Tranexamic acid for chronic subdural hematoma

Abstract

Background

There is no consensus on optimal treatment for a chronic subdural hematoma (cSDH). In patients with only moderate symptoms treatment with tranexamic acid (TXA) has been suggested. We report off-label use of TXA in seven patients.

Methods

Between August 2016 and May 2018 we identified seven patients for primary conservative treatment with TXA until satisfactory clinical and radiological status was achieved. Primary outcome was surgery for cSDH evacuation. Radiological follow-up was performed at regular intervals for hematoma volume measurements.

Results

Five patients experienced complete resolution of symptoms, one patient had a burr-hole craniostomy five days after initiation of TXA treatment due to an increase of left-sided weakness and dysarthria and in one patient symptoms did not improve. Median follow-up was 15 weeks (range 6–25, without the operated patient). The median total volume before start of treatment was 83 mL (range 11–137) for all patients. At the last follow-up, the median total volume in the non-operated patients decreased by 73% to 33 mL (range 0–77).

Conclusions

TXA could be considered as primary medical treatment in patients with a cSDH and mild symptoms. The results of current randomized clinical trials must be awaited.

Keywords:

• Chronic subdural hematoma
• tranexamic acid
• neurosurgery

Introduction

The current incidence of chronic subdural hematoma (cSDH), estimated to be 15/100,000 per year,¹ is expected to rise, due to the continuing growth of the elderly population and the increase in use of anticoagulation and anti-aggregation therapy.² Treatment usually consists of burr hole evacuation in symptomatic patients. A conservative wait-and-scan policy is an option when a patient is without symptoms. The use of tranexamic acid (TXA), an antifibrinolytic agent, has been described in several reports, with quite positive results.^3–10

Recently, we started a double-blind, placebo-controlled, multicenter, randomized clinical trial in the Netherlands, the TORCH-study (Tranexamic Acid to Prevent Operation in Chronic Subdural Hematoma),¹¹ to assess the efficacy of TXA to prevent surgery for patients diagnosed with cSDH for which a conservative treatment is selected as a primary treatment strategy. Here we describe the results of off-label TXA treatment in seven patients, in anticipation to this trial.

Methods

Patient population

Between August 2016 and May 2018 we prospectively identified seven patients eligible for treatment with TXA for cSDH at the department of Neurosurgery of Amsterdam University Medical Centers (the Netherlands). This study was conducted according to the ethical principles for medical research involving human subjects as stated in the Declaration of Helsinki (64th WMA General Assembly, Fortaleza, Brazil, October 2013). Approval of the Institutional Review Board was not necessary. Eligibility criteria were: age over 50 years, CT-scan-confirmed cSDH, and primary conservative treatment based on a Glasgow Coma Scale score of 14 or 15 and stable neurological symptoms. A cSDH is defined as a uni- or bilateral isodense, or hypodense, subdural collection, with or without some hyperdense compartments. Exclusion criteria were primary surgical treatment based on one or more of the following: medically intractable headache, midline shift >10 mm, imminent death within 24 h; structural causes for subdural hemorrhage, e.g., arachnoid cysts or cortical vascular malformations; aneurysmal subarachnoid haemorrhage; active treatment for deep vein thrombosis, pulmonary embolism or cerebral thrombosis (secondary prophylaxis was not considered to be active treatment).

Data collection

The following data were prospectively collected: demographic characteristics, neurological examination, relevant medical history, such as a history of head trauma, previous cSDH, cerebrovascular accidents, dementia, atrial fibrillation. At follow-up visits, neurological condition was reassessed. The total duration (in days) and total dose (in grams) of TXA treatment were noted.

Treatment

Antiplatelet and anticoagulant therapy were discontinued until the cSDH had resolved. TXA dosage was prescribed in a minimal dosage of 500 mg twice daily and could be increased or extended depending on persistent symptoms and physician’s preference. When neurological symptoms were resolved or minimal, showing complete resolution or significant decrease of the hematoma on the CT-scan, TXA treatment was stopped. Indication for surgical intervention was determined by the attending consultant in cases of persistent or worsening clinical symptoms.

Imaging

A non-contrast CT-scan was used at baseline to assess hematoma features in all patients, with radiological follow-up at regular intervals, depending on symptoms and preference of the treating physician. On all CT-scans, hematoma laterality, volume (in ml) and any midline shift were determined, using XERO Viewer 8.1.2 (AGFA HealthCare), by the first author (RL) and independently reviewed (SI). Hematoma volume (in milliliters) was determined by the first author (RL), using Brainlab Elements software version 1.5.0.520 (Brainlab AG, Munich, Germany). On the sagittal, coronal and axial plane the hematoma was visible and distinguished from normal brain tissue by the first author (RL). Subsequently, the hematoma was meticulously colored in the three planes, manually using SmartBrush^®, which yielded an automatic volume in milliliters. The automatic volume determination was corrected by hand by the first author (RL) and an experienced neuroradiologist (RvdB) reviewed all colored borders of the hematoma and corrected when necessary.

Outcome assessment

The primary outcome was surgery for cSDH evacuation within 12 weeks after start of TXA treatment. Secondary outcome measurements were the changes over time in hematoma volume and neurological signs and symptoms. Follow-up was performed depending on symptoms and treating physician’s preference till satisfactory clinical status was achieved.

Literature review

A literature search of the Pubmed database up to April 2019 without restrictions to language and publication date was conducted using the following keywords: tranexamic acid, cyklokapron, antifibrinolytics, antifibrinolytic drugs, antifibrinolytic therapy and chronic subdural hematoma. Studies had to include patients treated with TXA as first line treatment to prevent surgery or after surgical treatment to prevent a recurrent cSDH. The effect or complications of TXA had to be described.

Results

Patient and treatment characteristics

Baseline demographic characteristics of all seven patients (all male, mean age 78 years) are presented in Table 1. The most common symptoms were gait abnormality and headache. Six of the seven patients had a history of prior trauma. The daily TXA dosage varied from 1 to 3 grams, the duration from 5 to 56 days, and the total dose from 5 to 112 grams (Table 2).

Table 1. Baseline characteristics of seven patients treated with tranexamic acid for chronic subdural hematoma.

Case No.	Age (yrs), sex	Medical history	Prior trauma	Anticoagulant/antiplatelet medication	Symptoms on admission	Laterality
1	79, male	Myelodysplastic syndrome; hemochromatosis	No	No	Headache, gait disturbance, bradyphrenia, fatigue	Bilateral
2	76, male	DVT; hypertension	Yes	No	Gait disturbance	Bilateral
3	78, male	Surgery (2x) for cSDH	Yes	o	Headache, dysarthria, dyspraxia right hand, miction problems	Right
4	86, male	COPD; lumbar radicular syndrome; subscapular nerve damage (due to shoulder surgery); clubfoot	Yes	No	Gait disturbance, speaks softer	Right
5	79, male	Head injury 2x (1x with subarachnoid blood and a small epidural hematoma (no operation); 1x with bilateral hygroma (no operation)); cognitive disorder not specified	Yes	No	Increased memory loss	Bilateral
6	70, male	COPD; hypertension	Yes	Acetylsalicylic acid	Headache	Bilateral
7	79, male	Hypertension; CVA; AF	Yes	Acenocoumarol	Memory loss	Bilateral

DVT: deep vein thrombosis; cSDH: chronic subdural hematoma; COPD: chronic obstructive pulmonary disease; CVA: cerebrovascular accident; AF: atrial fibrillation; TXA: tranexamic acid.

Table 2. TXA Dosage, duration of treatment, total dosage and average dosage per day in seven patients treated with tranexamic acid for chronic subdural hematoma.

Case no.	Dosage	Amount per day	Duration (days)	Total dosage	Average dosage
1	1000 mg	3	28	84 gr
	500 mg	2	28	28 gr = 112 gr in total	2 gr/day
2	500 mg	2	56	56 gr	1 gr/day
3	500 mg	2	28	28 gr	1 gr/day
4	500 mg	2	5	5 gr	1 gr/day
5	500 mg	2	28	28 gr	1 gr/day
6	500 mg	4	30	60 gr	2 gr/day
7	500 mg	2	28	28 gr	1 gr/day

Clinical outcome

Five patients experienced a complete resolution of symptoms (Table 3). One patient (case no. 4) had a burr-hole craniostomy five days after initiation of TXA treatment due to progression of symptoms. A CT-scan revealed a right-sided hematoma with a volume of 140 mL and eight millimeter midline shift. Post-operatively, the patient did not improve neurologically and a repeat CT-scan showed a residual hematoma along the convexity which was aspirated percutaneously. At two months follow-up he regained most of his independence.

Table 4. Hematoma volumes and midline shift at time of diagnosis and at last follow-up and volume decrease of seven patients treated with tranexamic acid treatment for chronic subdural hematoma.

Case no.	At time of diagnosis			At last follow-up			Volume decrease		Period (days) from diagnosis to last follow-up from cSDH treatment
	Volume right (mL)	Volume left (mL)	Midlineshift (mm)	Volume right (mL)	Volume left (mL)	Midlineshift (mm)	Right (mL)	Left (mL)
1	103	74	5	77	37	3	26	37	172
2	93	91	3	25	25	0	68	66	135
3	75	–	4	14	–	0	61	–	45
4	120	–	4	140^a	–	5	NC	NC	5^b
5	92	63	2	24	0	1	68	63	116
6	137	11	9	0	0	0	137	11	120
7	95	39	2	42	16	2	53	37	71

^aVolume determined on the CT-scan before surgical intervention.

^bNumber of days from CT-scan at time of diagnosis and start TXA till CT-scan before surgical intervention. Follow-up from cSDH treatment was performed after surgical intervention but is not displayed here.

NC: not calculated.

One patient (case no. 3) experienced a seizure five days after initiation of TXA treatment. The TXA was stopped temporarily, the patient re-admitted, and scheduled for surgery. However, because of persisting fever due to a bladder infection, the operation was postponed. His symptoms diminished nevertheless, and he was discharged home without an operation. TXA was continued at discharge, six days after the seizure. At follow-up one month later, the symptoms had resolved and further follow-up was not necessary. One patient (case no. 5) reported memory loss, however, this was also present prior to initial presentation described as ‘cognitive disorder not otherwise specified’. The patient was referred to a neurologist for further analysis. One patient was operated 11 months after TXA treatment. Possibly this was related to his myelodysplastic syndrome, a hematologic disorder characterized by chronic anemia, neutropenia and thrombocytopenia.

In two patients (cases no. 3 and 7) follow-up in the out-patient clinic was performed less than the 12 weeks after which the primary outcome was measured (at 44 and 62 days after start of TXA treatment, respectively). As no surgery for cSDH was confirmed by telephone after 12 weeks we regard these two patients also as successfully treated.

Imaging

Hematoma volumes at time of diagnosis and last follow-up are presented in Table 4. The initial median total volume was 83 mL (range 11–137) for all patients. Hematoma volumes decreased in all patients during follow-up, over a median time of 15 weeks (range 7–25 weeks). At the last follow-up, the median total volume decreased by 72% (range 25%–100%) to 33 mL (range 0–77) excluding case no. 4 because of surgical intervention. The volume over time is shown in Figure 1 and the total relative volume decrease, or increase is shown in Figure 2.

Figure 1. Changes in volume (in mL) of 12 chronic subdural hematomas in seven patients. Each color represents one patient with case number and laterality shown in the graph. ^#Case no 4. underwent surgery at this point

Figure 2. Hematoma volumes (in mL) are visible per patient and separated on laterality. The left bar represents the volume at time of diagnosis and right bar the volume at last follow-up except for case no. 4 in which the right bar shows the volume before surgical intervention as no CT-scan has been made during follow-up. The percentage between the bars shows the relative decrease/increase of volume from time of diagnosis till last follow-up.

Table 3. Follow-up of clinical symptoms in seven patients treated with tranexamic acid for chronic subdural hematoma.

Case no.	Symptoms on admission	Operation within three months after start TXA	Reason for surgical intervention	Clinical outcome	Period (days) from diagnosis to last follow-up from cSDH treatment
1	Headache, gait disturbance, bradyphrenia, fatigue	No		Gait disturbance remained present	172
2	Gait disturbance	No		No symptoms	135
3	Headache, dysarthria, dyspraxia right hand, miction problems	No		No symptoms	45
4	Gait disturbance, speak more softly	Yes	Increased left-sided weakness, dysarthria	Clubfoot and a slight weakness of his left arm (both pre-existent)	71^a
5	Increased memory loss	No		Cognitive disorder remains (pre-existent)	116
6	Headache	No		No symptoms	120
7	Memory loss	No		No symptoms	71

^aPatient was operated upon 5 days after start of TXA treatment after which one follow-up was performed 71 days after time of diagnosis.

In one patient (case no. 1) only a minimal decline of hematoma volume occurred and despite high dosage of TXA, considerable bilateral hematomas persisted. The patient eventually underwent surgical evacuation 11 months after start TXA treatment. Unfortunately, his symptoms did not improve after surgery.

Literature review

The Pubmed search yielded 32 articles. In total, seven studies were included with 41 patients treated with TXA and 199 treated with TXA in combination with Gorei-San (Table 5).^3–7,9,10 Kageyama et al.³ described 18 patients with primary TXA treatment for cSDH and three patients after surgical treatment. In none of these 21 patients, a complication or recurrence was observed. Stary et al.⁴ treated three patients with TXA after surgical treatment and none experienced a complication or recurrence. Tanweer et al.⁵ described 14 patients with TXA after surgery for cSDH of whom none experienced a recurrence or complication. Kutty et al.⁶ and Moscote-Salazar⁹ each described one patient with primary TXA treatment for cSDH and complete resolution of het cSDH. Mikkelsen et al.¹⁰ described one patient with five recurrences for which surgical intervention was performed. After the fifth operation, TXA was administered intravenously after which the symptoms and the hematoma resolved. And finally, Wakabayashi et al.⁷ described 199 patients who were treated post-surgery with either no drugs, TXA, a combination of TXA and Gorei-San (a Japanese herbal Kampo medicine) and Gorei-San with recurrence rates of 6%, 11%, 3% and 8%, respectively.

Table 5. Overview of the existing literature on TXA treatment for chronic subdural hematoma.

Reference	Number of patients	Primary/post-surgery	Total dosage	Duration (days)	Clinical outcome	Hematoma volume
Kageyama^3	21	18 primary 3 post-surgery	750 mg	28–137 days	Symptoms improved; no recurrences	No progression
Stary^4	3	3 post-surgery (recurrent)	650 mg	28 days	Symptoms improved; no recurrences	Complete resolution
Tanweer^5	14	14 post-surgery	650 mg	Mean 90.3 ± 27 days	10 complete resolution of symptoms; 3 persistent but improved symptoms; 1 had baseline dementia which persisted; no recurrences	No expansion
Kutty^6	1	Primary	250 mg t.i.d.	42 days	Symptoms improved; no recurrence	Complete resolution
Moscote-Salazar^9	1	Primary	1 gr every 8 h for 72 h	3 days	Symptoms improved; no recurrence	Complete resolution
Mikkelsen^10	1	Post-surgery after 5 recurrences	Intravenous 10 mg/kg four times	24 h	Symptoms improved; no recurrence	Complete resolution
Wakabayashi^7	199	199 post-surgery	Unknown	Unknown	Recurrence rate in the TXA group was 10.9%; in the combination Gorei-San and TXA group 2.9%.	Unknown
Present series	7	6 primary 1 post-surgery	5 patients 500 mg b.i.d. 1 patient 500 mg q.d. 1 patients 1 gr t.i.d. and 500 mg b.i.d.	5–56 days	1 was operated after 5 days; 4 symptoms improved; 1 symptom remained present; 1 pre-existent cognitive disorder remains; no recurrences	1 increased; 5 decreased; 1 complete resolution;

Mg: milligram; t.i.d.: three times a day; gr: gram; kg: kilogram; b.i.d.: two times a day; q.d. : once a day; TXA: tranexamic acid.

Discussion

We treated seven patients off-label with TXA of whom six did not need surgery within 12 weeks after start of TXA treatment.

Summarizing the available data of 41 cases in the literature who received solely TXA for cSDH, TXA seems a promising treatment to avoid surgery for, or recurrence of a cSDH. In the majority of cases symptoms improved and complete resolution of the hematoma was observed. Published results show a 100% success rate at avoidance of surgery after TXA treatment. This seems hardly realistic and was not born out by our results.

TXA does not have prothrombogenic effects and does not lead to increased thrombin generation and fibrin formation.¹² It reduces clot breakdown by inhibiting plasmin, which is involved in fibrinolysis, and is effective in various clinical settings, in both intra- and extracranial bleeding.^13–19 Although active thrombo-embolic disease is regarded a contraindication for TXA, its use has shown no increase in fatal or non-fatal vascular occlusive events, thrombotic complications or death.^{14,18,20–22} Moreover, the risk of thrombo-embolic events is only 0.01–0.1%.²³ The most common adverse events occur mainly in a short period after the start of medication and are 1–10%; gastrointestinal: diarrhea, nausea, vomiting, and TXA-associated seizures, which are dose-dependent and 1.4% (95% CI 0.2–2.5)²⁴ in the dose described for this study; 0.1% to 1%: allergic skin reactions; 0.01–0.1%: thrombocytopenia, prolonged bleeding time, dizziness, impaired (color) vision and other visual disturbances. There are no known drug interactions with other drugs. In the literature, there were no complications in patients receiving TXA for cSDH and therefore never resulted in cessation of the medication.

In a randomized controlled trial of adult trauma patients with, or at risk of, significant bleeding, a loading dose of 1 g over 10 min followed by infusion of 1 g over 8 h significantly reduced the risk of death due to significant bleeding (systolic blood pressure < 90 mm Hg or heart rate >110 beats/min, or both).¹⁴ A systematic review and meta-analysis in scoliosis surgery showed high-dose TXA (>20 mg/kg) to be more effective than low-dose TXA (<20 mg/kg) in controlling blood loss.¹⁹ A randomized, placebo-controlled, double-blind, cross-over trial in hereditary hemorrhagic telangiectasia patients showed that 3 g TXA a day significantly decreased epistaxis.²⁵ The plethora of dosing schemes of TXA in various domains of medicine and surgery indicates that optimal dosing of TXA is not yet known.^17,20 In the few previous studies using TXA for cSDH, the dose ranged from 650 to 750 mg a day for a period of one to three months (Table 5). The dosage in our patients was 500 mg TXA twice daily in principle, but was tailored to persistent symptoms and treating physician’s preference, as was the case with two patients. We regarded a dosage of 500 mg twice daily for one month as safe. The rationale is based on the safe dosage of 750 mg a day in the Japanese study³ and the assumption that Dutch people on average are taller and heavier and therefore require a higher dosage of TXA.

It is possible that it is not the TXA treatment that is beneficial but the natural course of the disease, implying that spontaneous resolution of cSDH in this particular subset of patients is higher than previously reported.²⁶ As a consequence, we might be operating patients with a cSDH too soon and too often and that it is more beneficial to await the spontaneous resolution of the hematoma in patients with mild symptoms. This must be resolved by clinical randomized trials.

Conclusion

Tranexamic acid could be considered as primary medical treatment in patients with a cSDH based on the described results and the literature. Randomized, placebo-controlled trials are currently underway to evaluate the efficacy of TXA to prevent surgery for cSDH.

Author contributions

All authors contributed to the study’s conception and design. Data collection and analysis were performed by Roger Lodewijkx, The first draft of the manuscript was written by Roger Lodewijkx and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).