECTIVES

2.1.2.1 Hematoma volume change

As a secondary study objective, we sought to determine the efficacy of TXA treatment in

residual CSDH after burr-hole surgery.

Our primary outcome measure was defined as the hematoma-volume reduction (or

growth) as a percent change from pre-operative scan to follow-up scan after 4-8 weeks

of TXA therapy. These volumes were calculated by an observer-blinded analysis of the

CT scans.

37

Secondary outcome measures were the rate of reoperation, the time to reoperation

during the study course due to hematoma recurrence, and the number of patients with

resolution of the CSDH after 4-8 weeks and 8-12 weeks.

2.1.2.2 Neurological status

As another secondary study objective, we assessed neurological status at baseline and follow-

up.

Neurological outcome was assessed on the following scales: National Institutes of

Health Stroke Scale (NIHSS), modified Rankin Scale (mRS), Glasgow Coma Scale

(GCS), Markwalder Grading Score (MGS), and the Glasgow Outcome Scale-Extended

(GOSE).

2.1.2.3 Quality of life

As another secondary study objective, we also assessed patient quality of life (QOL).

Our outcome measures for this objective were scores on the 36-item Short Form health

survey (SF-36) (Brazier et al., 1992) and the Health Utilities Index (HUI®) (Horsman,

Furlong, Feeny, & Torrance, 2003a), two validated tools for health-related QOL

assessment.

2.1.2.4 TXA safety

Our final secondary study objective was to monitor drug safety and safety of our chosen TXA

dose regimen.

Our outcome measures for this objective were monitoring regular monitoring of patient

blood counts, urinalyses, and the occurrence of any adverse events (AE), serious

38

adverse events (SAE), and adverse drug reactions (ADRs) during the study course,

particularly thromboembolic events.

2.2 STUDY DESIGN

TRACE was designed as a single-centre, open-label randomized controlled trial. Study

participants were randomized to one of two treatment arms: the control arm, which received

standard postoperative treatment, and the treatment arm, which received standard

postoperative treatment in addition to daily oral tranexamic acid.

2.2.1 STUDY DURATION AND TIMELINE

Participants were enrolled in the study for up to 8-12 weeks, or until the time of their last

clinical follow-up in the neurosurgery clinic. We followed-up with participants at in-hospital

visits, as well as by telephone between the in-hospital visits. The timeline and follow-up

schedule are presented below in Figure 6.

Outpatient follow-ups were scheduled to coincide with standard neurosurgical clinic follow-

ups following surgery for CSDH. Clinically, the first neurosurgical follow-up is typically

scheduled between 4-8 weeks after burr-hole drainage. Therefore, the first of two outpatient

follow-up study visits were scheduled at 4-8 weeks after surgery, to align with neurosurgical

follow-up. While some patients return to clinic at first follow-up with complete hematoma

resolution, many still have residual CSDH. Patients with residual CSDH for whom a second

neurosurgical follow-up is clinically required are typically seen approximately one month after

their first follow-up visit. Therefore, the second in-hospital study follow-up was scheduled for

8-12 weeks, after which the study was completed and patients discontinued the study

medication.

39

Two telephone interviews were also scheduled as part of study follow-up to monitor TXA

safety as part of the secondary study outcome. With the phone calls, we evaluated participants

for concomitant medications, co-morbidities, study medication compliance, AEs or SAEs, and

ADRs.

The first telephone interview was conducted by research personnel 2-3 weeks after study

enrollment. The second telephone interview was scheduled approximately 2-3 weeks after the

first in-hospital visit. Patients typically spend less than one week in hospital after surgical

CSDH evacuation. If, however, the patient was still an in-patient at the scheduled time for the

2-3-week telephone interview, the interview was conducted in person by research personnel.

If participants were discharged from neurosurgical care at the first clinic follow-up, we

determined that they reached a study endpoint, and TXA was discontinued. If the participant

was scheduled to be seen again at a second clinic follow-up at 8-12 weeks, they continued

taking the TXA until the second visit, at which time the TXA or placebo was discontinued.

Participant consent was reconfirmed at each study visit and telephone call.

Figure 6. Timeline of study follow-up visits and phone calls. The overall study duration is up to 8-12 weeks, consisting of two in-hospital study visits and two telephone calls.

Study week 0 (Baseline

visit): Day of randomization

Study week 2-3: First

telephone follow-up

Study week 4-8: First in-hospital

follow-up visit at clinic

Week 2-3 after first visit: Second telephone follow-

up

Study week 8-12: Final in-

hospital follow-up visit at clinic

40

Study variables collected at each in-hospital and telephone follow-up are presented in Table 1. Table 1. Variables collected at each in-hospital and telephone follow-up for study duration

41

2.2.2 RESEARCH ETHICS BOARD AND HEALTH CANADA APPROVAL

Prior to trial initiation, institutional Research Ethics Board (REB) and Health Canada

approval were obtained. Our institutional REB also approved all study documents, including

the study protocol, case report forms (CRFs), participant informed consent forms,

recruitment scripts, and any study information given to patients. All pertinent staff were

trained in the study protocol and related study procedures, including all co-investigators,

neurosurgeons and neurosurgery residents, all involved registered nurses, nurse practitioners,

hospital pharmacists, and research pharmacists.

In accordance with Health Canada recommendations, the trial was registered at

ClinicalTrials.gov, a public clinical trial registry (ClinicalTrials.gov Identifier:

NCT03280212).

2.3 PARTICIPANT ELIGIBILITY

All patients admitted to St. Michael’s Hospital with radiologically-confirmed diagnosis of

chronic subdural hematoma were screened for study eligibility. We defined chronic subdural

hematoma as any subdural collection of liquefied or partially-liquefied blood, including

subacute and acute-on-chronic subdural hematomas.

2.3.1 INCLUSION CRITERIA

In order to be eligible for study participation, patients must have met the following criteria:

• been diagnosed with chronic subdural hematoma, and undergone unilateral or

bilateral burr-hole craniostomy or mini-craniotomy for hematoma evacuation;

• been above the age of 18;

42

• demonstrated competence to take study medication properly and regularly, or had

access to a caregiver that was able to comply with accurate study medication

administration

There were several reasons CSDH patients presenting to our institution were discharged

without neurosurgical intervention, including: mild symptoms that the primary neurosurgeon

felt did not require immediate surgical intervention; very small hematoma size that the

primary neurosurgeon felt would resolve on its own; or poor surgical candidacy, particularly

resulting from advanced cardiovascular comorbidities, advanced age, or multimorbid status.

2.3.2 EXCLUSION CRITERIA A comprehensive list of exclusion criteria was developed in light of contraindications and

warnings of TXA administration. Therefore, CSDH patients who met any of the following

criteria were deemed ineligible for study participation:

• Hypersensitivity to TXA or any of the ingredients

• Pregnancy

• Irregular menstrual bleeding with unidentified cause

• Newly-acquired colour vision disturbances

• Acute and chronic renal insufficiency, indicated by a glomerular filtration rate (GFR)

≤ 30 mL/min

• Hematuria, caused by diseases of renal parenchyma

• Current alcohol or drug abuse, or recreational drug use

• Concomitant intake of hormonal contraceptives, factor IX complex concentrates

prothrombin complex concentrate (PCC), and anti-inhibitor coagulant concentrates

(recombinant activated factor VII, activated factor IX complex, factor eight inhibitor

bypassing activity (FEIBA))

• Active, history, or increased risk (as defined by the attending physician) of

thrombotic events (including deep vein thrombosis, pulmonary embolism, cerebral

43

venous thrombosis, arterial thrombotic events), symptomatic carotid stenosis,

myocardial infarction, acute coronary syndrome, coronary artery disease, or

consumption coagulopathy within the past 2 years

• History of angioplasty with cardiac stent placement or mechanical heart valve

• Active or history of brain pathologies such as stroke (hemorrhagic and ischemic),

subarachnoid hemorrhage, or malignant brain tumors (glioma, metastasis and others)

as well as history of seizures within the past 2 years

• Contraindication to stopping full therapeutic doses of non-ASA antiplatelets,

warfarin, rivaroxaban, apixaban, dabigatran, or other anticoagulant for 2 weeks after

surgery

• Patients requiring immediate revision surgery (as defined by attending surgeon)

• Inability of oral drug intake or missing support to guarantee oral drug intake

2.3.3 PATIENT SCREENING AND DETERMINING PATIENT ELIGIBILITY

We screened all consecutive patients admitted to St. Michael’s Hospital with radiologically-

confirmed diagnosis of chronic subdural hematoma. We screened the patients’ medical charts

to determined their eligibility for study participation in light of the aforementioned eligibility

criteria. After initial screening, patient eligibility was discussed with and confirmed by the

principal investigator or a study co-investigator.

2.3.4 PARTICIPANT RECRUITMENT

Patient recruitment took place from the Neurosurgical Program at St. Michael’s Hospital.

Participants were primarily recruited from the Neurosurgery Ward, and in some instances from

the Emergency Department.

The study was introduced to each patient by a member of his or her circle of care, either a

physician, registered nurse, or nurse practitioner. We then explained the study in full detail to

44

eligible patients with unilateral or bilateral CSDH who were planned to or had undergone

surgery. We obtained written informed consent from patients who agreed to study

participation, or, the event where the patient could not provide informed consent due to

impaired neurological status, we obtained informed consent from the patients substitute

decision maker (SDM) or power of attorney (POA). If a patient refused to participate in the

study, we documented the reason for non-enrollment in the screening log.

2.3.5 PARTICIPANT RANDOMIZATION

Randomization was performed only after we obtained informed and written consent, and was

done so within 24 hours of obtaining consent. The randomization sequence was developed

independently by a statistician and clinical trials methodologist, prior to trial initiation.

Randomization was performed by trained technicians and pharmacists in the St. Michael’s

Hospital Research Pharmacy so that we remained blinded to the randomization sequence to

ensure allocation concealment. A computer-generated randomization sequence was developed

by the study statistician prior to study initiation, and this sequence was followed by the

Research Pharmacy for each patient enrolled to the trial.

2.4 STUDY DRUG

2.4.1 TXA DOSING REGIMEN

The TXA dosage regimen we determined for our trial was informed by previously detailed

data on pharmacokinetic as well as pharmacodynamic properties. We focused specifically on

assessing patient safety of the drug dose in particular.

On the basis of the current available data presented in our literature review, we decided to

investigate a post-operative dose regimen as follows: Patients of the TXA arm were given 500

mg TXA orally, 3 times a day (TID). Participants of the comparative control arm did not

receive any additional tablets.

45

The TXA dosage was conceptualized for the majority of patients with a body weight between

60 to 100 kg. Weight deviation from this were considered with a dose adjustment of 1000 mg

TXA two times a day (BID) for a body weight above 100 kg, and 500 mg TXA BID for body

weight below 60 kg. This regimen was selected, because the body weight of an average

Canadian is 80.7 kg and the maximum daily dosage of the present trial intended to be below

the dose recommendation according to the TXA product monograph (25 mg/kg) to avoid long

term toxicity. Dosage adjustment due to renal insufficiency was not required as patients with

acute and chronic renal insufficiency indicated by a GFR ≤ 30 mL/min were not deemed

eligible.

A logistical factor in our dose regimen selection was the availability of oral TXA in Canada,

where it is available in 500 mg tablets. Although TXA tablets are divisible, requiring patients

to divide their tablets could lead to improper drug intake or noncompliance, and was therefore

avoided. To mitigate these potential concerns, a three times-per-day dosage regimen was

proposed. The oral route for drug administration was chosen to enhance patient compliance

and minimize study withdrawals due to discomfort from intravenous administration. TXA

cannot be crushed for administration as this would alter pharmacologic properties.

Patients randomized to the TXA arm were started on the study drug within two days of surgery.

Concomitant medications were continued throughout the study course.

The inpatient dosing schedule is presented in Table 2.

Table 2. TXA dose administration schedule according to bodyweight Time of dose administration Bodyweight range 0830 1230 1630 60-100kg 1x 500mg tablet 1x 500mg tablet 1x 500mg tablet <60kg 1x 500mg tablet None 1x 500mg tablet >100kg 2x 500mg tablet None 2x 500mg tablet

Upon discharge, patients were advised to take the study drug as close to the inpatient dosing

schedule as possible, depending on their specific dosing regimen.

46

2.4.2 TXA DISPENSING PROCEDURES

TXA was stored in and dispensed by the Research Pharmacy under temperature-regulated

conditions, in accordance with Health Canada regulations.

TXA was first dispensed as an in-patient supply to be administered to the patient by their

registered nurse. The in-patient supply was dispensed in vials containing a day’s dose of

tablets, corresponding to the appropriate weight-adjusted dosing regimen. This in-patient

supply was stored in a locked, temperature-regulated medication box on the Neurosurgery

ward in the medication room.

At the time of discharge, an out-patient supply of two 100-tablet bottles was dispensed for

them to self-administer the tablets at home. A surplus of tablets was provided to ensure the

patients had enough to complete the study. At this time patients were also discharged with a

Discharge Information Package detailing proper study drug storage and administration.

2.4.3 MONITORING STUDY DRUG COMPLIANCE Study drug compliance was monitored by having participants log TXA intake in a study ‘Drug

Diary’. There, patients documented the time each of their doses was taken, as well as any

missed or forgotten doses.

Upon study completion, patients returned any remaining study drug tablets to the Research

Pharmacy.

47

3. STUDY METHODS

3.1 DATA COLLECTION

3.1.1 STUDY FEASIBILITY DATA

Reasons for ineligibility were collected and documented in the participant screening log.

Likewise, reasons for non-recruitment were collected and documented. Similarly, the number

of study withdrawals, time of study discontinuation after study onset, as well as reasons for

study discontinuation, were recorded.

3.1.2 RADIOLOGIC DATA The CT imaging department at St. Michael’s Hospital was notified immediately of the patients

enrolled in the trial to ensure all study patients were imaged using the GE Revolution CT

Scanner for consistency.

3.1.2.1 Hematoma volume calculation

Subdural hematoma volumes are typically not measured for clinical purposes, and therefore a

standard 3D volume-rendering software for these hemorrhages was not in use for clinical

purposes. The measurements collected for clinical purposes most often include the maximum

thickness of the hematoma, and occasionally the maximum anterior-posterior dimension.

Intracranial hematomas have been measured using a validated ABC/2 method (Kothari et al.,

1996; Kwak, Kadoya, & Suzuki, n.d.). This equation is a simplification of the equation for

calculating an ellipsoid volume. The measurement is calculated in the axial imaging plane as

follows: A represents the maximum diameter of the hemorrhage; B represents the maximum

48

width, taken at 90 to A; and C represents the number of axial CT thin-slices on which

hemorrhage is appreciable, times the thickness of the CT slice.

This method is efficient and accurately generates a volume estimate for an ellipsoid-shaped

hemorrhage. Based on mathematical derivation, some have shown that the ABC/2 method

can be accurately applied to SDH volume estimation (Gebel et al., 1998; Kasner, 1999; Sucu,

Gokmen, & Gelal, 2005). Sucu et al. (2005) assessed the validity of the ABC/2 method for

measuring typically crescent-shaped subdural hematomas in comparison to the ‘gold

standard’ of computer-assisted 3D-volumetric analysis, and found that, based on

mathematical theory and derivation, the volume estimates were sufficiently accurate.

However, an inherent limitation of this method is that it assumes the lesion has an ellipsoid

morphology, and overestimates the volume of more irregular shapes. Therefore, the greater

the lesion’s deviation from an ellipsoid geometry, the less accurate the volume estimate.

Several more recent studies using ABC/2 method to calculate actual CSDH found it

inaccurate, concluding that the imprecision of this mathematical estimation would be

insufficient for a clinical trial in which even small SDH volume differences can be clinically

significant (Manickam, Marshman, & Johnston, 2016). Further, Stanisic et al. (2014) showed

that using radiologic features such as maximum thickness and anterior-posterior dimension

to estimate SDH size is also inaccurate (Stanišić, Groote, Hald, & Pripp, 2014).

The Carestream PACS medical imaging viewing software available at our institution has a

semi-automated lesion measurement tool which allows the viewer to delineate the borders of

lesion, with the aid of computer-recognition software that guides the demarcation. The

computer system subsequently generates a 3-Dimensional lesion volume by estimating the

overall shape of the lesion based on the 2-Dimensional tracings made at each slice. This tool

is fairly accurate in clinical use for measuring the volumes of tumors or hematomas, as well

as liver and lung lesions for which the PACS system has predefined measurement algorithms

based on the generally predictable shape of these lesions. However, the tool is not as accurate

in predicting the 3-Dimensional shape of a subdural hematoma, as it generates too uniform a

shape, typically omitting the hematoma fluid at its boundaries that only appears as a thin strip

49

on some CT slices. Furthermore, this tool is only functional on CT scans produced with 2.5

mm slices or smaller, such as those used for scans for preoperative planning taken with the

GE Revolution scanner.

In light of these volume measurement techniques and their limitations, in order to produce

the most accurate estimate of hematoma volume, we employed the ‘gold standard’

measurement technique. This approach begins with manually delineating the area of the

hematoma on each axial thin slice of the CT scan. Each of these areas is then multiplied by

the thickness of the CT slice (depending on the CT scanner used, the thickness was either

1.25 mm, 1.63 mm, 2.5 mm or 5 mm, though 2.5 mm and 5 mm are most common) to

produce a volume, and these volumes were added together to produce an estimate of the

entire hematoma volume (Figure 7). We carried out these volume measures for each of the

available pre-operative, immediate post-operative, and follow-up CT scans for all study

participants. The change in hematoma volume was reported as a percent resolution or

growth, calculated by dividing the hematoma volume at 4-8 weeks by the preoperative

volume, and multiplying by 100 to yield a percentage.

50

A

B

C

51

Figure 7. Hematoma tracing technique and measurement of other radiologic features using the Carestream PACS viewer. In order to calculate the hematoma volume using the gold standard method, the area of the hematoma is manually delineated on each CT thin slice where the hematoma is visible in the axial view, as shown in this figure (A, B, C). Each area is multiplied by the thickness of the CT thin-slices (for this CT, 0.125 cm), and the areas are summed to yield a cumulative hematoma volume. The measurement of radiologic features including midline shift (A), maximum hematoma thickness (B), and maximum anterior-posterior dimension (B), are also shown here.

3.1.2.2 Other radiologic features

All other radiologic hematoma features were collected on the axial-view, preoperative CT

scans. Other radiologic variables collected were those related to mass-effects of the SDH,

and included: presence of midline shift, direction of midline shift (left to right, or right to

left), sulcal effacement, subfalcine herniation, brainstem compression, cisternal compression,

ventricular compression, and hydrocephalus. The size of midline shift was measured by first

drawing a line connecting the anterior and posterior insertions of the falx cerebri, and

drawing a second perpendicular line measuring the distance from this line to the septum

pellucidum (Stanišić et al., 2013a).

C

52

Other radiologic variables collected with respect to the hematoma were: hematoma laterality

(left, right, or bilateral), hematoma location (frontal, parietal, temporal, or occipital),

hematoma density (heterogenous or homogenous; hyperdense, isodense, or hypodense),

presence of septations or loculations, presence of a fluid-fluid level, presence of an

appreciable hematoma membrane, maximum hematoma thickness and maximum anterior-

posterior dimension. When reporting the maximum anterior-posterior dimension for bilateral

subdural hematomas, the largest maximum dimension was used. When reporting the

maximum hematoma thickness of bilateral hematomas, the thicknesses of each of the

hematomas was summed to for a cumulative maximum thickness.

We also sub-classified the study participants’ subdural hematoma types according to the

grading scale developed by Alves et al. (2016), which is described in Table 4 (Alves,

Santiago, Costa, & Pinto, 2016).

Table 3. Subdural hematoma radiologic sub-classification system*

Type Imaging Setting I Hyperdense relative to brain, relatively

homogeneous Acute

II Isodense relative to brain, relatively homogeneous

Subacute

III Hypodense retlative to brain, relatively homogeneous

Chronic

IV Isodense to hypodense, relatively heterogeneous Evidence of recent rebleeding V Hypodense in its liquefied component,

relatively heterogeneous; internal septations and loculations

Chronic

VI Calcified hyperdense, relatively homogeneous Chronic

*Alves et al. (2016) For each study patient, the hematoma volumes and these radiologic variables were collected

for preoperative, immediate post-operative, first follow-up, and second follow-up CT scans.

53

3.1.3 NEUROLOGICAL TESTS AND ASSESSMENTS

As indicated in Table 2, we performed all neurological tests and evaluations at baseline, at

the first in-hospital study visit, and the second in-hospital study visit, where applicable.

Details of each grading scale are provided as appendices.

3.1.3.1 Glasgow Coma Scale

The Glasgow Coma Scale (GCS) is a universal neurological scale that uses defined stimuli to

assess for impaired consciousness (Teasdale & Jennett, 1974). It is used for its objective

assessment of impaired consciousness. Individuals are assessed and graded on three response

elements: eye response, verbal response, and motor response, each with a minimum possible

grade of 1, and maximum possible grades of 4, 5 and 6, respectively. Lower grades indicate

severely impaired responding. Grades from each response are then summed to yield a

cumulative score, where the maximum achievable score is 15, meaning full consciousness,

and the minimum achievable score is 3, indicating the lowest level of conscious awareness

(Appendix A).

3.1.3.2 Glasgow Outcome Scale-Extended

The Glasgow Outcome Scale-Extended (GOSE) is a widely-used neurological scale for

assessing functional outcome (Jennett, Snoek, Bond, & Brooks, 1981; Weir et al., 2012). The

GOSE is measured on an ordinal scale with five categories: Death, Vegetative State, Severe

Disability, Moderate Disability, and Good Recovery. The categories of Severe Disability,

Moderate Disability, and Good Recovery category are each subsequently split into upper and

lower levels yielding a total of eight categories, in order to increase the scale’s sensitivity in

detecting clinically-significant treatment effects (Appendix B).

54

3.1.3.3 Markwalder Grading Score

The Markwalder Grading Score (MGS) is a scale that was developed for assessing the

neurological status of patients with chronic subdural hematomas (Markwalder, Steinsiepe,

Rohner, Reichenbach, & Markwalder, 1981). The scale ranges from 0 to 4, with 0 indicating

the patient has normal neurological status and no symptoms, and 4 indicating the patient is

comatose and non-responsive to stimuli (Appendix C).

3.1.3.4 modified Rankin Scale

The modified Rankin Scale (mRS) is a neurological scale that measures degree of disability

and dependency, most commonly used for patients who have suffered a stroke or other

neurological trauma or disability (Bonita & Beaglehole, 1988; Rankin, 1957a, 1957b;

RANKIN, 1957). It is scored on a scale from 0 to 6, with 0 meaning no symptoms and

perfect health, and 6 meaning death. A median score of 3 indicates moderate disability,

requiring some help, but able to walk without assistance, while a score of 4 indicates not

being able to walk without assistance and 5 meaning the patient is bedridden (Appendix D).

3.1.3.5 National Institutes of Health Stroke Scale

The National Institutes of Health Stroke Scale (NIHSS) is a comprehensive tool used to

assess the neurological disability caused by a stroke (Brott et al., 1989). We administered the

NIHSS because it allows for an objective assessment of several functional modalities. It was

designed for use in clinical trial settings, and is widely used by investigators in stroke trials.

It is composed of 11 assessments, which examine degree of impairment with respect to 11

functional capacities: level of consciousness, horizontal eye movement, visual fields, facial

palsy, arm mobility, leg mobility, limb ataxia, sensory capacity, language, speech, and

extinction and inattention. The lowest possible score on each section is 0, indicating normal

function in that specific capacity, and higher scores indicating increasingly severe

55

impairment in that capacity. The scores on each assessment are totaled, yielding a total

possible overall NIHSS score from 0 to 42.

3.1.4 QUALITY OF LIFE (QOL) MEASURES

The RAND 36-Item Short Form Health Survey 1.0 (SF-36) (Brazier et al., 1992) and Health

Utilities Index (HUI®) (Horsman et al., 2003a) were administered at baseline, at first follow-

up, and at final follow-up, as measures of mental, physical, and health-related quality of life

(QOL) and health-related (QOL). Participants completed the questionnaires on their own,

with the help of a family member if they were unable to circle the answers. Regardless, the

patients were encouraged to answer the questions honestly and for themselves.

3.1.4.1 SF-36

3.1.4.1.1 SF-36 questionnaire overview

The RAND 36-Item Short Form Health Survey 1.0 (SF-36) is a validated questionnaire that

is used as a subjective measure of quality of life (J. E. Ware & Sherbourne, 1992; J. Ware,

Kosinski, & Keller, 1994). The questionnaire is self-administered, and is often chosen in

clinical research for its timely and straightforward completion, as well as its comprehensive

assessment of a variety of health categories.

Composed of 36 questions, the questionnaire assesses health over eight categories: physical

functioning, bodily pain, role limitations due to physical health problems, role limitations

due to personal problems, role limitations due to emotional problems, emotional well-being,

social functioning, energy and fatigue, and overall perception of one’s own general health.

56

3.1.4.1.2 Scoring of the SF-36

The responses to each of the 36 questions are converted to scores on a scale of 0 to 100, with

scores closer to 0 indicating a poorer health state, and scores closer to 100 indicating a more

favorable health state. The scores on certain preset questions are averaged to yield an overall

score for each of the eight health categories assessed by the questionnaire. The mean (STD)

scores for health controls on each category have been reported as: 70.61 (27.42) for physical

functioning; 52.97 (40.78) for role limitations due to physical health; 65.78 (40.71) for role

limitations due to emotional health; 52.15 (22.39) for energy and fatigue; 70.38 (21.97) for

emotional well-being; 78.77 (25.43) for social functioning; 70.77 (25.46) for pain; and 56.99

(21.11) for general health.

3.1.4.2 HUI

3.1.4.2.1 HUI questionnaire overview

All necessary permissions for use of the Health Utilities Index (HUI) questionnaire were

obtained prior to beginning any study activities.

The HUI is a 15-item questionnaire assessing health-related quality of life (HRQL) (Furlong,

Feeny, Torrance, & Barr, 2001; Grootendorst, Feeny, & Furlong, 2000; Horsman et al.,

2003a; Horsman, Furlong, Feeny, & Torrance, 2003b). It has been validated by several

studies and favored for its sensitivity (Kaplan & Haenlein, 2010). The questionnaire was

designed to be minimally intensive for health subjects to complete, while obtaining the

maximum amount of information needed to classify an individual's health status according to

two classification systems: the Health Utilities Index Mark 3 (HUI3) and Health Utilities

Index Mark 2 (HUI2). The questionnaire asks respondents to focus on their usual or current

health within a specified health status assessment period. The questionnaire used in this study

focused on a specified health status assessment period of the previous one week.

57

The questionnaire is suitable for use among individuals who are experiencing cognition or

attention deficits such as neurosurgery patients, as it can be completed by either the subject

or a respondent other than the subject including a substitute decision maker or other family

member that may act as a proxy on behalf of the respondent. In our study, patients who were

unable to complete the questionnaire on their own were typically those who were consented

to the study by a Substitute Decision Maker (SDM). In those situations, the SDM was the

respondent who completed the HUI questionnaire. Further, not all patients enrolled to the

study spoke fluent English. Because the questionnaire was only available to us in the English

language, the questions were translated to the patient in the dominant language and the

questionnaire was completed by the patient.

The HUI3 and HUI2 health status classification systems are considered to be complementary

to one another. Each scale measures the individual functionality of specified health attributes.

The eight health attributes evaluated by the HUI3 classification system are: vision, hearing,

speech, ambulation, dexterity, emotion, cognition, and pain. The seven health attributes

evaluated by the HUI2 classification system are: sensation, mobility, emotion, cognition,

self-care, pain and fertility (while not directly asked as a question in the questionnaire,

patients are assumed to have full fertility (a score of 1) unless fertility is being assessed

separately for the purposes of the study in question).

3.1.4.2.2 Scoring of the HUI questionnaire

Responses to the survey questions are converted to health attribute levels using a predefined

scoring system. The answers provided by respondents to the 15 items in the questionnaire are

first converted to attribute scores based on preset algorithms. When scoring the

questionnaire, the health attribute level codes are determined from either a response to a

single pre-specified question, or from combinations of responses from a specified subset of

questions. These converted scores – either individual or combinations of scores – represent

the functional level of a specific health attribute, such as hearing. Scores range from 1 to 6,

with 1 indicating the best possible health state for a given attribute, and higher scores

indicating the poorest possible health state for a given attribute, meaning that the health

58

attribute is at its lowest functional level and the individual is at their most disabled for that

given health attribute. Detailed descriptions of each single-attribute level for the HUI3 and

HUI2 are presented in Appendix E.

The HUI3 and HUI2 single attribute utility scores are subsequently combined to determine

HUI3 and HUI2 overall multi-attribute health-related quality of life (HRQL) utility scores.

These scores range from a value of 0 meaning dead, to 1 meaning perfect health, though

negative values are also permitted. Negative multi-attribute HRQL scores imply a health

state worse than death. Mean population-norm HUI3 and HUI2 multi-attribute HRQL scores

in individuals 65 years old or older have been reported as 0.697 0.016 and 0.798 0.009,

respectively.

These HUI3 and HUI2 multi-attribute scores are also subsequently classified into four

disability categories: none, mild, moderate, and severe.

According to the scoring guideline recommendations, single and multi-attribute HUI3 and

HUI2 scores are presented using conventional summary statistics, as well as with plots of

frequency distributions.

59

3.2 CASE REPORT FORM AND DATA COLLECTION MONITORING

The Case Report Form (CRF) – including all study related medical test results,

questionnaires, and data collection forms – were identified by a unique identification number

assigned to the study participant after receipt of the signed consent form. The hardcopies of

all questionnaires, scoring sheets and medical testing were stored at the Injury Prevention

Research Office in a locked filing cabinet. All results obtained from QOL questionnaires and

study-related medical assessments were filled in the CRF as an encrypted file on a secure St.

Michael’s Hospital Network for analysis. Any and all protocol deviations were documented

in a protocol deviations log, and assessed and signed-off by the study principal investigator.

Necessary steps were taken to mitigate the re-occurrence of any protocol deviations.

60

3.3 SAFETY MONITORING

3.3.1 LABORATORY TESTS

Routine blood tests and urinalyses were performed at baseline, and at both in-hospital study

visits, to assess any changes that could have been associated with TXA administration. Blood

testing was used to monitor for adverse events and included: complete blood count; sodium,

potassium, glucose, and creatinine levels; prothrombin time (PT); International Normalized

Ratio (INR); activated partial thromboplastin time (APTT); and serum pregnancy test, if

applicable. The estimated glomerular filtration rate (eGFR) was calculated using the

validated CKD-EPI online formula (Levey et al., 2009).

3.3.2 OPHTHALMOLOGICAL EVALUATIONS

Due to the possible risk of vision-related adverse events, we asked participants to report any

visual disturbances experienced during the study course during telephone and follow-up

interviews. Ophthalmological examinations were also performed at baseline and both in-

hospital follow-up visits to rule out degenerative changes of the retina.

Fluctuations and deviations from normal values in vital signs, blood chemistry, urinalyses,

and ophthalmological tests were clinically expected. Abnormal results – as determined by the

qualified testing physician, neurosurgeon, ophthalmologist, laboratory or diagnostic

personnel – were noted as clinically significant. If there were significant deviations from

normal levels, they were evaluated by the study principal investigator (PI) to determine

whether they were related to an existing comorbidity or concomitant medication, or whether

they were possibly related to the study drug. Any potential for study discontinuation as a

result of such safety concerns was discussed by the research team and ultimately determined

by the study PI.

61

3.3.3 MONITORING AND MANAGING ADVERSE EVENTS AND ADVERSE

DRUG REACTIONS

Serious adverse events (SAE) as well as adverse events (AE) occurring during the study

schedule were documented throughout the study course. AEs were defined as any

unfavorable event occurring during the study course. All adverse events were assessed and

graded by the principal investigator, and their occurrence led to immediate investigation and

medical treatment, if deemed necessary by the principal investigator and/or most responsible

physician. Any related, possibly related, and unexpected SAEs and AEs were reported to our

institutional REB at St. Michael’s Hospital according to their reporting guidelines. Likewise,

although we did not encounter any serious and unexpected adverse drug reactions (ADRs),

they would have been documented and reported to Health Canada in accordance with

regulations. Any serious ADRs would have resulted in immediate study discontinuation.

3.4 STUDY ENDPOINTS, PARTICIPANT DISCONTINUATION, AND

PARTICIPANT WITHDRAWAL

The occurrence of thrombotic events (including transient ischemic attack), allergic reaction

to TXA, and colour vision disturbances were decided upon as adverse events that would lead

to study drug discontinuation. However, patient would still be followed to continue safety

monitoring and resolution of adverse events. Any and all adverse events and adverse drug

reactions were evaluated by the principal investigator, who regularly monitored participant

safety to determine which adverse events warranted study discontinuation.

Readmission for reoperation constituted a study endpoint, and data collected at that time-

point will be analyzed as first follow-up data. Hematoma resolution as seen at first follow-up

and discharge from neurosurgical follow-up also constituted a study endpoint.

62

3.5 DATA ANALYSIS

3.5.1 STATISTICAL TEST

For continuous demographic variables, the standard mean difference and confidence

intervals are reported. For normally distributed variables, the Student’s t-test was used to

compare means between the treatment and control groups for continuous variables. Where

data was not normally distributed, the Mann-Whitney U test was used for continuous

variables.

For dichotomous and discrete variables, the Chi-square test was used to compare treatment to

control groups. For dichotomous variables for which the expected cell count was less than 5,

the Chi-square test was invalid, and the Fisher’s exact test was used. For ordinal variables for

which the expected cell count was less than 5, the Chi-square test was invalid, and the Mann-

Whitney U test was used. A p-value <0.05 was considered statistically significant. All

statistical analyses were performed with IBM® SPSS® Statistics Software Version 24 or

with R 3.5.0.

3.5.2 SAMPLE SIZE CALCULATION

Using the data presented by Kageyama et al. (Kageyama et al., 2013), in 18 patients who did

not undergo surgery the median hematoma volume was 55.6 mL (7.5 – 140.5 ml) before

TXA administration and 3.6 mL (22.1 – 0 ml) at the end of follow-up. The mean decrease in

hematoma volume would therefore amount to 53.9 mL. To calculate our sample size, we

used a more conservative estimate of the volume change in each study group: 1=20 mL

(change in hematoma volume in the TXA group) and 2=10 mL (change in hematoma

volume in the control group). Assuming a standard deviation of = 10mL and a power value

of 0.9, we determined that 23 patients would be required per study arm to power the trial

(G*Power 3.1 Software; http://www.gpower.hhu.de/) (Buchner, Erdfelder, Faul, & Lang,

2010). We planned to recruit a sample size of at least 60 patients, 30 in each arm, to account

for attrition.

63

4. RESULTS

4.1 CONSORT FLOW DIAGRAM

Assessed for eligibility (n=183)

Excluded (n=158) Not meeting inclusion criteria (n=106) Declined to participate (n=52) Other reasons (n=0)

Analysed (n=11) Excluded from analysis (n=0)

*Patients with missing data were excluded from some analyses, but included in others

Lost to follow-up (n=1) Discontinued intervention (n=1: patient withdrew consent)

Allocated to TXA (n=12) Received allocated intervention (n=12) Did not receive allocated intervention (n=0)

Lost to follow-up (n=0) Discontinued intervention (n=0)

Allocated to control (n=13) Received allocated intervention (n=13) Did not receive allocated intervention (n=0)

Analysed (n=13) Excluded from analysis (n=0)

Allocation

Analysis

Follow-Up

Randomized (n=25)

Enrollment

64

Figure 8. CONSORT flow diagram. The CONSORT flowchart outlines number of patients screened, number of eligible patients, number of patients recruited, and number of patients included in analysis (Moher, Schulz, Altman, & CONSORT GROUP (Consolidated Standards of Reporting Trials), 2001).

4.2 PARTICIPANT RECRUITMENT AND STUDY FEASIBILITY

We screened all subdural hematoma patients admitted to the neurosurgery department at St.

Michael’s Hospital between February 27, 2017 and January 29, 2018 for patients who met

the study criteria. During this time period, 183 SDH patients were admitted. Of these

patients, 77 were eligible for study enrollment. The most common reasons for study

ineligibility are presented in Figure 9.

*Atrial fibrillation removed as exclusion criterion in July, 2017

Figure 9. Most common reasons for patient ineligibility. The primary reason for patient ineligibility was that they did not undergo operative management of their subdural hematoma. ICH: intracranial hemorrhage; SAH: subarachnoid hemorrhage; CAD: coronary artery disease.

0

5

10

15

20

25

30

Nooperative

management

Atrialfibrillation*

Increasedthrombotic

risk

History ofICH, SAH,

stroke

Alcoholabuse/elicit

drug use

CAD Seizures Mechanicalvalve

Num

ber

of p

atie

nts

Exclusion criteria

65

Over the 11-month study period 25 patients were recruited (Figure 10). One patient

subsequently withdrew consent two days after starting the study drug, leaving a sample size

of 24 patients.

Figure 10. Cumulative participant recruitment. Number of patients recruited (orange) and cumulative enrolment (orange + blue) each month of study period. The overall study recruitment during this period was 32.5%. A decreasing trend occurred

over the study duration, as well as significant fluctuations in month-to-month recruitment

rate (Figure 11). This decreasing trend is contrary to the increasing trend in number of

eligible participants over the study course (Figure 12).

66

*Atrial fibrillation removed as exclusion criterion in July, 2017

Figure 11. Recruitment per month. Overall recruitment for the 11-month study period was 32.5%. Since recruitment of the first patient in March 2017, an overall decreasing trend in recruitment per month was observed, with significant month-to-month variability.

Figure 12. Proportion of eligible patients per month. Overall, there was a general trend towards an increasing number of eligible patients over the study period.

The most common reason for eligible patients to refuse enrollment was disinterest in trial

participation. Other common reasons included concerns regarding risk of side effects; not

wanting to make a decision without consulting their family physician; not wanting to take

0%10%20%30%40%50%60%70%80%90%

Rec

ruitm

ent r

ate

Month

0%

10%

20%

30%

40%

50%

60%

70%

Prop

ortio

n of

pat

ient

s

Month

67

additional medications; feeling they had insufficient time to make a decision regarding

participation; worrying about participation safety for ‘older people’; and not wanting to be

treated as a ‘guinea pig’.

4.3 BASELINE DEMOGRAPHICS AND CLINICAL CHARACTERISTICS

Of the 25 recruited participants, 12 were randomized to the TXA treatment arm, and 13 were

randomized to the control arm. One patient in the TXA arm withdrew consent, leaving 11

patients in the TXA arm and 13 in the control arm. The baseline demographic and clinical

features of the study participants are presented in Table 4.

Table 4. Baseline demographic and clinical characteristics, n (%) or mean (STD) Tranexamic acid

(n=11) Control (n=13)

SMD

Mean age, years 70.18 (12.03) 70.85 (9.31) 0.062 Male 10 (91) 6 (46) 1.055 Weight, kg 81.64 (24.90) 69.42 (18.81) 0.685 Admit GCS 0.395 15 6 (55) 9 (69) 14 3 (27) 3 (23) 13 2 (18) 0 (0) 7 0 (0) 1 (8) Comorbidities Hypertension 6 (55) 10 (77) 0.464 Hypercholesterolemia 4 (36) 4 (31) 0.114 Diabetes mellitus 4 (36) 3 (23) 0.114 Benign prostatic hyperplasia 2 (18) 2 (15) 0.302 Dementia 3 (27) 0 (0) 0.826 Hypothyroidism 0 (0) 2 (15) 0.579 Depression 2 (18) 0 (0) 0.636 Bipolar disorder 0 (0) 1 (8) 0.392 Rheumatic heart disease 2 (18) 0 (0) 0.636 Gout 0 (0) 1 (8) 0.392 Sleep apnea 0 (0) 1 (8) 0.392 GERD 1 (9) 0 (0) 0.426 Stomach ulcers 0 (0) 1 (8) 0.579 Meniere’s disease 0 (0) 1 (8) <0.001 Osteoporosis 0 (0) 1 (8) 0.392 Cancer 0 (0) 1 (8) 0.392 Medications upon admission Anticoagulants 0 (0) 0 (0) <0.001 Antiplatelets 1 (9) 0 (0) 0.426

68

Statins 4 (36) 4 (31) 0.114 Levothyroxine 0 (0) 2 (15) 0.579 Hypotensives 3 (27) 9 (69) 0.886 Hypoglycemics 2 (18) 1 (8) 0.302 Osteoporosis medications 0 (0) 1 (8) 0.422 Proton pump inhibitors 2 (18) 1 (8) 0.302 Uricosurics 1 (9) 1 (8) 0.048 Cholinesterase inhibitors 1 (9) 0 (0) 0.636 Diuretics 0 (0) 1 (8) 0.392 Glucocorticoids 0 (0) 1 (8) 0.392 NSAIDs 0 (0) 2 (15) 0.579 Antidepressants or mood

stabilizers 2 (18) 2 (15) 0.072

Atypical antipsychotic 0 (0) 1 (8) 0.392 Antihistamines 0 (0) 1 (8) 0.392 Dietary supplements 1 (9) 2 (15) 0.185 Melatonin 0 (0) 1 (8) 0.392 Presenting symptoms Headache 4 (36) 7 (54) 0.191 Confusion 3 (27) 3 (23) 0.093 Memory impairment 0 (0) 1 (8) 0.392 Dysarthria 1 (9) 2 (15) 0.185 Gait impairment 7 (64) 1 (8) 1.374 Incoordination 0 (0) 1 (8) 0.392 Weakness 2 (18) 4 (31) 0.443 Hemiparesis 2 (18) 3 (23) 0.072 Facial droop 1 (9) 1 (8) 0.048 Numbness 0 (0) 2 (15) 0.579 Lightheadedness 1 (9) 0 (0) 0.048 Dizziness 2 (18) 3 (23) 0.116 Increased fatigue 3 (27) 1 (8) 0.826 Nausea 0 (0) 2 (15) 0.579 Difficulty sleeping 0 (0) 1 (8) 0.392 Decreased appetite 0 (0) 1 (8) 0.392 Decreased attentiveness 0 (0) 1 (8) 0.392 Disorientation 0 (0) 1 (8) 0.579 History of head trauma 9 (82) 11 (85) 0.072 History of fall 8 (73) 10 (77) 0.074 GCS: Glasgow Coma Scale; GERD: gastroesophageal reflex disease; NSAIDs: non-steroidal anti-inflammatory drugs.

The study groups were comparable in baseline medical comorbidities (Table 4). The most

commonly presenting comorbidities were hypertension (n=16, 67%), hypercholesterolemia

(n=8, 33%), and diabetes mellitus (n=7, 29%).

69

The study groups were comparable in medications being taken upon admission (Table 4).

All medications taken upon admission by study participants were classified according to

medication class or mechanism of action.

With regards to symptoms upon admission, the most frequent presenting symptom was

headache (n=11, 46%). Six patients (24%) presented with some degree of confusion. Eight

patients overall (33%) presented with gait impairment, seven of which were randomized to

the TXA treatment arm (Table 4).

Finally, 20 (83%) patients reported having experienced a minor head trauma ranging from

days, weeks, or months prior to hospital presentation, and 18 of these patients (75%) reported

having had a fall. Head traumas that were not falls included motor vehicle collisions,

collisions during sports, or hitting one’s head on a cabinet or door.

4.4 RADIOLOGIC SUBDURAL HEMATOMA FEATURES

4.4.1 BASELINE RADIOLOGIC CHARACTERISTICS

Radiologic data for the subdural hematomas are presented in Table 5. One patient in the

TXA arm was lost to follow-up, and therefore no follow-up CT scan was available. Further,

the baseline CT scans of two patients in the TXA arm were unavailable at the time of

analysis because their baseline images were taken at outside institutions.

All hematomas at baseline were crescent-shaped. There were no differences in hematoma

laterality between the two study arms. There were more bilateral than unilateral hematomas

in the control arm (n=6, 46%) compared to the treatment arm (n=2, 22%).

The study groups overall were balanced with regards to hematoma location, though just over

half of the hematomas among the control group were located in the fronto-parietal region

70

(n=7, 54%) compared to only 1 (11%) in the TXA group. Altogether, more than half of the

hematomas (n=12, 55%) had frontal, parietal, and temporal involvement.

Table 5. Radiologic hematoma characteristics at baseline, n (%) or mean (STD)

Tranexamic acid (n=9)

Control (n=13) SMD

Laterality 0.315 Left 3 (33) 4 (31) Right 4 (44) 3 (23) Bilateral 2 (22) 6 (46) Hematoma location 0.456 Frontal 1 (11) 0 (0) Fronto-parietal 1 (11) 7 (54) Fronto-parieto-temporal 6 (67) 6 (46) Fronto-parieto-temporo-occipital 1 (11) 0 (0) Hematoma density Heterogeneous 5 (56) 10 (77) 0.441 Hyperdense components 4 (44) 10 (77) 0.670 Isodense components 7 (78) 11 (85) 0.167 Hypodense components 6 (67) 11 (85) 0.228 Septated/loculated 4 (44) 7 (54) 0.180 Fluid-fluid levels 3 (33) 3 (23) 0.218 Appreciable membrane 1 (11) 7 (54) 0.980 Maximum thickness, mm 23.97 (9.27)

26.16 (8.92) 0.241

Maximum anterior-posterior dimension, mm

138.21 (12.91) 136.28 r 13.79 0.144

Midline shift 9 (100) 12 (92) 0.392 Direction of midline shift (left to right)

4 (44) 7 (54) 0.267

Size of midline shift, mm 10.64 7.51 0.641 Sulcal effacement 9 (100) 13 (100) <0.001 Subfalcine herniation 5 (56) 8 (62) 0.116 Brainstem compression 1 (11) 0 (0) 0.471 Cisternal compression 1 (11) 1 (8) 0.111 Ventricular compression 9 (100) 13 (100) <0.001 Hydrocephalus 2 (22) 2 (15) 0.167 Hematoma subtype classification 0.426 I 0 (0) 0 (0) II 3 (33) 4 (31) III 3 (33) 1 (8) IV 1 (11) 2 (15) V 2 (22) 6 (46)

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In both study groups, the majority of hematomas were heterogenous, having hyperdense

components as well as isodensities and hypodensities. Eleven (50%) hematomas had

loculations and septations and six (27%) had fluid-fluid levels. For eight (36%) of the

hematomas overall, a membrane was appreciable on imaging: seven (54%) hematomas in the

control group compared to only one (11%) in the TXA treatment group.

Sulcal effacement and ventricular compression were present on all CT scans, and 4 (18%)

CT scans overall showed some degree of hydrocephalus. Nearly all scans (n = 21, 95%)

showed some degree of midline shift and 11 (46%) produced a shift from left to right. Only

one CT scan (5%) showed brainstem compression and two (9%) showed cisternal

compression.

The hematoma subtype classifications were balanced among the two groups. As expected, no

hematomas in either group were Type I (predominantly hyperdense and acute). Seven (32%)

hematomas were Type II (subacute). Eight hematomas (36%) were classified as Type IV

(heterogenous with septations and loculations). No hematomas were classified as Type VI

(calcifed and hyperdense).

4.4.2 HEMATOMA VOLUME CHANGE OVER STUDY COURSE

Mean hematoma volumes for each study group measured at baseline, immediate

postoperative 4-8 week follow-up, and 8-12 week follow-up are presented in Figure 13.

The volumes on baseline pre-operative and post-operative scans were comparable between

the two study groups (Figure 13, Table 5). Only 5 patients returned for the 8-12 week

follow-up. For all patients who did not return for the second follow-up, their primary treating

neurosurgeon discharged them from neurosurgical care after determining that they were

clinically and radiologically stable.

A.

72

Figure 13. Mean hematoma volume over time. A. For each treatment group, there was an overall trend toward decreasing hematoma volumes over time.

B.

PREOP VOLUME

IMMEDIA

TE POSTOP VOLUME

4-8 W

EEK FU VOLUM

E

8-12 W

EEK FU VOLUM

E-50

0

50

100

150

200

250

Timepoint

Vol

ume (

mL)

Hematoma Volume over Study Duration

Control ArmTXA Arm

73

B. Hematoma volume per participant over the study course shows a trend towards decreasing volume over time, with three participants having larger hematoma volumes at the first follow-up than at baseline. These were three of the four patients in our cohort who required reoperation for hematoma reaccumulation.

Hematoma volume change, calculated as percent hematoma resolution from preoperative to

4-8 week follow-up scan, was slightly higher in the TXA treatment arm (mean = 82.36, STD

= 30.85) compared to the control arm (mean = 75.74, STD = 27.83), however this difference

did not reach statistical significance (Table 6).

Table 6. Procedure type and hematoma volume change over study course, n (%) or mean (STD)

PREOP VOLUME

IMMEDIA

TE POSTOP VOLUME

4-8 W

EEK FU VOLUM

E

8-12 W

EEK FU VOLUM

E0

100

200

300

400V

olum

e (m

L)

Hematoma Volume over Study Duration

74

Tranexamic acid

(n=11)

Control (n=13)

SMD p-value

Preoperative hematoma volume, mL

158.13 (37.32)

153.37 (62.59)

0.092 -

Immediate post-operative hematoma cavity volume, mL

63.75 (36.35) 95.85 (73.75) - 0.469

Hematoma volume at 4-8 week, mL

41.45 (61.98) 61.39 (93.86) - 0.494

Hematoma volume at 8-12 week follow-up, mL

12.30 (15.14) 23.66 (39.28) - 1.000

Percent hematoma resolution from preoperative to 4-8 week follow-up, %

82.36 (30.85) 75.74 (27.83) - 0.219

Percent hematoma resolution from immediate post-operative to 4-8 week follow-up, %

39.54 (86.14) 56.59 (42.63) - 0.852

Patients who did not undergo burr-hole craniostomy underwent mini-craniotomy.

4.4.3 HEMATOMA RECURRENCE RATE AND NEED FOR REOPERATION

Overall, four patients (17%) – two in the TXA treatment arm and two in the control arm –

returned during the study period with re-accumulation of their subdural hematoma requiring

re-operation. There was therefore an 18% recurrence rate in the TXA group, and 15%

recurrence rate in the control group. Both patients from the TXA arm were compliant with

the study drug. The patients in the TXA-group underwent re-evacuation of their re-

accumulated CSDHs seven and six days after initial surgery, respectively. One patient in the

TXA arm was still an inpatient at the time of reoperation, which was performed six days

after the initial procedure. The two patients in the control group underwent re-operation 16

days and 30 days after initial treatment. Both patients from the control arm returned a third

time with recurrent symptoms, but neither underwent a third evacuation surgery.

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4.5 NEUROLOGICAL STATUS ASSESSMENTS AT BASELINE AND 4-8 WEEK

FOLLOW-UP

On most assessments, control patients did not differ from patients in the TXA arm with

respect to neurological status at baseline (Table 7). The study groups did differ in baseline

GCS score, with all control patients (n=13, 100%) having a GCS score of 15, and seven TXA

patients (64%) having a GCS score of 15. Of the patients with GCS scores of 14, three

patients scored four out of five possible points on the verbal response, consistent with some

confusion or disorientation to time, person, or place. One patient scored three out of four

possible points on the eye opening response, consistent with eyes opening in response to

sound as opposed to spontaneously, as they would at a full state of consciousness.

Table 7. Neurological status at baseline and 4-8 week follow-up, n (%)

Baseline assessment 4-8 week follow-up assessment TXA

(n=11) Control (n=13)

SMD TXA (n=10)

Control (n=13)

p-value

GCS total 1.019 0.435 15 7 (64) 13 (100) 9 (90) 13 (100) 14 4 (36) 0 (0) 1 (10) 0 (0) Eye opening 0.426 - 4 10 (91) 13 (100) 10 (100) 13 (100) 3 1 (9) 0 (0) 0 (0) 0 (0) Verbal 0.826 5 8 (73) 13 (100) 9 (90) 13 (100) 4 3 (27) 0 (0) 1 (10) 0 (0) Motor <0.001 - 6 11 (100) 13 (100) 10 (100) 13 (100) GOSE 0.361 0.541 8 4 (36) 7 (54) 8 (80) 8 (62) 7 6 (55) 5 (38) 0 (0) 4 (31) 6 0 (0) 1 (8) 2 (20) 1 (8) 5 1 (9) 0 (0) 0 (0) 0 (0) mRS 0.689 0.708 0 1 (9) 6 (46) 5 (50) 4 (31) 1 6 (55) 4 (31) 3 (30) 8 (62) 2 2 (18) 2 (15) 1 (10) 1 (8) 3 0 (0) 1 (8) 1 (10) 0 (0) 4 2 (18) 0 (0) 0 (0) 0 (0) MGS 0.641 0.586 0 3 (27) 7 (54) 6 (60) 5 (38) 1 5 (45) 5 (38) 2 (20) 7 (54)

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2 3 (27) 1 (8) 2 (20) 1 (8) NIHSS 0.011 - 0 7 (70)** 11 (85) 9 (100)*** 13 (100) 1 3 (30)** 1 (8) 0 (0) 0 (0) 3 0 (0)** 1 (8) 0 (0) 0 (0) GCS: Glasgow Coma Scale; GOSE: Glasgow Outcome Score, Extended; mRS: modified Rankin Score; MGS: Markwalder Grading Score; NIHSS: National Institutes of Health Stroke Scale. *denotes a statistically significant result. **n=10: one patient was unable to follow commands to complete the NIHSS at baseline. ***n=9: one patient was unable to follow commands to complete the NIHSS at follow-up, and another was lost to follow-up. There were no baseline imbalances in GOSE score between groups. Six patients (25%)

scored zero out of six possible points on the mRS, consistent with being neurologically

asymptomatic (Table 7). Ten patients (42%) overall scored one out of six, consistent with

reporting no significant disability despite some symptoms, and feeling they were able to

carry out their usual duties and activities. Four patients had an mRS score of two at baseline,

feeling slightly disabled, and feeling unable to carry out all previous activities, but able to

look after their own affairs without assistance. One patient in the control group scored an

mRS of three, presenting with moderate disability and requiring some help with activities

and personal affairs, but largely being able to walk without assistance. Two patients, both in

the TXA group, scored an mRS of four, consistent with being moderately to severely

disabled, and unable to walk or attend to bodily affairs without the assistance of others.

There were no baseline imbalances between groups in Markwalder Grading Scores (MGS)

(Table 7). Ten patients (42%) scored zero out of four possible grades, consistent with being

neurologically normal. A further 10 patients received a grade of one, indicating they were

alert and oriented, and had some mild symptoms such as headache or even some minor

neurologic deficit. Four patients (17%) had an MGS of two, indicating they were drowsy or

disoriented with some neurological deficit.

Seventeen patients (74%) of the 23 patients who were able to complete the NIHSS at

baseline scored zero out of 42, consistent with no impairment across any of the tested

functional domains. Four patients (17%) scored one out of 42, a result of disorientation and

77

confusion at baseline. One patient scored three out of 42, resulting from facial hemiparesis

and dysarthria, which were presenting symptoms that persisted after surgery.

At the first follow-up, only one patient was GCS 14, disoriented to time and place (Table 7).

This patient was one of the four patients in our cohort who returned with hematoma growth

that led to reoperation. The remaining patients (96%) were GCS 15.

Table 8. Neurological status change from baseline to 4-8-week follow-up, n (%) TXA

(n=11) Control (n=13)

Baseline

4-8 week follow-up**

p-value Baseline

4-8 week follow-up

p-value

GCS total 0.221 0.083 15 7 (64) 9 (90) 13 (100) 13 (100) 14 4 (36) 1 (10) 0 (0) 0 (0) Eye opening 0.059 0.083 4 10 (91) 10 (100) 13 (100) 13 (100) 3 1 (9) 0 (0) 0 (0) 0 (0) Verbal 0.066 0.083 5 8 (73) 9 (90) 13 (100) 13 (100) 4 3 (27) 1 (10) 0 (0) 0 (0) Motor 0.083 0.083 6 11 (100) 10 (100) 13 (100) 13 (100) GOSE 0.058 1.000 8 4 (36) 8 (80) 7 (54) 8 (62) 7 6 (55) 0 (0) 5 (38) 4 (31) 6 0 (0) 2 (20) 1 (8) 1 (8) 5 1 (9) 0 (0) 0 (0) 0 (0) mRS 0.863 0.062 0 1 (9) 5 (50) 6 (46) 4 (31) 1 6 (55) 3 (30) 4 (31) 8 (62) 2 2 (18) 1 (10) 2 (15) 1 (8) 3 0 (0) 1 (10) 1 (8) 0 (0) 4 2 (18) 0 (0) 0 (0) 0 (0) MGS 0.495 0.040* 0 3 (27) 6 (60) 7 (54) 5 (38) 1 5 (45) 2 (20) 5 (38) 7 (54) 2 3 (27) 2 (20) 1 (8) 1 (8) NIHSS 0.679 0.106 0 7 (70)** 9 (100)*** 11 (85) 13 (100) 1 3 (30)** 0 (0) 1 (8) 0 (0)

78

3 0 (0)** 0 (0) 1 (8) 0 (0) GCS: Glasgow Coma Scale; GOSE: Glasgow Outcome Score, Extended; mRS: modified Rankin Score; MGS: Markwalder Grading Score; NIHSS: National Institutes of Health Stroke Scale. *denotes a statistically significant result. **n=10: one patient was unable to follow commands to complete the NIHSS at baseline. ***n=9: one patient was unable to follow commands to complete the NIHSS at follow-up, and another was lost to follow-up. Sixteen patients (70%) at the 4-8 week follow-up scored an eight on the GOSE, indicating

upper Good Recovery. This was increased from the 11 patients who scored a GOSE of eight

at baseline. Further, four patients scored a GOSE of seven, indicating lower Good Recovery,

an improvement from the 11 patients who were GOSE seven at baseline. No patients scored

less than a GOSE of six at the first follow-up, consistent with upper Moderate Recovery.

Overall, there was no statistically significant difference in 4-8-week follow-up GOSE score

between treatment groups.

There was also no statistically significant difference in mRS, MGS, or NIHSS scores

between groups at the 4-8 week follow-up. Scores on these scales were lower at 4-8 week

follow-up than at baseline, consistent with clinical improvement in neurological status

(Table 8).

Too few patients (n=5) returned for the 8-12 week follow-up to compare neurological status

between groups.

4.6 QUALITY OF LIFE ASSESSMENT SCORES AT BASELINE AND FOLLOW-UP

One patient in the TXA group was unable to complete the questionnaires at baseline, and

another left too many questions incomplete to be scored. One patient in the control group

refused to fill out the questionnaires at both baseline and follow-up. This left 21

questionnaires complete for baseline assessment.

79

4.6.1 SF-36 QUESTIONNAIRE SCORES AT BASELINE AND 4-8 WEEK FOLLOW-

UP

Baseline SF-36 scores across all eight tested domains did not differ between study groups

(Table 9). The control group scored somewhat worse on the ‘Energy and fatigue’ domain

(mean = 10.42, STD = 29.11) than the TXA group (mean = 30.56, STD = 39.09), indicating

lower energy levels and more fatigue. The control group also scored worse on the role

limitations due to physical health domain (mean = 33.41, STD = 32.31) compared to the

TXA group (mean = 51.94, STD = 26.98), indicating they felt more limited in activities they

were able to perform as a result of decreased overall physical functionality. This difference

did not reach statistical significance (0.136).

Table 9. SF-36 scores at baseline and 4-8 week follow-up, mean (STD) Baseline assessment 4-8 week follow-up assessment

SF-36 TXA (n=9)

Control (n=12)

p-value

TXA (n=8)

Control (n=9)

p-value

Physical functioning 42.78 (33.51) 44.77 (32.57) 0.803 50.42 (33.15) 58.89 (26.78) 0.500 Energy and fatigue 30.56 (39.09) 10.42 (29.11) 0.167 21.88 (36.44) 30.56 (32.54) 0.383 Emotional well-being 37.04 (48.43) 33.33 (49.24) 0.739 50.00 (53.45) 51.85 (44.44) 1.000 Social functioning 38.89 (30.19) 37.73 (21.61) 0.970 54.79 (21.05) 58.52 (14.68) 0.662 Pain 54.22 (31.63) 61.09 (19.44) 0.541 74.38 (20.80) 79.33 (15.68) 0.662 General health 47.22 (31.73) 43.75 (30.39) 0.746 57.81 (33.37) 61.11 (27.56) 0.921 Role limitations due to physical health

51.94 (26.98) 33.41 (32.31) 0.136 59.06 (25.74) 74.72 (13.08) 0.143

Role limitations due to emotional health

53.33 (23.85) 68.75 (20.90) 0.108 67.08 (15.09) 64.44 (15.50) 0.743

SF-36: Short-form 36-item health survey. Higher scores indicate a better quality of life for each given category. At the 4-8 week follow-up, the control group had a trend towards better scores than the TXA

group on nearly all tested domains, with ‘Role limitations due to emotional health’ as the

only exception (Table 9). These differences in scores between groups were not statistically

significant.

Table 10. Change in SF-36 scores from baseline to 4-8-week follow-up, mean (STD) TXA

(n=8) Control (n=9)

SF-36 Baseline

4-8 week follow-up

p-value

Baseline

4-8 week follow-up

p-value

Physical functioning 42.78 (33.51) 50.42 (33.15) 0.499 44.77 (32.57) 58.89 (26.78) 0.214 Energy and fatigue 30.56 (39.09) 21.88 (36.44) 0.102 10.42 (29.11) 30.56 (32.54) 0.306

80

Emotional well-being 37.04 (48.43) 50.00 (53.45) 0.655 33.33 (49.24) 51.85 (44.44) 0.748 Social functioning 38.89 (30.19) 54.79 (21.05) 0.173 37.73 (21.61) 58.52 (14.68) 0.078 Pain 54.22 (31.63) 74.38 (20.80) 0.206 61.09 (19.44) 79.33 (15.68) 0.051 General health 47.22 (31.73) 57.81 (33.37) 0.553 43.75 (30.39) 61.11 (27.56) 0.324 Role limitations due to physical health

51.94 (26.98) 59.06 (25.74) 0.207 33.41 (32.31) 74.72 (13.08) 0.035*

Role limitations due to emotional health

53.33 (23.85) 67.08 (15.09) 0.128 68.75 (20.90) 64.44 (15.50) 0.752

SF-36: Short-form 36-item health survey. Higher scores indicate a better quality of life for each given category. *denotes a statistically significant result. 4.6.2 HUI QUESTIONNAIRE SCORES AT BASELINE AND 4-8 WEEK FOLLOW-UP

4.6.2.1 HUI Mark 3

Health utility levels across the eight HUI3 domains – vision, hearing, speech, ambulation,

dexterity, emotion, cognition, and pain – were similar between the control and TXA groups

at baseline (Table 11). Table 11. Frequency distribution of HUI3 single-attribute levels among study participants at baseline and 4-8 week follow-up, n (%) Attribute level

Baseline assessment 4-8 week follow-up assessment TXA (n=9)

Control (n=12)

p-value TXA (n=8)

Control (n=9)

p-value

Vision 0.964 0.665 1 1 (11) 3 (25) 2 (25) 2 (22) 2 8 (89) 7 (58) 6 (75) 7 (78) 3 0 (0) 1 (8) 0 (0) 0 (0) 4 0 (0) 1 (8) 0 (0) 0 (0) 5 0 (0) 0 (0) 0 (0) 0 (0) 6 0 (0) 0 (0) 0 (0) 0 (0) Hearing 0.815 0.735 1 8 (89) 10 (83) 7 (87.5) 8 (89) 2 0 (0) 0 (0) 0 (0) 0 (0) 3 0 (0) 1 (8) 1 (12.5) 1 (11) 4 0 (0) 0 (0) 0 (0) 0 (0) 5 0 (0) 1 (8) 0 (0) 0 (0) 6 1 (11) 0 (0) 0 (0) 0 (0) Speech 0.687 0.122 1 7 (78) 8 (67) 6 (75) 9 (100) 2 0 (0) 0 (0) 1 (12.5) 0 (0) 3 1 (11) 3 (25) 1 (12.5) 0 (0) 4 0 (0) 1 (8) 0 (0) 0 (0) 5 1 (11) 0 (0) 0 (0) 0 (0) 6 N/A N/A N/A N/A Ambulation 0.971 0.369

81

1 4 (44) 4 (33) 5 (62.5) 7 (78) 2 1 (11) 3 (25) 0 (0) 1 (11) 3 0 (0) 2 (17) 2 (25) 1 (11) 4 2 (22) 1 (8) 0 (0) 0 (0) 5 2 (22) 2 (17) 1 (12.5) 0 (0) 6 0 (0) 0 (0) 0 (0) 0 (0) Dexterity 0.152 0.080 1 4 (44) 9 (75) 4 (50) 8 (89) 2 2 (22) 1 (8) 3 (37.5) 1 (11) 3 0 (0) 1 (8) 1 (12.5) 0 (0) 4 3 (33) 1 (8) 0 (0) 0 (0) 5 0 (0) 0 (0) 0 (0) 0 (0) 6 0 (0) 0 (0) 0 (0) 0 (0) Emotion 0.739 0.324 1 2 (22) 1 (8) 4 (50) 6 (67) 2 1 (11) 5 (42) 2 (25) 3 (33) 3 4 (44) 4 (33) 2 (25) 0 (0) 4 1 (11) 1 (8) 0 (0) 0 (0) 5 1 (11) 1 (8) 0 (0) 0 (0) 6 N/A N/A N/A N/A Cognition 0.578 0.758 1 0 (0) 1 (8) 4 (50) 4 (44) 2 2 (22) 0 (0) 0 (0) 1 (11) 3 3 (33) 3 (25) 1 (12.5) 2 (22) 4 2 (22) 6 (50) 2 (25) 2 (22) 5 1 (11) 2 (17) 1 (12.5) 0 (0) 6 1 (11) 0 (0) 0 (0) 0 (0) Pain 1.000 0.168 1 0 (0) 0 (0) 5 (62.5) 0 (0) 2 1 (11) 3 (25) 0 (0) 6 (67) 3 4 (44) 2 (17) 3 (37.5) 3 (33) 4 1 (11) 3 (25) 0 (0) 0 (0) 5 3 (33) 4 (33) 0 (0) 0 (0) 6 N/A N/A N/A N/A N/A: not applicable. Scores range from 1 to 6, lower scores indicating perfect health and higher scores indicating worse health.

Based on the baseline attribute levels, one of the most severely affected health attributes in

the week prior to questionnaire completion was pain, with all patients in both study groups

reporting some degree of pain, and no patients scoring perfect health (a score of one).

Likewise, all but one study patient had some degree of cognitive impairment. Eighteen

patients (86%) had impaired emotional faculties, and 13 (62%) had impaired ambulation. Six

patients (29%) had some degree of speech impairment, and eight (38%) had impaired

dexterity. Three patients had impaired hearing at baseline, all of which were consistent with

age-related hearing loss.

82

At the 4-8 week study follow-up, there was again no difference in HUI3 utility level scores

between control and TXA patients (Table 11). Compared to baseline assessments, patients in

both study groups had lower scores on pain, cognition, speech, and ambulation, indicating

improved health across those domains.

There were no baseline imbalances between study groups in the overall HUI3 multi-attribute

health related quality of life (HRQL) utility scores, which were derived from the single-

attribute scores (Table 12, Figure 14A and B). No patients in either group reported perfect

health (an HRQL score of 1). Three patients in the control group and three patients in the

TXA group had multi-attribute HRQL scores below zero, indicating a quality of life self-

rated worse than death. Table 12. Mean overall HUI3 multi-attribute HRQL utility scores at baseline and 4-8 week follow-up, mean (STD) Baseline assessment 4-8 week follow-up assessment TXA

(n=9) Control (n=12)

p-value TXA (n=8)

Control (n=9)

p-value

HUI3 HRQL 0.23 (0.38) 0.27 (0.33) 0.831 0.61 (0.39) 0.76 (0.12) 0.791

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Figure 14. Frequency distribution of overall HUI3 Multi-attribute (HRQL) Utility Scores. Scores are presented at baseline for (A) TXA-treated participants, and (B) control participants, and at follow-up for (C) TXA-treated participants, and (D) control participants. An optimal HRQL score is closer to 1, with 1 indicating perfect health.

The mean overall HUI3 multi-attribute HRQL utility scores at 4-8 week follow-up did not

differ significantly between the two groups (Table 12, Figure 14B and C). No patients had

HRQL scores below zero, compared to six patients at baseline.

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Compared to baseline, the mean overall HUI3 HRQL scores at 4-8 week follow-up were

higher, though this improvement only reached statistical significance in the control group

(Table 13, Figure 14B and C). At 4-8 week follow-up, no patients had HRQL scores below

zero, compared to six patients at baseline.

Table 13. Change in overall HUI3 multi-attribute HRQL utility scores from baseline to 4-8 week follow-up, mean (STD) TXA

(n=9) Control (n=12)

Baseline 4-8 week follow-up**

p-value Baseline 4-8 week follow-up***

p-value

HUI3 HRQL 0.23 (0.38) 0.61 (0.39) 0.128 0.27 (0.33) 0.76 (0.12) 0.008 **n=8. ***n=9. Conversion of these HRQL scores to disability categories showed that most patients were

severely impaired across the HUI3 health attributes at baseline (Table 14). No patients had

perfect overall health or even mild impairment.

Table 14. Frequency distribution of disability category based on overall HUI3 Multi-attribute (HRQL) Utility Score at baseline and 4-8 week follow-up, n (%) Baseline assessment 4-8 week follow-up assessment Disability Category TXA

(n=9) Control (n=12)

p-value TXA (n=8)

Control (n=9)

p-value

Mild 0 (0) 0 (0) 0.686 3 (37.5) 1 (11) 0.815 Moderate 1 (11) 1 (8) 2 (25) 6 (67) Severe 8 (89) 11 (92) 3 (37.5) 2 (22) At the 4-8 week follow-up, the study groups did not differ significantly in HUI3 disability

category (Table 14). While five patients (31%) were still categorized as having severe

disability at 4-8 week follow-up, four patients (25%) were categorized as having mildly-

impaired overall function across the eight HUI3 health attributes compared to zero patients at

baseline.

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4.6.2.2 HUI Mark 2

Single-attribute healthy utility levels across the seven HUI2 domains – sensation, mobility,

cognition, self-care, emotion, pain, and fertility – were similar between the control and TXA

groups at baseline (Table 15). Similar to HUI3 level scores, 23 patients had some level of

impairment in cognition and pain. Further, sensation was also impaired in all but one study

patient. Thirteen patients (62%) were impaired to some degree in their ability to maintain

self-care.

Table 15. Frequency distribution of HUI2 single-attribute levels among study participants at baseline and 4-8 week follow-up, n (%) Attribute level

Baseline assessment 4-8 week follow-up assessment TXA (n=9)

Control (n=12)

p-value TXA (n=8)

Control (n=9)

p-value

Sensation 0.493 0.495 1 0 (0) 1 (8) 2 (25) 2 (22) 2 7 (78) 5 (42) 4 (50) 7 (78) 3 1 (11) 6 (50) 2 (25) 0 (0) 4 1 (11) 0 (0) 0 (0) 0 (0) 5 0 (0) 0 (0) 0 (0) 0 (0) 6 0 (0) 0 (0) 0 (0) 0 (0) Mobility 0.911 0.369 1 4 (44) 4 (33) 5 (62.5) 7 (78) 2 1 (11) 3 (25) 0 (0) 1 (11) 3 2 (22) 3 (25) 2 (25) 1 (11) 4 2 (22) 2 17) 1 (12.5) 0 (0) 5 0 (0) 0 (0) 0 (0) 0 (0) 6 0 (0) 0 (0) 0 (0) 0 (0) Cognition 0.475 0.957 1 0 (0) 1 (8) 4 (50) 4 (44) 2 7 (78) 9 (75) 3 (37.5) 5 (56) 3 1 (11) 2 (17) 1 (12.5) 0 (0) 4 1 (11) 0 (0) 0 (0) 0 (0) 5 0 (0) 0 (0) 0 (0) 0 (0) 6 0 (0) 0 (0) 0 (0) 0 (0) Self-care 0.702 0.426 1 4 (44) 5 (42) 6 (75) 8 (89) 2 4 (44) 4 (33) 1 (12.5) 1 (11) 3 0 (0) 1 (8) 1 (12.5) 0 (0) 4 1 (11) 1 (8) 0 (0) 0 (0) 5 0 (0) 2 (17) 0 (0) 0 (0) 6 N/A N/A N/A N/A Emotion 0.236 0.173 1 1 4 (33) 4 (50) 7 (78) 2 3 5 (42) 2 (25) 2 (22) 3 4 1 (8) 2 (25) 0 (0) 4 1 1 (8) 0 (0) 0 (0)

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5 0 (0) 1 (8) 0 (0) 0 (0) 6 0 (0) 0 (0) 0 (0) 0 (0) Pain 0.331 0.261 1 0 (0) 1 (8) 5 (62.5) 1 (11) 2 5 (56) 4 33) 1 (12.5) 8 (89) 3 3 (33) 2 (17) 2 (25) 0 (0) 4 1 (11) 2 (17) 0 (0) 0 (0) 5 0 (0) 3 (25) 0 (0) 0 (0) 6 0 (0) 0 (0) 0 (0) 0 (0) Fertility 1.000 1.000 1 9 (100) 12 (100) 8 (100) 9 (100) 2 0 (0) 0 (0) 0 (0) 0 (0) 3 0 (0) 0 (0) 0 (0) 0 (0) 4 0 (0) 0 (0) 0 (0) 0 (0) 5 0 (0) 0 (0) 0 (0) 0 (0) 6 0 (0) 0 (0) 0 (0) 0 (0) N/A: not applicable. Scores range from 1 to 6, lower scores indicating perfect health and higher scores indicating worse health. At the 4-8 week follow-up, more patients had lower levels of pain than at baseline, with six

patients (35%) reporting no pain at all (Table 15). There were also nearly twice as many

patients (n=14, 82%) with no self-care limitations at the 4-8 week follow-up compared to at

baseline (n=9, 43%). Overall, patients between treatment groups did not differ significantly

across the HUI2 attribute levels at the 4-8 week follow-up.

There was no difference in overall HUI2 multi-attribute HRQL utility scores between study

groups at baseline or at 4-8 week follow-up (Table 16, Figure 15).

Table 16. Mean overall HUI2 multi-attribute HRQL utility scores at baseline and 4-8 week follow-up, mean (STD) Baseline assessment 4-8 week follow-up assessment TXA

(n=9) Control (n=12)

p-value TXA (n=8)

Control (n=9)

p-value

HUI2 HRQL 0.55 (0.24) 0.50 (0.27) 0.570 0.72 (0.27) 0.87 (0.07) 0.632

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Figure 15. Frequency distribution of overall HUI2 Multi-attribute (HRQL) Utility Scores. Scores are presented at baseline for (A) TXA-treated participants, and (B) control participants, and at follow-up for (C) TXA-treated participants, and (D) control participants. An optimal HRQL score is closer to 1, with 1 indicating perfect health.

Similar to the HUI3 HRQL utility scores, the HUI2 HRQL scores were higher at the 4-8

week follow-up than at baseline (Table 17). This change reached statistical significance in

the control group but not the TXA group. However, this change may still suggest a clinically

relevant improvement in functionality across the HUI2 levels.

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Table 17. Change in overall HUI2 multi-attribute HRQL utility scores from baseline to 4-8 week follow-up, mean (STD) TXA

(n=9) Control (n=12)

Baseline 4-8 week follow-up**

p-value Baseline 4-8 week follow-up***

p-value

HUI2 HRQL 0.55 (0.24) 0.72 (0.27) 0.176 0.50 (0.27) 0.87 (0.07) 0.008* *denotes a statistically significant result. **n=8. ***n=9.

Finally, the distribution of disability categories based on HUI2 attributes showed that most

patients (n=19, 90%) were severely impaired across these health domains, 2 (10%) were

moderately impaired, and no patients were at full or at least mild health utility (Table 18).

Table 18. Frequency distribution of disability category based on overall HUI2 Multi-attribute (HRQL) Utility Score at baseline, n (%) Baseline assessment 4-8 week follow-up assessment Disability Category TXA

(n=9) Control (n=12)

p-value TXA (n=8)

Control (n=9)

p-value

Mild 0 (0) 0 (0) 0.686 2 (25) 3 (33) 0.539 Moderate 1 (11) 1 (8) 3 (37.5) 4 (44) Severe 8 (89) 11 (92) 3 (37.5) 2 (22) At the 4-8 weeks follow-up, five patients (31%) were classified as having severely impaired

functionality across HUI2 health attributes compared to 19 patients (90%) at baseline (Table

18). While no patients at baseline had better than moderate functionality, at follow-up, four

patients (67%) were categorized as having only mild impairment. There was no significant

difference between treatment groups in frequency distribution of disability categories at 4-8

weeks.

4.7 ADVERSE EVENTS AND TXA SAFETY

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The number of expected and unexpected adverse events experienced by patients in the

control group did not differ significantly from the number experienced by patients in the

TXA treatment arm (Table 19). There were no serious unexpected adverse events.

Headache was the most frequently reported adverse event (n = 6, 25%), and was most

commonly reported in the acute period after surgery, often resolved or highly infrequent by

the time of the 4-8 week clinical follow-up.

Table 19. Frequency of adverse events and serious adverse events during study period, n (%)

AE or SAE TXA (n=11) Control (n=13) p-value Weakness 0 (0) 1 (8) 1.000 Headache 2 (18) 4 (31) 0.649 Sinus pain 1 (9) 0 (0) 0.458 Jaw pain 1 (9) 0 (0) 0.458 Dysphagia 1 (9) 0 (0) 0.458 Acute swelling 2 (18) 0 (0) 0.199 Dry skin on scalp 1 (9) 0 (0) 0.458 Intermittent dizziness 1 (9) 2 (15) 1.000 Shortness of breath 0 1 (8) 1.000 Chest pain 0 1 (8) 1.000 Nausea or stomach upset 1 (9) 1 (8) 1.000 Stomach pain 0 2 (15) 0.482 Bladder infection 1 (9) 0 (0) 0.458 Muscle pain 1 (9) 0 (0) 0.458 Back pain 0 0 (0) 1.000 Seizure 1 (9) 0 (0) 0.458 Fatigue 1 (9) 2 (15) 1.000 Attention and memory impairment

1 (9) 0 (0) 0.458

Hematoma recurrence requiring revision surgery

2 (18) 2 (15) 1.000

AE: adverse event; SAE: serious adverse event.

While not significantly different between groups, some adverse events, such as shortness of

breath, chest pain, and generalized weakness were experienced only by control patients,

while others, including dysphagia, jaw pain, sinus pain, dry skin, muscle pain, bladder

infection, and attention and memory impairment were only experienced by patients in the

TXA group. Acute swelling was also experienced by two patients in the TXA group: in the

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jaw of one patient, and in the left ankle of the other. Two patients (8%) experienced nausea

or stomach upset.

No patients reported experiencing an allergic reaction to TXA. No patients reported sudden

or unexpected visual disturbances, and no retinal changes were detected. While one patient

experienced some intermittent dizziness, no patients experienced persistent dizziness or long-

lasting hypotension.

No patients experienced thrombotic or thromboembolic events, including cerebral infarction

or thrombosis, myocardial infarction, angina, deep vein thrombosis or arterial thrombosis.

No changes in renal function or urination were reported.

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5. DISCUSSION

5.1 BASELINE DEMOGRAPHIC AND CLINICAL CHARACTERISTICS

The baseline demographic and clinical characteristics were largely balanced between the two

groups. There was, however, an imbalance in sex between the two groups, with more males

in the TXA treatment arm than the control arm. This observed difference was attributed to

the small sample size, and may balance out with increased recruitment. It is also important to

note that many studies have reported a predominance in incidence and prevalence of SDHs in

males compared to females (Baechli, Nordmann, Bucher, & Gratzl, 2004). Likewise at our

institution, 79% of admitted SDH patients were male, and 70% of eligible SDH patients were

male. Demographic differences among patients likely follows from the heterogeneity of the

natural disease course.

Comorbidities at baseline were also balanced between the two groups. The most frequent

comorbidities were hypertension, hypercholesterolemia, and diabetes mellitus, which is

consistent with some of the most common chronic health diseases suffered by senior

populations (Salive, 2013).

No patients in our study were taking anticoagulants upon admission, and only two (8%) were

taking antiplatelets (neither of these patients were restarted on antiplatelets by their treating

physician until after the follow-up and study period, to mitigate the risk of re-bleeding).

Given the senior demographic of our study population, we expected more patients to be

taking these medications for other comorbidities. It is likely that most patients with

comorbidities that would have entailed anticoagulant treatment – including coronary artery

disease (CAD), recent ischemic stroke, or other medical condition causing an increased

thrombotic risk – were excluded upon screening, based on our predefined eligibility criteria.

Expanding the eligibility criteria to include these patients may lead to greater recruitment of

patients taking anticoagulants and antiplatelets. However, these clinical variables would have

to be controlled for as they are potential risk factors for SDH development and recurrence,

and may potentially confound the secondary outcome measure.

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20 patients (83%) reported some history of head trauma in the weeks or months prior to

admission. This is consistent with the fact that more than 60% of CSDH patients report a

history of minor head trauma (Sousa et al., 2013), making head trauma one of the leading

risk factors for CSDH. The incidence of falls and head traumas among seniors is rising as our

population ages (Cigolle et al., 2015; Taylor, Bell, Breiding, & Xu, 2017). This increases not

only the risk of CSDH development, but potentially the risk of postoperative recurrence,

especially if patients experience unstable gait or dizziness after surgery.

5.2 RADIOLOGIC SUBDURAL HEMATOMA CHARACTERISTICS

The radiologic characteristics did not differ significantly between the two study groups at

baseline. Most hematomas (n=15, 60%) were heterogenous, and eleven (50%) were loculated

or septated on the preoperative scan. Hematomas with these separated and heterogenous

features have been associated with a higher tendency to rebleed and possibly increased

potential to recur postoperatively (Nakaguchi, Tanishima, & Yoshimasu, 2001; Stanišić et

al., 2013), though the number of patients in our cohort who experienced a recurrence was too

small to detect an association between these radiologic features and recurrence.

5.3 PRIMARY OUTCOME

5.3.1 STUDY FEASIBILITY AND RECRUITMENT RATE

We believe that we have demonstrated that conducting a clinical trial investigating the

efficacy of TXA therapy in post-operative patients is feasible at our institution. Despite not

reaching our target sample size, study procedures were largely unremarkable, and therefore

with respect to the study procedures and technicalities, we were able to carry out this pilot

trial at our institution. As discussed below, improvements to our recruitment methods to

enhance participant recruitment would be ideal to demonstrate the feasibility of conducting a

larger, multi-center trial.

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Of the 189 patients admitted to St. Michael’s Hospital with SDH over the 11-month time

period during which the patients in our cohort were recruited, 77 (41%) were eligible, and we

were able to recruit 32.5% of these patients, with one patient subsequently withdrawing

consent. With this overall recruitment and given the average number of SDH patients

admitted to St. Michael’s Hospital annually, it is reasonable to expect that we would be able

to reach the 46-person sample size needed to sufficiently power the study within a

conservative estimate of approximately 12 more months of recruitment.

In order to establish the foundations of a feasible trial, we first needed to ensure that all of

the various study procedures could operate smoothly at our site. Therefore, prior to study

initiation, we met with the clinical nurse managers, educators, clinical pharmacists, research

pharmacists, and CT department technicians to discuss details of the study procedures. These

meetings informed the development of our study Standard Operating Procedures (SOPs).

After procedures and SOPs were established, we held training sessions for all pertinent staff

with direct involvement in study procedures, namely the research pharmacists, RNs, and

clinical pharmacists, who would be directly involved in ordering, dispensing, documenting,

and administering the study IP to patients. These training sessions were led by the study PI,

and included a visual presentation with slide decks, as well as opportunities for staff to ask

questions.

The study procedures, mostly pertaining to IP dispensation by the research pharmacists and

IP administration to inpatients by the RNs on the neurosurgery ward, ran largely without

issue over the study course. For instance, during feedback sessions, no RNs reported having

difficulty finding the study IP in the designated temperature-monitored drug box.

We found that all study procedures were facilitated with regular reinforcement and reminders

from the study coordinator. For instance, we regularly needed to remind RNs that participant

weights needed to be documented in the medical chart, not only for accurate IP dosing but

for the purposes of source documentation. There was often a discrepancy as RNs assumed

the weight would be documented in the anaesthesia record or operating room report, but

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rarely was. These discrepancies in clinical and study procedures were resolved with regular

oversight by the study coordinator.

One procedural difficulty we faced was with regards to standardizing the CT scan protocol.

Despite our efforts ensure all patients were scanned with the GE Revolution scanner at

follow-up, including specifying this study protocol directly on the CT order form, this was

not always possible. This was due to the restricted availability of the scanner. At our

institution, this is the scanner used for trauma patients, preoperative imaging following the

BrainLab protocol, or other priority scans, which take precedence. Therefore, if the machine

was not available at the time of the patient’s follow-up scan, the imaging was performed by

the other available CT scanners.

While these efforts yielded an overall recruitment just above 30%, which would in theory be

sufficient to reach our recruitment goal, it would be ideal to improve the recruitment rate as

much as possible. Failing to recruit enough patients to a clinical trial substantially limits the

power of the study to detect a minimal clinically important difference, and therefore the

study’s potential to impact the clinical problem in question. Low recruitment rates and

encouraging trial participation among patients are challenges that have long been faced by

clinical trial sites. In fact, a review of 151 randomized controlled trials found that the median

recruitment rate was less than one patient per site per month (Walters et al., 2017). Further,

attrition and participant drop-out rates are also a significant problem, particularly for longer

trials where study follow-ups extend over the course of months or years.

In an effort to improve recruitment, we first repeated the training sessions with the

neurosurgery RNs, pharmacists, and staff, ensuring that everyone involved in key study

procedures was aware of their roles. Every time there was a change in study protocol,

pertinent staff were informed of the changes to ensure smooth operation of study procedures.

These training sessions, in addition to regular communication with the study coordinator,

seemed to encourage RN involvement in the study. Soon after training sessions, RNs

occasionally told the study coordinator is a CSDH patient was admitted under their care,

which was helpful to ensure all consecutively-admitted patients were screened for eligibility.

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Based on this, we found that regular communication, particularly with the RNs, boosted their

involvement in the study.

We also re-examined our original study exclusion criteria in an attempt to increase the

number of eligible patients at our site. After extensive literature searches and clinical

consultations, we determined our initial criteria to be overly-restrictive, and in July 2017

modified the exclusion criteria to be less restrictive. For instance, we removed atrial

fibrillation as an exclusion criterion, which was one of the most significant contributors to

patient ineligibility. Atrial fibrillation is not listed as a contraindication on the TXA product

monograph. Further, the use of TXA may be useful in mitigating the risk of major bleeding

in patients with atrial fibrillation who are taking novel oral anticoagulants (NOACs), without

increasing the risk of a major thrombotic event (Kowey, Piccini, Naccarelli, & Reiffel,

2017). We found that following this change, the number of eligible SDH patients increased

steadily over time (Figure 11). Despite this however, our recruitment rate still showed a

decreasing trend. This suggested that increasing the proportion of eligible patients alone

would not be sufficient in improving our recruitment rate.

Others have gone to great lengths to identify the best quality improvement strategies for

improving recruitment rates in clinical trials (Sauers-Ford et al., 2017; Sauers, Beck, Kahn,

& Simmons, 2014). The most effective strategies appear to be holding regular (ideally,

weekly) meetings with key trial stake-holders to reflect on recruitment rates and procedures,

as well as barriers to recruitment. These meetings also serve as platforms for

multidisciplinary input, feedback, and discussion, which contribute to well-thought out

recruitment strategies. Engaging key staff and personnel in particular is crucial, as quality

improvement among study staff requires their leadership and oversight. While these

initiatives have been shown to be very effective (Sauers-Ford et al., 2017; Sauers et al.,

2014), they are unfortunately quite time-intensive. Arranging weekly meetings with trial co-

investigators, especially if multiple sites are involved, proves a nearly impossible task in the

wake of busy clinical schedules. Arranging regular meetings with the co-investigators proved

difficult due to conflicting and busy schedules, however, we did see a positive effect when

the study coordinator spoke to the co-investigators about their eligible patients, whether to

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discuss eligibility or simply to update them on trial status. These conversations served as

frequent reminders of the ongoing study, seemingly encouraging the investigators to tell the

study coordinator that a CSDH patient had been admitted under their care. However, this did

not encourage the co-investigators to speak to the patients about the study, even when

reminded by the study coordinator. While we would have hoped these efforts would have

encouraged greater involvement from the study co-investigators, this did again demonstrate

the positive effects of regular oversight of study procedures and communication from the

study coordinator in conducting the clinical trial.

In order to improve recruitment rates, we undertook several other quality improvement

initiatives. Beginning with increasing staff awareness and engagement, we hosted quality

improvement “huddles” with key staff – namely RNs and clerical personnel – on the

neurosurgery ward, providing study updates as well as receiving their feedback and

perspective on the clinical trial feasibility on the ward, including their suggestions for

increasing staff engagement. We presented the trial to neurosurgery residents and staff at

neurosurgery teaching rounds, roughly every 6-months, updating them on trial status to

engage them in participation. This was done at key time-points, such as when new residents

arrived at our institution. We also used more visual reminders, hanging posters on the

neurosurgery ward in areas frequented by staff and nurses, and sending regular updates on

the current trial status and our goals for completion. The most effective of these initiatives

were the staff “huddles” with the RNs, which seemed to boost their enthusiasm for the study

and serve as reminders that the study was ongoing. Despite these efforts to encourage

neurosurgery resident involvement, we found the best strategy was if the study coordinator

asked them to introduce the study to a potentially eligible patient while they were rounding

on patients on the ward. Otherwise, residents rarely introduced the study to patients without a

direct reminder, which we understand given the demands of their primary clinical work.

We also focused on mitigating patient-specific barriers to recruitment, particularly on

eliminating modifiable reasons for non-recruitment. We found that questions asked during

the consent discussion revealed some of the most common concerns patients had about trial

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participation, and reasons they would ultimately refuse consent. Some of the most commonly

asked questions during the consent discussion were:

· What are the side-effects?

· Is it safe to take this medication alongside the ones I am already taking?

· I live far away – if I participate, how many times would I have to come back to

the hospital?

· Is the medication safe for older people?

· Can I make an appointment with my family doctor and discuss this with him/her

before making a decision?

· Can I have more than couple of days to decide?

Based on these insights, we used several communication strategies when engaging in the

consent discussion to mitigate these modifiable reasons for refusing to enroll in the trial.

Safety was evidently one of the biggest concerns among patients. We therefore found that

introducing the study to patients by study co-investigators or physicians within their circle of

care made them less ‘skeptical of the experimental nature’ of the medication. Further,

emphasizing the potential benefits of trial participation, such as closer neurological follow-

up, seemed to counter some of the anxiety patients had about potential risks and side-effects.

Some of the most common reasons for refusal to participate were related to advanced age,

which is our primary target population. We found that despite clarifying the natural history

of subdural hematomas and their higher incidence in senior populations, many eligible

patients still refused participation on the basis of their age. The difficulties of recruiting

elderly patients to clinical trials have been extensively discussed in the literature (Cassidy,

Baird, & Javaid Sheikh, 2001; Macias, Ramsay, & Rowan, 2007; McHenry et al., 2015), and

are of increasing concern now, as our population is rising at an unprecedented rate. There is

therefore a need now more than ever to focus on medical interventions in senior age groups.

Distrust, caregiver burden, medical concerns, and barriers to transportation are all recognized

reasons for refusal to participate among senior patients (Crawford Shearer, Fleury, & Belyea,

2010; Gonzalez, Gardner, & Murasko, 2007; Ory et al., 2002; Saunders, Greaney, Lees, &

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Clark, n.d.). While incentives have been used in some studies to overcome some of these

barriers (Gonzalez et al., 2007), building a trusting relationship between the research team

and the patient seems to be the most substantial, albeit difficult, way to improve recruitment

among the elderly. In fact, on study suggested that a potential method for improving

recruitment rate among seniors is by maintaining a close relationship with general

practitioners, who can refer their senior patients – with whom they have an established

patient-physician relationship – to actively-recruiting clinical trials (Cassidy et al., 2001).

This suggests that support from a senior patient’s family doctor with whom they have a

trusting rapport may encourage study participation.

5.3.2 STUDY DRUG COMPLIANCE AND OUTCOME MEASURE

COMPLETION

We found that the dosing regimen supported drug compliance, and therefore feasibility of

this trial. Based on the drug diaries and remaining tablets returned to us from study patients,

we had no problems with drug compliance. In the event a dose was missed, patients were

able to follow the instructions for handling missed doses without issue. We believe that

having oral tablets that patients did not need to break, and that could be taken with meals,

made the study IP easily introducible into the patients’ existing medication regimens,

contributing to study drug compliance.

The dosing regimen also proved feasible if patients were repatriated or discharged to a

rehabilitation centre before returning home. Nineteen patients were discharged home, five

were discharged to a rehabilitation centre, and one was repatriated to another hospital. In

fact, patients who were repatriated or discharged to a rehabilitation centre were less likely to

miss a dose because TXA was administered by RNs or other staff at these institutions.

We also had few problems with completion of the 4-8 week clinical follow-up. Coordinating

the trial so that it coincided with clinical follow-up helped us ensure that all but one patient

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returned for the follow-up CT scan, yielding an attrition rate of 4%. It also aided the

recruitment process, where most patients stated they would have refused study participation

if extra visits were required. Also, some patients were fearful of the radiation exposure

associated with CT scans; by using the clinical CT scan, the patients did not have to undergo

more scans than clinically necessary.

Moreover, patients did not report having difficulty completing the questionnaires, and if they

were unable to do so, had a family member or proxy complete it with their help. The self-

completion nature of the SF-36 and HUI assessments – as well as the option to have the

HUI3 completed by a proxy – in general aided in the feasibility of this trial. Overall, most

patients reported no trouble completing the questionnaires in a timely way, and did not report

feeling stressed or overwhelmed in doing so. This allowed the patients to complete the

questionnaires at their discretion for as long as they needed, and also allowed for a family

member to help complete it if the patient felt too unwell to do so. However, not all patients

were compliant in completing the QOL assessments. One patient in the control group refused

to fill out the questionnaires altogether. Some patients felt too unwell to try to complete it at

baseline, and asked to fill it out at home when they could have more time to think about their

answers. In these situations, the study coordinator followed up with the patients soon after

discharge to ensure it was completed, then again before the follow-up appointment to remind

them to return the questionnaire – this was often, but not always, sufficient. Some patients

forgot to complete baseline questionnaires while inpatients, however, reminders by the study

coordinator ensured that these patients filled them out before discharge. Altogether, it seems

persistent reminders from the study coordinator were beneficial in ensuring that

questionnaires were completed.

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5.4 SECONDARY OUTCOMES

5.4.1 HEMATOMA VOLUME CHANGE FROM BASELINE TO FOLLOW-

UP

The baseline hematoma volumes and postoperative hematoma cavity volumes are consistent

with values reported in the literature (Stanišić et al., 2013). Though the difference was not

statistically significant, the mean immediate post-operative hematoma volume was higher in

the control group than the TXA group. This could have contributed to the lower degree of

hematoma resolution in the control group compared to the treatment arm.

The ‘gold standard’ hematoma measurement technique has been compared to, and found to

be more accurate than, other mathematical estimates of hematoma volume (Stanišić, Groote,

Hald, & Pripp, 2014). It is important to note however that despite our best efforts, not all CT

scans could be performed on the same machine, and therefore volumes calculated from

thinner slices (for instance, 1.25 mm compared to 5mm) may yield more precise volume

estimates than those calculated from thicker slices. Therefore, given the small sample size,

small differences in volume may affect the volume comparison between groups.

The percent resolution from the preoperative to 4-8 week follow-up scan was slightly greater

in the TXA treatment arm compared to the control arm, however this difference did not reach

statistical significance. It is therefore possible that with a larger sample size with complete

data available, this trend may reach statistical significance. These results also inform the

feasibility of a future, double-blind trial. When calculating the sample size needed to power

this pilot, we estimated a hematoma volume change of 10 mL in the control group and 20 mL

in the TXA-treated group. Our results showed that the mean decrease in hematoma volume

in millilitres from baseline to 4-8 week follow-up was 92.0 mL in the control group, and

143.49 mL in the TXA-treated group. With respect to the TXA-treated group, this volume

decrease is more than twice that reported by Kageyama et al., whose data were used in our

sample size calculation (Kageyama, Toyooka, Tsuzuki, & Oka, 2013). However, it is

important to note that Kageyama et al. investigated the efficacy of TXA treatment in non-

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surgical treatment. Therefore, it is reasonable that our hematoma volume change would be

larger as our patients first underwent surgical evacuation.

The standard post-operative follow-up time period for subdural hematoma is between 4-8

weeks, with the variation a result of the surgeon’s clinical opinion and clinical availability.

Patients are discharged because they are clinically asymptomatic, and no longer require

neurosurgical intervention or follow-up, often regardless of whether or not there is still a

residual hematoma as seen on the CT scan. Therefore most study patients were discharged

from neurosurgical care at the first follow-up. However, most patients still had residual

hematoma at the first follow-up: only four patients – two in the TXA group and two in the

control group – had complete hematoma resolution on the 4-8 weeks follow-up scan. They

were discharged because their treating neurosurgeon felt that given the degree of hematoma

resolution and stable clinical presentation, they no longer required neurosurgical follow-up.

To date, none of these discharged patients have returned to our institution for continued

follow-up of their CSDH. Further, of the five patients who returned for the 8-12 week

follow-up, one had complete resolution at this time point. The subset of patients with

complete resolution was insufficient to produce a Kaplan-Meier curve comparing time to

complete resolution between the two groups. Further, because patients with residual

hematoma were discharged from neurosurgical care, it is unclear if and when their

hematomas completely resolved.

5.4.2 HEMATOMA RECURRENCE AND REOPERATION RATE

Four patients (17%) in the study cohort – two from each treatment group – experienced re-

accumulation of their CSDH requiring repeat surgical evacuation. Three patients returned to

our institution seven days, 16 days, and 30 days after discharge from initial hospital stay.

One patient in the TXA arm was still an inpatient at the time of reoperation, which was

performed six days after the initial procedure. The two patients in the control group each

returned a third time, twenty-two and forty days after discharge from their initial hospital

visit. One of these patients returned with symptoms consistent with CSDH accumulation, but

did not undergo a third evacuation procedure. The other returned with stroke-like symptoms,

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and was briefly admitted to the neurology unit where a workup confirmed he did not have a

stroke.

This small number of outcomes, in addition to the small sample size, was insufficient to

carry out a Kaplan-Meier analysis on time to recurrence. Larger sample sizes sufficient to

power the study would be needed to detect a statistically significant difference in recurrence

rate between the groups, therefore, a conclusion as to whether there is a correlation between

TXA and reduced hematoma recurrence cannot be supported by our findings. Despite this,

the 17% overall recurrence rate in our cohort is consistent with CSDH recurrence rates

reported in other reports (Abouzari et al., 2007; Qian, Yang, Sun, & Sun, 2017; Santarius et

al., 2009).

5.4.3 NEUROLOGICAL STATUS FROM BASELINE TO FOLLOW-UP

There was largely no statistically or clinically significant difference in neurological status

between the two groups at baseline or at 4-8 week follow-up. At baseline however, control

patients did differ from the TXA group in total GCS score: all patients in the control arm

were GCS 15 at baseline, compared to 64% of patients in the TXA arm. The remaining 36%

of patients had a GCS of 14. Despite the statistical significance of this difference, the

difference is not likely to be clinically significant. It is common for the level of

consciousness to fluctuate in neurosurgery patients both before and after surgery, particularly

between GCS 15 and 14. This is often due to some confusion or disorientation to date, time,

or place, leading to a verbal component score of four rather than five and subsequent overall

GCS score of 14 rather than 15. This was in fact the case for three of the four patients in the

TXA arm with a baseline GCS of 14.

Scores on the neurological status assessments improved from baseline to follow-up in both

groups. The only statistically-significant improvement was seen in the control group on the

MGS. This could potentially be due to a small sample size that is insufficient to power the

test. Improvement in neurological status is clinically expected from baseline to follow-up,

and while most improvements were not statistically significant, this does not mean they were

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not clinically significant. For instance, an improvement from a score of 2 to a score of 1 on

the MGS indicates a change from drowsiness or disorientation with variable neurological

deficit, to alertness and orientation with mild clinical or neurological symptoms.

While patients over all scored better on the mRS, GOSE, and MGS at the 4-8 week follow-

up compared to baseline and scores between groups did not differ at either time point, it

would be interesting to see if the patient groups differed on these assessments pre-operatively

when the patients were most symptomatic. In our cohort, most patients were recruited to the

trial after surgery, and therefore prospective evaluations of neurological status using these

scales could not have been made pre-operatively prior to obtaining written informed consent.

The same could be said for the NIHSS. Throughout the study, only one patient had an

NIHSS score greater than one at baseline, and at the 4-8 week follow-up, all patients had a

score of zero. The NIHSS may not be sensitive enough for this patient population in the post-

operative and follow-up period, because many of the functional impairments this scale

detects – such as confusion and disorientation, hemiparesis, dysarthria, and ataxia – are often

resolved after surgery. It may therefore be a more sensitive test in the preoperative period,

when patients are typically at their most symptomatic. One study that used the NIHSS as a

measure of functional improvement in patients with spontaneous ICH found that the test was

reliable and reproducible, but that scores on the assessment needed to change at least 10

points in order for the authors to be confident that a clinically-significant change in

functional status had occurred (Specogna, Patten, Turin, & Hill, 2013). The largest change in

NIHSS from baseline to 4-8 week follow-up in our cohort was by 3-points. Given the

symptoms as well as functional and cognitive limitations experienced by our patients upon

admission, it is possible we would have seen larger changes in NIHSS if follow-up was

compared to a pre-operative assessment.

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5.4.4 QUALITY OF LIFE FROM BASELINE TO FOLLOW-UP

5.4.4.1 SF-36

There was no difference in quality of life score across any of the eight health dimensions

measured by the SF-36 questionnaire both at baseline and the 4-8 week follow-up. As

expected, scores were higher on the 4-8 week follow-up questionnaires than at baseline,

consistent with an improvement in quality of life. Only the control group showed a

statistically significant improvement in scores with respect to role limitations due to physical

health. While there is no published or advised minimum time period required between

questionnaire administration to ensure validity and avoid recall bias, the SF-36 questionnaire

has been validated in other patient populations with good test-retest reliability (Dorman,

Waddell, Slattery, Dennis, & Sandercock, 1997).

5.4.4.2 HUI

Single-attribute scores on the HUI3 and HUI2 did not differ between study groups at follow-

up. Single-attribute utility scores are useful in determining the level of functionality on am

individual health attribute, such as dexterity, pain, or cognition (Feeny et al., 2002).

Mean overall HUI3 and HUI2 multi-attribute HRQL utility scores also did not differ between

groups at 4-8 week follow-up. Within groups, patients in the TXA arm and control arm both

scored higher at the 4-8 week follow-up QOL assessments than at baseline, consistent with

an expected improvement in multi-attribute quality of life. Only the control group showed a

statistically significant improvement in HUI3 and HUI2 HRQL scores from baseline to 4-8

week follow-up. In any case, these improvements would be considered clinically significant.

For instance, at baseline, three patients in the control group and three patients in the TXA

group had an HUI3 HRQL score below zero, indicating an overall multi-attribute health state

worse than death. At follow-up, no patients in either group had an overall HUI3 HRQL score

below zero, a clinically-significant improvement.

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The use of the HUI has been validated in both general and patient populations, including

individuals with diabetes mellitus, dementia, arthritis, or who have suffered a severe trauma

(Kavirajan, Hays, Vassar, & Vickrey, 2009; Khanna et al., 2011; Mo, Morrison, Choi, &

Vardy, 2006; Ringburg et al., 2011). To our knowledge, ours is the first study to use the HUI

as a QOL assessment tool in CSDH patients. Still, future studies would be needed to further

assess the construct validity of the HUI questionnaire in this patient population.

A study that compared the discriminative ability of the HUI3 to the SF-36 preference-based

SF-6D assessment in chronic kidney disease patients found the HUI3 to be better able to

discriminate depressive symptoms, and better suited in patients with greater disability that

the general population (Davison, Jhangri, & Feeny, 2009). One study found the HUI3 in

particular to be most sensitive in assessing health-related QOL resulting from older age

(great than 65-years old) and comorbidity (Polinder et al., 2010). They also found that the

HUI3 and HUI2 had greater discriminative ability and was more informative than other HR-

QOL assessment tools for a number of diseases, including skull-brain injury.

The HUI questionnaire in particular was a very sensitive tool for assessing the degree to

which important health attributes are affected. Impairments on the functional domains

assessed by the HUI3 and HUI2 levels were often consistent with the presenting symptoms

caused by the mass effect of a subdural hematoma. For instance, pain levels at baseline

consistent with the headaches patients reported upon admission. However, it is also

important to note that many of the health levels measured by this questionnaire are already

impaired in senior populations as a function of old age, including vision, dexterity,

ambulation, and cognition. The objective improvement in scores from baseline to follow-up

does however suggest that the CSDH did contribute to impairment across these health

attributes.

It is also interesting to note that according to HUI HRQL score classifications into disability

categories, no patients reached perfect health across all attributes at the 4-8 week follow-up.

This has potentially important clinical implications – while neurosurgical follow-up and

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intervention is often not required after 4-8 weeks, patients may still benefit from some form

of clinical follow-up.

5.4.5 TXA SAFETY: ADVERSE EVENTS AND SAFETY OF TXA

DOSING REGIMEN

There was no significant difference in number of adverse events experienced by patients in

the TXA treatment arm compared to the control arm. We acknowledge however that this

does not translate to equivalent safety among the groups. A larger clinical trial would be

needed to distinguish whether or not TXA significantly increases the risk of certain AEs

compared to control patients. A larger sample size in the full trial may see the occurrence of

more serious adverse events, and potentially a difference between the two groups.

There were no mortalities in our study cohort, and no intra-operative or post-operative

complications. There were no AEs associated with abnormal laboratory test results, including

blood-work or urinalysis.

There were also no occurrences of thromboembolic events in our study cohort. Several times

over the past few decades, the notion that TXA increases the risk of thromboembolic events

has resurfaced, despite much evidence against it. While our study is too small to draw a

conclusion from this finding with regards to the risk of thromboembolic events from TXA,

this finding does support the large-scale research refuting this claim. Many studies have

refuted this claim, showing in controlled studies that TXA does not increase the risk of

thromboembolic events. Studies with higher daily dosing regimens than our 1500 mg daily

dose have also not reported any thromboembolic events in their patients (Lukes et al., 2010).

Larger-scale trials of the safety of TXA in heavy menstrual bleeding also found that TXA

does not increase the risk of thromboembolic events with thromboembolism rates even

comparable to that of the general population (Lukes, Freeman, Van Drie, Baker, &

Adomako, 2011).

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Another concern related to TXA treatment is ophthalmic changes, including new visual

acuity deficits, retinal vein occlusion, and sudden chromatopsia. These events have been

rarely reported in the post-marketing period, particularly in higher and longer-duration

dosing regimens, and have therefore been highlighted as a concern in the TXA product

monograph. No patients in our cohort experienced vision-related AEs, including new visual

deficits or any self-reported changes in colour vision. In a study investigating the efficacy

and safety of a daily TXA dosing regimen in patients with menorrhagia, taken for five days

over nine menstrual cycles, the authors reported no ophthalmic AEs related to colour vision

(Lukes et al., 2010). However, there was one case of high intraocular pressure, two

occurrences of blurred vision in the same patient, and one case of retinal artery stenosis. It is

important to note however that the mean daily dose of oral TXA in this study was 3800 mg

for an average of 3.5 days per cycle – more than twice that of our trial. It is possible then that

our dosing regimen is not high enough to substantially increase the risk of ophthalmic-related

AEs, supporting the safety of our chosen dosing regimen.

Overall, there were 33 occurrences of 18 different adverse events, none of which were

serious and unexpected. These numbers, along with the insignificant difference in number of

AEs between treatment groups, suggest that the TXA dosing regimen is safe for this patient

population.

Most adverse events were experienced in the acute post-operative period and resolved within

a couple of days. The most frequently reported adverse event was headache. This is a

potential side-effect of TXA and was therefore an expected adverse event. However,

headache is experienced by nearly if not all neurosurgery patients in the acute post-operative

period, so this adverse event is more likely attributable to neurosurgical intervention than the

study drug. Moreover, in our study cohort, there was no statistically significant difference in

headaches experienced by patients in the control group compared to the TXA group,

supporting the fact that TXA use did not increase the occurrence of headaches. In fact, more

patients in the control group reported headache compared to the TXA group, though this may

be related to the fact that more patients in the control group presented with headache upon

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admission. It is possible that our TXA dose was not high enough to significantly increase the

risk of headache, thereby supporting the safety of our selected study drug dose regimen.

Most other adverse events experienced were also common post-operative risks, such as post-

operative dysphagia, for which many patients are referred to rehabilitation centers for days to

weeks after surgery to aid in recovery. Two patients (8%) experienced nausea or stomach

upset, which is a potential side-effect of TXA, but also a common occurrence post-

anesthesia.

Overall there were four occurrences of GI-related AEs, and no significant differences

between the two groups. Two patients in the control group experienced stomach pain, and

two patients – one in the control group and the other in the TXA group – experienced nausea

or stomach upset. These events were graded by the PI as mild in severity, and are consistent

with the literature, where most GI-related events are mild or moderate in severity (Lukes et

al., 2010). These were not considered by the PI to be likely related to the study drug.

It is important to clarify that many reported adverse events related to TXA are also common

post-operative side effects, either with relation to the procedure or the exposure to a general

anesthetic. Therefore, it is difficult to distinguish study-related adverse events from surgical

side effects.

The most serious adverse event experienced was seizure, reported by one study patient in the

TXA treatment arm. Seizures have been associated with TXA treatment, possibly due to a

mechanism involving the inhibitory neurotransmitter GABA. While the risk of seizure from

TXA is still being investigated, it is likely dose related, with the risk of seizure increasing

with increasing dose (Schwinn, Mackensen, & Brown, 2012). Regarding the patient in our

cohort who experienced a seizure within two days of hematoma evacuation, it is also

possible the occurrence of a seizure was more likely related to another of the patient’s

concomitant medication with higher seizure risk than TXA, or possibly due to the post-

operative risk of seizure related to burr-hole procedures. Aging and cognitive impairment

also predisposes an individual to seizures. In any case, it is plausible that the seizure was

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related to TXA, and this correlation cannot be excluded. The literature does consider seizures

as a major AE related to TXA treatment and is therefore a risk that should continue to be

disclosed to patients during the consent procedure. Additionally, patients with a history of a

seizure disorder should not be eligible in investigational trials until more safety-related

evidence with respect to the risk of seizures is accumulated.

5.5 STUDY LIMITATIONS

Our study is not without limitation. The largest study limitation we faced was a small sample

size. According to our sample size calculation, which was based off of previous literature

investigating CSDH volume change after TXA treatment, we needed at least 46 participants

to detect a statistically significant treatment effect. Therefore, our study cohort of 24 patients

was likely too small to sufficiently power the study for this outcome measure. However, the

sample size was still sufficient to evaluate the feasibility of conducting this trial at our

institution.

We made substantial effort to improve the recruitment rate, through quality improvement

initiatives, modification of eligibility criteria, and regular oversight by the study team.

We did see some improvement in recruitment, particularly after modifying eligibility criteria,

however overall there was still a decreasing trend in overall recruitment rate over time. In

future studies, we should do our best to organize regular meetings with key study

stakeholders, including the study PI and co-investigators, to report on recruitment rate and

study progress.

Another limitation is the limited number of patients who returned for the second follow-up

visit. Patients were often informed by their attending physician that clinically and

radiologically, they no longer required follow-up and were therefore cleared from

neurosurgical care. This discouraged study participants from wanting to return for the second

follow-up, as it was no longer clinically needed according to the attending neurosurgeon.

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Further, there was missing data across several outcome measures in our study. Most

importantly, the baseline CT scans for two patients were performed at outside institutions

from which the patients were subsequently transferred to St. Michael’s Hospital for subdural

hematoma management. We are still in the process of trying to obtain those baseline images.

As discussed above, another limitation is the standardization of the CT images. Despite ours

and the imaging departments best efforts to standardize the CT scanner used for subdural

hematoma patients, not all patients had their post-operative and follow-up CT scans in the

GE Revolution scanner. Therefore, there was not a uniform CT thin-slice thickness across all

images – while most CT scans were 2.5 mm thin-slices, others were either 1.25 mm, 1.63

mm, or 5 mm. This may have affected the standardization of the hematoma volume

measurement technique.

While manual delineation of CSDH area on each slice is considered the ‘gold standard’ for

volume measurement, it is quite time-intensive. Moreover, a possible limitation of this

volume measurement technique arises when measuring an isodense hematoma. By definition,

these hematomas are the same density as the surrounding brain tissue, making their borders

difficult to delineate even when adjusting the brightness and contrast of the image.

Therefore, the CSDH measurements may be subjective as the hematomas borders are at the

discretion of the blinded assessor. Potential solutions include consultation with a second

viewer when the margins are difficult to see, or having two independent blinded assessors

each measure all of the hematoma volumes, and calculating an inter-rater reliability score to

validate the objectivity and accuracy of this measurement technique.

With regards to our statistical analysis plan, multiple testing increases the risk of Type I error

– that is, falsely rejecting the null hypothesis. This Type I error “inflation” results from

multiple comparisons sharing control, or baseline, data. Caution must therefore be taken with

the interpretation of these study results. It is possible and often recommended to statistically

correct for the effects of multiple hypothesis testing. However, the literature is not

conclusive as to whether or not post-hoc correction for multiple testing should always be

carried out in clinical trials, and there is definitely a need for standardized guidelines with

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respect to this issue (Howard, Brown, Todd, & Gregory, 2018; Wason, Stecher, & Mander,

2014). After running the post-hoc Benjamini-Hochberg correction on our results, controlling

the false discovery rate at 5%, no results remained statistically significant. Ideally, when

planning a clinical trial, minimizing the number of variables and using composite endpoints

will reduce the degree of multiplicity in statistical analyses.

Many of the measured outcomes are also analyzed in terms of change, namely, the change in

hematoma volume from baseline to follow-up. These statistical tests comparing units of

change however are not sufficiently powerful analyses for a clinical trial, as they are subject

to regression artifact. The future main trial will be designed so that the follow-up measures

are analyzed with the baseline values as covariates, using Analysis of Covariance

(ANCOVA) as the statistical testing method.

A larger, multi-centre pilot trial would have been beneficial to inform feasibility issues more

broadly across different centres, helping in the implementation of a larger multicenter RCT.

Due to limited study funding and personnel, it would have been difficult to conduct the trial

across several sites.

Despite the fact that the trial had an open-label design, we did make an effort to blind study

outcomes. For instance, all CT scans were anonymized and only linkable to treatment arm

through a master linking log. All neurological assessments and QOL measures were only

identifiable through a linking log connecting the anonymized patient study ID to the patient’s

name. Despite these efforts, complete blinding was unfortunately not possible, especially

because the same study coordinator to enroll patients was also the one to collect outcome

measures including for instance administering QOL assessments. For the main trial, which

will be placebo-controlled, these assessments will all be completely blinded as not even the

research coordinator will be privy to study assignment.

Further, we acknowledge that we did not define thresholds or metrics for our feasibility

measures, which are needed to objectively determine whether the pilot trial sufficiently

demonstrates study feasibility. This is particularly important because we did not meet our

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intended sample size recruitment. In the future main trial, we will define specific feasibility

metrics, including recruitment rates over a pre-specified study duration, attrition rates, and

eligibility rates.

Finally, it is important to recognize the potential dangers of reporting efficacy measures

when conducting a feasibility trial, especially if the target sample size is not reached as in our

pilot trial. Reporting efficacy results could mislead readers because of Type I or Type II

errors from underpowered analyses, and sample sizes in pilot feasibility trials are never

sufficient to power measures of efficacy.

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6. CONCLUSIONS

In conclusion, we have demonstrated the feasibility and safety of a trial investigating TXA in

patients with residual CSDH after surgical evacuation.

While the results were not statistically significant, there was a trend towards a greater

hematoma volume reduction in TXA-treated participants compared to control participants.

There was no difference between groups in hematoma recurrence and reoperation rate, with

two patients in each treatment group experiencing accumulation of their hematomas that

required another surgical evacuation. Overall, there was a trend towards improvement in

neurological status and QOL from baseline to 4-8 week follow-up in both TXA-treated and

control subjects, with control subjects showing a statistically-significant improvement in

QOL in the ‘role limitations due to physical health’ category on the SF-36 questionnaire and

in the HUI3 multi-attribute HRQL utility score. There were no significant difference in AE

occurrences between study groups and all AEs were mild or moderate in nature. There were

no cases of thromboembolic events. There were no or reported or measured ophthalmic

changes in either retinal integrity, colour vision, or visual acuity.

The results of this study will inform the conduct of a future, double-blind, randomized

controlled trial investigating the efficacy of TXA therapy in residual CSDH and its potential

to prevent post-operative CSDH recurrence.

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7. FUTURE DIRECTIONS

7.1 DOUBLE-BLINDED EFFICACY TRIAL

The primary outcome of this pilot trial was to determine the feasibility of such a study, and

therefore the potential of running a larger, multi-centre double-blind randomized controlled

trial. The primary outcome of this future trial would be to assess the efficacy of TXA in

residual CSDH resolution, and in preventing hematoma recurrence.

We have shown that such a study is feasible. Further, with the preliminary radiological data

from this pilot, we can re-calculate the sample size needed to power a future trial using the

change in hematoma volumes of the patients in our cohort, rather than relying solely on

values in the literature.

Therefore, based on our experiences with this pilot study, we are now in the stages of

initiating a double-blinded, placebo-controlled randomized controlled trial (TRACE-2).

TRACE-2 will differ from this pilot investigation in several ways. First, it will be double-

blind and placebo-controlled. This is particularly important to mitigate the potential for

placebo effect with respect to the secondary QOL measures.

Second, the first dose of TXA will be an intraoperative 1g-loading dose (all subsequent doses

will be in the form of 500 mg oral tablets, following the same dosing regimen as our pilot).

As a result, participant recruitment and informed-consent will necessarily take place pre-

operatively. This protocol change will allow us to collect preoperative baseline clinical data,

including MGS and NIHSS at baseline.

Do date, we have received Health Canada approval to conduct this study, secured grant

funding, and finalized a contract with the Bay Area Research Logistics (BARL), a

pharmacological company that will provide matching placebo.

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Finally, based on the safety data of our pilot trial, we are modifying the exclusion criteria to

increase the proportion of CSDH patients that are eligible for TRACE-2. One criterion in

particular is in relation to thrombotic events. No patients in our pilot study experienced a

thromboembolic event, consistent with other larger reports in the literature.

Following this trial, depending on whether future trial results support the use of TXA as an

adjunct to surgical treatment of CSDH, our long-term goal would be to carry out an efficacy

trial in conservatively-managed CSDH patients, and see whether TXA could be used as an

alternative treatment for patients who might otherwise not be good surgical candidates.

7.2 SCOPING REVIEW OF CSDH PATHOGENESIS

To further a more comprehensive understanding of subdural hematoma pathogenesis, we

undertook a comprehensive systematic scoping review of primary literature in an attempt to

elucidate 1) the temporal ordering of pathogenic processes involved in CSDH development,

and 2) potential biomarkers as predictors of recurrence.

We conducted the literature search and review according to Arksey and O’Malley’s

methodological framework for scoping reviews to synthesize the current literature regarding

pathophysiology of CSDH (Arksey & O’Malley, 2005; Levac, Colquhoun, & O’Brien,

2010). In comparison to a systematic review which asks a research question about the

effectiveness of an intervention, a scoping review asks a broad question to synthesize

existing knowledge pertaining to a particular field. We therefore elected to conduct a

systematic scoping review because of the broad nature of the question of interest, intended to

provide a comprehensive synthesis of the current knowledge as well as highlight the gaps in

the literature regarding CSDH pathogenesis; the variety of hypotheses tested (i.e.

angiogenesis, inflammation, etc.) and methodologies employed (i.e. immunohistochemistry,

enzyme-linked immunosorbent assay (ELISA), etc.) by the studies included in the review;

and the unavailability of research quality appraisal tools for exploratory studies of this

nature.

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We performed a systematic search of five electronic databases (Medline, PubMed,

EMBASE, Web of Science, and Cochrane) from their time of inception to July 2017. The

search was conducting according to the Preferred Reporting Items for Systematic Reviews

and Meta-Analyses (PRISMA) guidelines using search terms comprised of keywords and

medical subject heading (MeSH) terms encompassing CSDH and pathophysiology (Moher,

Liberati, Tetzlaff, Altman, & Altman, 2009). We also consulted an experienced information

specialist to assure accuracy and comprehensiveness of the search.

We screened all article titles and abstracts against predetermined eligibility criteria. We

included peer-reviewed primary literature investigating CSDH membrane and fluid

histopathology, morphology, genetic profile, expression profiles, and molecular, cellular, and

metabolic markers and pathways, using either microscopy, immunohistochemistry, ELISA,

Western blots, or other validated laboratory technique. We excluded non-English articles,

reviews, letters, conference papers or abstracts, case reports, and studies based on animal

models. After arriving at the articles to be included in our review, we extracted data from

each paper according to pre-defined data collection variables. These variables included

sample demographics (number of participants, number of samples, country, age,

comorbidities, history of trauma), study hypothesis and objective, imaging data,

methodology, findings and conclusions. Our paper search and screening process, conducted

according to PRISMA, is presented in Figure 16.

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Figure 16. PRISMA Flowchart. Systematic search process and results according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines

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We are currently still in the process of data extraction and compiling the results, and will

present the results thematically based on predominant underlying mechanism explored in

each paper.

7.3 DEVELOPING A PROGNOSTIC MODEL TO ESTIMATE RISK OF CSDH

RECURRENCE

Identifying predictors of recurrence would be instrumental to the current neurosurgical care

of subdural hematoma patients. Stanisic et al. (Stanišić & Pripp, 2017) and Jack et al. (Jack,

O’Kelly, McDougall, & Max Findlay, 2015) created grading systems for predicting

recurrence requiring reoperation. However, these prognostic models included only radiologic

hematoma features as factors that could significantly predict recurrence. Despite these

systems, a comprehensive model – one that can integrate clinical, demographic, operative,

and radiographic factors into a predictive model – is lacking. We believe that a machine-

learning algorithm capable of estimating recurrence risk based on the presence or absence of

a variety of clinical factors would be able to achieve this. We understand that a substantially

larger sample size would be required in order to produce an algorithm that is both internally

and externally validated.

We will retrospectively review the cases of all subdural hematoma patients consecutively-

admitted to St. Michael’s Hospital within the past decade, and collect demographic, clinical,

radiologic, and surgical factors as pre-operative and post-operative predictors of hematoma

recurrence. This data will also be useful for identifying predictors of overall health outcome.

We will use this comprehensive dataset to develop a machine-learning algorithm that will

incorporate clinical, demographic, operative, and radiographic factors into a prognostic

grading system for predicting risk of hematoma recurrence. To test, develop, and validate the

machine-learning algorithm, we will use the PythonTM programming language and

MATLAB® programming software.

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7.4 INVESTIGATING CSDH PATHOGENESIS

In this study we categorized the subdural hematoma subtypes according to a classification

system proposed by Alves et al. (Alves, Santiago, Costa, & Pinto, 2016). These

classifications are based on radiologic imaging. Further research is needed to understand the

pathophysiology and characteristics underlying each subdural hematoma subtype, and how

the histology and molecular pathology correlates to radiologic subtypes. This could also help

elucidate the mechanism of CSDH pathogenesis, which would be helpful in determining

causative factors for post-operative recurrence.

Thus far we have focused on hyperfibrinolysis, however, as the literature suggests, CSDH

progression is likely multifactorial. We are therefore curious to explore other potential

mechanisms involved in hematoma development and recurrence, such as angiogenesis. For

instance, re-bleeding from the hematoma’s outer membrane may contribute to the acute

bleeds within these hematomas. A possible explanation is that higher levels of angiogenesis

in the outer membrane increase the amount of re-bleeding into the CSDH, which then

increases the risk of recurrence and therefore the need for re-operation. While measures of

VEGF in hematoma fluid have supported the theory that angiogenesis is occurring in

CSDHs, we believe that quantifying angiogenesis in the hematoma could more specifically

elucidate the extent to which it plays a role in CSDH pathogenesis.

Cluster of differentiation 31 protein (CD31) (also known as Platelet endothelial cell adhesion

molecule (PECAM-1)) is a highly-specific protein marker for endothelial cells. It has a

significant role in endothelial cell interactions during angiogenesis (Escosa Baé, Wessling,

Salca, & de las Heras Echeverría, 2011). This marker is used in immunohistochemical

preparations to quantify angiogenesis and neovascularization in a tissue sample (Wang et al.,

2008). To our knowledge, it has not been used previously to quantify angiogenesis in the

outer membrane of CSDH. This may allow us to develop a classification system that

correlates degree of angiogenesis with risk of recurrence.

120

We therefore propose a study where we will classify chronic subdural hematomas into

subtypes based on the degree of angiogenesis measured immunohistochemically with CD31

staining, and with immunoassays specific for VEGF. To our knowledge this would be the

first study to quantify angiogenesis in the outer membrane in relation to a hematoma-type

classification system.

The primary objective of this study is to investigate and elucidate the pathophysiological

mechanism underlying CSDH development and enlargement, and study potential

histopathological risk factors for post-operative recurrence.

We propose quantifying angiogenesis in the outer membrane by determining the mean

microvessel density (MVD) with CD31 immunohistochemical staining. Mean MVD per unit

area and intensity scores will be determined from these preparations. We will also measure

VEGF levels in the hematoma outer membrane, hematoma fluid, and systemic serum.

Because CD31 has not previously been used to quantify angiogenesis in hematoma

membrane tissue, we will compare angiogenesis levels as quantified by CD31 staining to

VEGF levels in the outer membrane and hematoma fluid, as VEGF has been used as a

marker to indicate angiogenesis in CSDH in previous literature, thereby also aiming to

validate the use of CD31 staining in CSDH.

We will use ELISA to measure VEGF expression (concentration in pg/mL) in samples of the

hematoma outer membrane, the hematoma fluid, and systemic serum. We will obtain

commercially-available ELISA kits to carry out the assays. We will also use ELISA to

measure levels of pro-inflammatory (IL-6, IL-8, TNF-alpha) and anti-inflammatory

cytokines (IL-10) in hematoma fluid, which have previously been identified in CSDH.

Levels of pro- and anti-inflammatory cytokines will be correlated to levels of VEGF and

angiogenesis as quantified with CD31 staining.

Secondarily we will also study the cytoarchitecture of the outer hematoma membrane,

elucidating some of the inflammatory processes underlying CSDH development such as

eosinophilic infiltration. To do so, histological slides of hematoma outer membrane samples

121

will be prepared with standard hematoxylin and eosin (H&E) staining techniques. We will

use light microscopy to perform inflammatory (eosinophil) cell counts as a measure of

eosinophilic infiltration and inflammation in the outer membrane, as well as study the

general cellular architecture of the outer membrane.

We hypothesize that the degree of angiogenesis – as measured by mean microvessel density

(MVD) – will be highest in the outer membranes of hematoma subtypes with acute

components and loculations and septations, as seen on CT imaging. Concurrently we also

hypothesize higher VEGF concentrations in the hematoma fluid of these subtypes compared

to the other hematoma types. We expect higher post-operative recurrence rates in patients

with these hematoma subtypes.

We have already begun collecting hematoma samples, including hematoma fluid, the inner

membrane, and outer membrane, which are collected from patients at the time of surgery by

the treating surgical team, and stored in a brain tissue biobank in a nitrogen freezer.

Results from this study would provide insight into the pathologies underlying CSDH

development, enlargement, and recurrence. Elucidating inflammatory and angiogenic

biomarkers of CSDH pathogenesis could inform the currently unknown mechanism of

CSDH pathogenesis, potentially exposing specific targets for medicinal interventions that

could be personalized for patients with certain CSDH radiographic subtypes. For example, if

higher angiogenesis is observed in hematoma types that have previously been suggested to

be more likely to recur, medicinal interventions targeting angiogenesis could be provided for

those patients. Future studies could investigate the use of antiangiogenic medications in

CSDH patients, such as bevacizumab (a monoclonal antibody that binds to VEGF,

preventing it from acting at its receptor site), which is currently used in certain cancer types

and age-related macular degeneration.

120

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APPENDIX A: Glasgow Coma Scale

Eye Opening (E) 4 = spontaneous 3 = to voice 2 = to pain 1 = none Verbal Response (V) 5 = normal conversation 4 = disoriented conversation 3 = words, but not coherent 2 = no words, only sounds 1 = none Motor Response (M) 6 = normal 5 = localized to pain 4 = withdraws to pain 3 = decorticate posture (an abnormal posture that can include rigidity, clenched fists, legs held straight out, and arms bent inward toward the body with the wrists and fingers bend and held on the chest) 2 = decerebrate (an abnormal posture that can include rigidity, arms and legs held straight out, toes pointed downward, head and neck arched backwards) 1 = none

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APPENDIX B: Glasgow Coma Scale-Extended

1 Death D 2 Vegetative state VS 3 Lower severe disability SD - 4 Upper severe disability SD + 5 Lower moderate disability MD - 6 Upper moderate disability MD + 7 Lower good recovery GR - 8 Upper good recovery GR +

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APPENDIX C: Markwalder Grading Score

Score Description 0 Neurologically normal 1 Alert and orientated: absence of mild symptoms such as headache, or mild

neurological deficit such as reflex asymmetry 2 Drowsy or disorientated, or variable neurological deficit such as hemiparesis 3 Stuporous, but responding appropriately to noxious stimuli, several focal

signs such as hemiplegia 4 Comatose with absent motor responses to painful stimuli, decerebrate or

decorticate posturing

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140

APPENDIX D: modified Rankin Scale

Score Description 0 No symptoms at all 1 No significant disability despite symptoms; able to carry out all usual duties

and activities 2 Slight disability; unable to carry out all previous activities, but able to look

after own affairs without assistance 3 Moderate disability; requiring some help, but able to walk without assistance 4 Moderately severe disability; unable to walk without assistance and unable to

attend to own bodily needs without assistance 5 Severe disability; bedridden, incontinent and requiring constant nursing care

and attention 6 Dead

Rankin, J. (1957a). Cerebral Vascular Accidents in Patients over the Age of 60: I. General

Considerations. Scottish Medical Journal, 2(4), 127–136.

https://doi.org/10.1177/003693305700200401

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APPENDIX E

HUI Mark 3 (HUI3) Classification System

ATTRIBUTE LEVEL DESCRIPTION

VISION 1 Able to see well enough to read ordinary newsprint and recognize a friend on the other side of the street, without glasses or contact lenses.

2 Able to see well enough to read ordinary newsprint and recognize a friend on the other side of the street, but with glasses.

3 Able to read ordinary newsprint with or without glasses but unable to recognize a friend on the other side of the street, even with glasses.

4 Able to recognize a friend on the other side of the street with or without glasses but unable to read ordinary newsprint, even with glasses.

5 Unable to read ordinary newsprint and unable to recognize a friend on the other side of the street, even with glasses.

6 Unable to see at all.

HEARING 1 Able to hear what is said in a group conversation with at least three other people, without a hearing aid.

2 Able to hear what is said in a conversation with one other person in a quiet room without a hearing aid, but requires a hearing aid to hear what is said in a group conversation with at least three other people.

3 Able to hear what is said in a conversation with one other person in a quiet room with a hearing aid, and able to hear what is said in a group conversation with at least three other people, with a hearing aid.

4 Able to hear what is said in a conversation with one other person in a quiet room, without a hearing aid, but unable to hear what is said in a group conversation with at least three other people even with a hearing aid.

5 Able to hear what is said in a conversation with one other person in a quiet room with a hearing aid, but unable to hear what is said in a group conversation with at least three other people even with a hearing aid.

6 Unable to hear at all.

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SPEECH 1 Able to be understood completely when speaking with strangers or friends.

2 Able to be understood partially when speaking with strangers but able to be understood completely when speaking with people who know me well.

3 Able to be understood partially when speaking with strangers or people who know me well.

4 Unable to be understood when speaking with strangers but able to be understood partially by people who know me well.

5 Unable to be understood when speaking to other people (or unable to speak at all).

AMBULATION 1 Able to walk around the neighbourhood without difficulty, and without walking equipment.

2 Able to walk around the neighbourhood with difficulty; but does not require walking equipment or the help of another person.

3 Able to walk around the neighbourhood with walking equipment, but without the help of another person.

4 Able to walk only short distances with walking equipment, and requires a wheelchair to get around the neighbourhood.

5 Unable to walk alone, even with walking equipment. Able to walk short distances with the help of another person, and requires a wheelchair to get around the neighbourhood.

6 Cannot walk at all.

DEXTERITY 1 Full use of two hands and ten fingers.

2 Limitations in the use of hands or fingers, but does not require special tools or help of another person.

3 Limitations in the use of hands or fingers, is independent with use of special tools (does not require the help of another person).

4 Limitations in the use of hands or fingers, requires the help of another person for some tasks (not independent even with use of special tools).

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5 Limitations in use of hands or fingers, requires the help of another person for most tasks (not independent even with use of special tools).

6 Limitations in use of hands or fingers, requires the help of another person for all tasks (not independent even with use of special tools).

EMOTION 1 Happy and interested in life.

2 Somewhat happy.

3 Somewhat unhappy.

4 Very unhappy.

5 So unhappy that life is not worthwhile.

COGNITION 1 Able to remember most things, think clearly and solve day to day problems.

2 Able to remember most things, but have a little difficulty when trying to think and solve day to day problems.

3 Somewhat forgetful, but able to think clearly and solve day to day problems.

4 Somewhat forgetful, and have a little difficulty when trying to think or solve day to day problems.

5 Very forgetful, and have great difficulty when trying to think or solve day to day problems.

6 Unable to remember anything at all, and unable to think or solve day to day problems.

PAIN 1 Free of pain and discomfort.

2 Mild to moderate pain that prevents no activities.

3 Moderate pain that prevents a few activities.

4 Moderate to severe pain that prevents some activities.

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5 Severe pain that prevents most activities.

HUI Mark 2 (HUI2) Classification System.

ATTRIBUTE LEVEL DESCRIPTION

SENSATION 1 Able to see, hear, and speak normally for age.

2 Requires equipment to see or hear or speak.

3 Sees, hears, or speaks with limitations even with equipment.

4 Blind, deaf, or mute.

MOBILITY 1 Able to walk, bend, lift, jump, and run normally for age.

2 Walks, bends, lifts, jumps, or runs with some limitations but does not require help.

3 Requires mechanical equipment (such as canes, crutches, braces, or wheelchair) to walk or get around independently

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4 Requires the help of another person to walk or get around and requires mechanical equipment as well.

5 Unable to control or use arms and legs.

EMOTION 1 Generally happy and free from worry.

2 Occasionally fretful, angry, irritable, anxious, depressed, or suffering night terrors

3 Often fretful, angry, irritable, anxious, depressed, or suffering night terrors

4 Almost always fretful, angry, irritable, anxious, depressed.

5 Extremely fretful, angry, irritable, anxious, or depressed usually requiring hospitalization or psychiatric institutional care.

COGNITION 1 Learns and remembers school work normally for age.

2 Learns and remembers school work more slowly than classmates as judged by parents and/or teachers.

3 Learns and remembers very slowly and usually requires special educational assistance.

4 Unable to learn and remember.

SELF-CARE 1 Eats, bathes, dresses, and uses the toilet normally for age.

2 Eats, bathes, dresses, or uses the toilet independently with difficulty.

3 Requires mechanical equipment to eat, bathe, dress, or use the toilet independently.

4 Requires the help of another person to eat, bathe, dress, or use the toilet.

PAIN 1 Free of pain and discomfort.

2 Occasional pain. Discomfort relieved by non-prescription drugs or self-control activity without disruption of normal activities.

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3 Frequent pain. Discomfort relieved by oral medicines with occasional disruption of normal activities.

4 Frequent pain; frequent disruption of normal activities. Discomfort requires prescription narcotics for relief.

5 Severe pain. Pain not relieved by drugs and constantly disrupts normal activities.

FERTILITY 1 Able to have children with a fertile spouse.

2 Difficulty in having children with a fertile spouse.

3 Unable to have children with a fertile spouse.

Horsman, J., Furlong, W., Feeny, D., & Torrance, G. (2003). The Health Utilities Index (HUI):

concepts, measurement properties and applications. Health and Quality of Life

Outcomes, 1, 54. https://doi.org/10.1186/1477-7525-1-54