Clinical trial NCT02618382
Conditions: Subdural Hematoma
Sponsor: St. Joseph's Hospital and Medical Center, Phoenix
Start date: 2015-11-01; Completion date: 2018-06-12
Enrollment: 32 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a single center single arm study of 50 patients to 1) determine the safety of tranexamic acid in the chronic subdural hematoma population following surgical drainage of chronic subdural hematomas and 2) determine if the use of oral tranexamic acid reduces the rate of ipsilateral recurrence following drainage of chronic subdural hematomas. This will be compared to historical controls. This study intends to be a prerequisite to a large nationally funded randomized control trial.

Detailed description:
Chronic subdural hematomas are a common problem faced by neurosurgery with an annual incidence of 13.5/100,00 persons per year and up to 58/100,000 in the over 65 years old population. Their treatment is often complicated by recurrence with rates reported as high as 33%. Currently there is no good strategy to help avoid this problem, which adds significantly to patient morbidity. The pathogenesis of this problem is believed to be related to the propensity of the associated neo-membranes to bleed. It has been shown with labeled red blood cells that bleeding continues to occur into the hematoma cavity. It has also been shown that there are high levels of tissue plasminogen activator in the outer membrane of chronic subdural hematomas. It has been found that ratio of tissue plasminogen activator to plasminogen activator inhibitor contributed to the pathogenesis. It has also been shown that chronic subdural hematomas have high levels of fibrin degradation products which in addition to marking the breakdown of fibrin are themselves antihemostatic by enhancing tissue plasminogen activator activity, having an antithrombin affect and inhibiting platelet aggregation and fibrin polymerization. Essentially, a scenario of ongoing hemorrhage and repeated clot formation and hyperfibrinolysis leads to the expansion and recurrence of chronic subdural hematomas.

Given the importance of plasmin and hyperfibrinolysis in the pathophysiology of chronic subdural hematomas, interrupting its action and the vicious cycle it propagates seems an ideal therapeutic target. Tranexamic acid is a synthetic lysine amino acid derivative. It binds to the fibrin binding sites on plasmin or plasminogen and prevents its interaction and degradation of fibrin. This effect on the neo-membranes of chronic subdural hematomas should prevent rebleeding and the reaccumulation of the subdural hematoma.

Tranexamic acid has been shown to be safe and effective in reducing blood loss and transfusions in a number of types of surgery, reduced mortality and need for urgent surgery in patients with GI bleeding, and reduced bleeding associated with menorrhagia and pregnancy. Adverse effects are generally mild. Thought there is a theoretical increased risk of thromboembolic complications, multiple randomized controlled trials have not shown an increased risk. Furthermore, in a study of over 3000 gynecologic patients using tranexamic acid, there were no thromboembolic complications. This is likely because tranexamic acid has been shown to not have an effect on plasminogen in the vein wall.

Arms: arm 1: Patients will undergo standard treatment of their chronic subdural hematoma with the addition of preoperative and postoperative oral tranexamic acid treatment. Patients will receive a dose of 1300mg orally three to four hours prior to surgery. They will then take 1300mg orally three times daily for three days or until discharge, whichever occurs first.
Interventions: intervention 1: Tranexamic Acid
Intervention descriptions: intervention 1: 1300mg tranexamic acid by mouth once before surgery and then three times a day for up to three days or until they are discharged from the hospital, whichever comes first

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
TRANEXAMIC ACID FOR cSDH- 
A PILOT STUDY ON THE SAFETY OF TRANEXAMIC ACID 
 FOR THE CHRONIC SUDURAL HEMATOMA POPULATION 
 
 
 
 
 
 
 
NCT02618382 
 
 
 
 
 
 
 
 
 
Nov 9, 2017 
 
 


 Tranexamic acid for cSDH –  A Pilot Study on the Safety of Tranexamic Acid for the 
Chronic Subdural Hematoma Population 
 
IRB NUMBER: PHXA-15BN048 
Original: 5/26/15 
Revised:  6/2/15; 8/1/16; 11/6/17 
IRB APPROVALPaDgAeT2Eo:f 151/09/2017 
 
 
 
Study Objectives 
1. Establish the safety of using tranexamic acid in the treatment of chronic subdural 
hematomas 
2. Determine if the use of oral tranexamic acid reduces the rate of ipsilateral 
recurrence following drainage of chronic subdural hematomas 
 
Background 
Chronic subdural hematomas are a common problem faced by neurosurgery with an 
annual incidence of 13.5/100,000 persons per year and up to 58/100,000 in the over 65 years old 
population (Kudo). Their treatment is often complicated by recurrence with rates reported as high 
as 33% (Muzii). Currently there is no good strategy to help avoid this problem, which adds 
significantly to patient morbidity. The pathogenesis of this problem is believed to be related to the 
propensity of the associated neo-membranes to bleed (Ito, Weir, Lim, Labadie). Ito et.al. showed 
with labeled red blood cells that bleeding continues to occur into the hematoma cavity (1976). It 
has also been shown that there are high levels of tissue plasminogen activator in the outer 
membrane of chronic subdural hematomas (Ito 78 and Labadie 74). Lim et.al. found that ratio of 
tissue plasminogen activator to plasminogen activator inhibitor contributed to the pathogenesis 
(Lim 95). It has also been shown that chronic subdural hematomas have high levels of fibrin 
degradation products which in addition to marking the breakdown of fibrin are themselves anti-
hemostatic by enhancing tissue plasminogen activator activity (Nieuwenhuizen 83), having an 
anti-thrombin affect (fletcher 62) and inhibiting platelet aggregation (kowalski 64) and fibrin 
polymerization (Alkjaersig 62). Essentially, a scenario of ongoing hemorrhage and repeated clot 
formation and hyperfibrinolysis leads to the expansion and recurrence of chronic subdural 
hematomas. 
Given the importance of plasmin and hyperfibrinolysis in the pathophysiology of chronic 
subdural hematomas, interrupting its action and the vicious cycle it propagates seems an ideal 
therapeutic target. Tranexamic acid is a synthetic lysine amino acid derivative. It binds to the 
fibrin binding sites on plasmin or plasminogen and prevents its interaction and degradation of 
fibrin. This effect on the neo-membranes of chronic subdural hematomas should prevent 
rebleeding and the re-accumulation of the subdural hematoma. 
 
Supporting Data 
Kageyama et.al. showed the safety and potential efficacy of treating chronic subdural 
hematomas in their retrospective study of 21 patients. There were no recurrences in their 21 
patients. Vujkovac et.al. also showed that tranexamic acid could be used safely and effectively 
in their case report of a hemodialysis patient who begun therapy following another recurrence 
after the third operation. The hematoma completely resolved and the patient made a complete 
recovery. 
Tranexamic acid has been shown to be safe and effective in reducing blood loss and 
transfusions in a number of types of surgery, reduced mortality and need for urgent surgery in 
patients with GI bleeding and reduced bleeding associated with menorrhagia and pregnancy. 
Adverse effects are generally mild. Thought there is a theoretical increased risk of 
thromboembolic complications, multiple randomized controlled trials have not shown an 
increased risk (McCormack, Dunn, Katsaros, Barer, Benon). Furthermore, in a study of over 
3000 gynecologic patients using tranexamic acid, Bekassy et.al. had no thromboembolic 
complications. This is likely because tranexamic acid has been shown to not have an effect 
on plasminogen in the vein wall (Astedt). 
 
 
 


 Tranexamic acid for cSDH –  A Pilot Study on the Safety of Tranexamic Acid for the 
Chronic Subdural Hematoma Population 
 
IRB NUMBER: PHXA-15BN048 
Original: 5/26/15 
Revised:  6/2/15; 8/1/16; 11/6/17 
IRB APPROVALPaDgAeT3Eo:f 151/09/2017 
 
 
 
 
Study Design 
 
This study is a single center single armed study of 50 patients to determine the safety of 
tranexamic acid in the chronic subdural hematoma population following surgical drainage of 
chronic subdural hematomas. This will be compared to historical controls. This study intends to 
be a prerequisite to a large nationally funded randomized control trial. 
 
Selection and Enrollment of subjects 
 
Inclusion Criteria: 
-all patients undergoing intervention for cSDH including drainage 
-cSDH will be defined as hematoma on CT imaging that is predominantly isodense to 
hypodense to brain 
- 18-85 years of age 
 
Exclusion Criteria 
-cSDH not requiring surgical drainage 
-patients undergoing bedside twist drill craniostomy 
-medically unstable for surgery 
-patients requiring long-term anticoagulation- unable to stay off for less than 30 days 
-patients not expected to survive to the completion of follow-up 
-patients comatose prior to the initiation of treatment 
-history of thromboembolic problem including stroke, MI, DVT, PE 
-pregnant 
-minor 
-allergy/sensitivity to tranexamic acid 
-irreversible coagulopathy 
-known clotting disorder 
-bilateral hematomas with both requiring drainage 
-incarcerated 
-any patient not judged suitable for the study by the investigators 
-women who are taking combination oral contraceptive 
 
Study Enrollment 
 
Patients meeting all of the inclusion and exclusion criteria will undergo standard treatment of 
their chronic subdural hematoma including operative treatment with the addition of preoperative 
and postoperative oral tranexamic acid treatment. Patients will receive a dose of 1300mg orally 
three to four hours prior to surgery. They will then take 1300mg orally three times daily for three 
days or until discharge, whichever occurs first. Tracking and follow-up will be explained to the 
patients and arranged by the study coordinator. 


 Tranexamic acid for cSDH –  A Pilot Study on the Safety of Tranexamic Acid for the 
Chronic Subdural Hematoma Population 
 
IRB NUMBER: PHXA-15BN048 
Original: 5/26/15 
Revised:  6/2/15; 8/1/16; 11/6/17 
IRB APPROVALPaDgAeT4Eo:f 151/09/2017 
 
 
 
 
Study Interventions 
 
All patients will undergo an intervention for the drainage of their subdural hematoma. The type of 
procedure i.e. burr-hole drainage or craniotomy excluding twist drill craniostomy will be at the 
discretion of the treating physician 
 
All patients will be followed daily during their hospitalization 
 
All patients will have follow-up CTs on postop days 1, 3, 7 and 30 +/- 7days 
All patients will have clinical follow-up on Day 30 +/- 7 days 
All patients will be treated using standard ICU protocols 
-neurologic status will be assessed at least every four hours for the first 48 hours 
-care will be directed toward the goal of normotension and adequate oxygenation 
 
All patients will have DVT prophylaxis with spontaneous compression devices. Pharmacologic 
prophylaxis will be at the discretion of the treating physician. 
 
 
Experimental Interventions 
 
Patients will receive tranexamic acid in the following dosing regimen: 
1. 1300 mg times one immediately prior to surgery 
2. 1300 mg orally three times daily for three days or until discharge- whichever comes first. 
-First postop dosing will start 8 hours after preop dose is given. 
 
All patients will have creatinine monitored daily while on study drug. Patients with creatinine > 1.4 
will have dosage adjustments as follows: 
 
 
Prohibited Interventions 
 
Therapeutic anticoagulation 


 Tranexamic acid for cSDH –  A Pilot Study on the Safety of Tranexamic Acid for the 
Chronic Subdural Hematoma Population 
 
IRB NUMBER: PHXA-15BN048 
Original: 5/26/15 
Revised:  6/2/15; 8/1/16; 11/6/17 
IRB APPROVALPaDgAeT5Eo:f 151/09/2017 
 
 
 
 
Clinical and Laboratory Evaluations 
 
Presentation Day 0- CT scan, NIH stroke scale, pregnancy test, informed consent, modified Rankin Score 
(mRS) 
 
Postop- 
Day 1 CT Scan 
 
Day 14 clinical follow-up, CT scan 
 
Follow-up Day 30- CT scan, NIH stroke scale, mRS 
 
Timing of Evaluations 
 
Registration- the start of the screening process when the study team is notified of a potentially 
eligible subject 
 
Pre-Enrollment- all screening evaluations will be performed prior to enrollment 
Enrollment- will occur prior to surgical intervention or receiving experimental medication 
Medication period- Patients will continue on medication from immediately preoperatively to three 
days postoperatively or until discharge 
 
Post Medication period- follow-up will continue until the patient is discharged from the 
neurosurgeon’s care 
 
Management of Adverse Events 
 
All adverse events will be closely monitored and evaluated 
 
Management of recurrent bleeding: recurrent SDHs will be managed according to best practices 
as determined by the treating physician 
 
Criteria for Intervention Discontinuation 
 
1. patient unable to tolerate side effects 
2. thromboembolic complication including stroke, MI, DVT or PE 
3. if in the investigator’s judgment, withdrawal from the trial will be in the patients best 
interest 
4. consent is withdrawn by the patient or their legal representative 
 
End Points 
 
1* Incidence of medication related complications including stroke, MI, DVT, or PE and other 
drug related adverse events 
2- Return to OR for same sided surgery 
2* Postop hematoma expansion, functional outcome (mRS, NIHSS) discharge location, LOS, 
volume of hematoma at 30 days


 Tranexamic acid for cSDH –  A Pilot Study on the Safety of Tranexamic Acid for the 
Chronic Subdural Hematoma Population 
 
IRB NUMBER: PHXA-15BN048 
Original: 5/26/15 
Revised:  6/2/15; 8/1/16; 11/6/17 
IRB APPROVALPaDgAeT6Eo:f 151/09/2017 
 
 
 
 
 
Data Points 
Age, presenting symptom, admission GCS, language and motor function, preoperative living 
situation, width of hematoma, visible septations present, extent of MLS, operative approach, 
drain used, new preoperative deficit, immediate postop hematoma width, LOS, discharge 
GCS, language and motor function, discharge location, width of hematoma on follow up 
imaging, medication not tolerated, medication side effects, thromboembolic complications, 
other complications, blood loss, NIH stroke scale Day 0 and 30, mRS day 0 and 30 
 
Statistical Data Analysis 
Frequencies will be reported for ordinal and categorical variables. Descriptive analyses of 
central tendency (mean) will be used for continuous variables. Nonparametric tests will be 
used for statistical comparison, including the Kruskal–Wallis rank-sum test for multiple groups 
and the Mann-Whitney U test for 2 groups. Data tabulation and analysis will be analyzed using 
R statistical software version 3.4.2 (R Foundation for Statistical Computing, Vienna, Austria).  
Chi-square test, analysis of variance (ANOVA), and multivariate linear and log-linear 
regression models where appropriate. A P value < 0.05 will be considered statistically 
significant. P values for difference among time point means (preoperative, postoperative days 
3, 7 and 30) to be determined by ANOVA.