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 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. ii 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. iii 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 iv 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. v 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. vi 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. vii 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 viii 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 ix 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