Two weeks administration of tranexamic acid for acute intracerebral hemorrhage: A hospital-based pilot study
- Department of Neurosurgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
- Department of Neurosurgery, Saiseikai Fukuoka General Hospital, Fukuoka, Japan
- Clinical Research Center, Hitoyoshi Medical Center, Hitoyoshi, Japan
- Neurosurgery Unit, Hitoyoshi Medical Center, Hitoyoshi, Japan
- Community Medical Cooperation Office, Hitoyoshi Medical Center, Hitoyoshi, Japan
- Department of Neurosurgery, Kumamoto Medical Center, Kumamoto, Japan
- Department of Neurosurgery, Hitoyoshi Medical Center, Hitoyoshi, Japan
- Healthcare Center, Kumamoto Red Cross Hospital, Kumamoto, Japan.
Hirotaka Inoue, Department of Neurosurgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
DOI:10.25259/SNI_1110_2022Copyright: © 2023 Surgical Neurology International This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, transform, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.
How to cite this article: Hirotaka Inoue1, Takayuki Kawano2, Yuri Iwasaki3, Izumi Imada4, Kazuhiro Yamada5, Kouzo Tashima6, Daisuke Muta7, Keizo Yamamoto8, Akitake Mukasa1. Two weeks administration of tranexamic acid for acute intracerebral hemorrhage: A hospital-based pilot study. 24-Feb-2023;14:76
How to cite this URL: Hirotaka Inoue1, Takayuki Kawano2, Yuri Iwasaki3, Izumi Imada4, Kazuhiro Yamada5, Kouzo Tashima6, Daisuke Muta7, Keizo Yamamoto8, Akitake Mukasa1. Two weeks administration of tranexamic acid for acute intracerebral hemorrhage: A hospital-based pilot study. 24-Feb-2023;14:76. Available from: https://surgicalneurologyint.com/surgicalint-articles/12162/
Background: A previous report suggested that functional status does not differ between patients who received tranexamic acid and those who received placebo within the early hours of intracerebral hemorrhage (ICH). Our pilot study tested the hypothesis that 2 weeks administration of tranexamic acid would contribute to functional improvement.
Methods: Consecutive patients with ICH were administered 250 mg tranexamic acid 3 times a day continuously for 2 weeks. We also enrolled historical control consecutive patients. We collected clinical data that involved hematoma size, level of consciousness, and Modified Rankin Scale (mRS) scores.
Results: Univariate analysis showed that the mRS score on day 90 was better in the administration group (P = 0.0095). The mRS scores on the day of death or discharge suggested a favorable effect of the treatment (P = 0.0678). Multivariable logistic regression analysis also showed that the treatment was associated with good mRS scores on day 90 (odds ratio [OR] = 2.81, 95% confidence interval [CI]: 1.10–7.21, P = 0.0312). In contrast, ICH size was associated with poor mRS scores on day 90 (OR = 0.92, 95% CI: 0.88–0.97, P = 0.0005). After propensity score matching, there was no difference in the outcomes between the two groups. We did not detect mild and serious adverse events.
Conclusion: The study could not show the significant effect of 2 weeks administration of tranexamic acid on functional outcomes of ICH patients after the matching; however, suggested that this treatment is at least safe and feasible. A larger and adequately powered trial is needed.
Keywords: Antifibrinolytic effect, Anti-inflammatory effect, Intracerebral hemorrhage, Kallikrein-Kinin system, Tranexamic acid
The survival rate after spontaneous acute intracerebral hemorrhage (ICH) has not changed for several decades, and it is well known that the only treatment possibility for functional improvement on day 90 is early intensive blood pressure control.[
Tranexamic acid, an antifibrinolytic drug, is often used for hemostasis. The CRASH-3 trial showed that administration of tranexamic acid within 3 h reduced head injury-related death in patients with traumatic brain injury.[
Tranexamic acid, which inhibits plasmin activity, has both antifibrinolytic and anti-inflammatory effects.[
Therefore, we considered a different method of tranexamic acid administration from the TICH-2 trial. Our pilot study tested the hypothesis that 2 weeks administration of tranexamic acid inhibits fibrinolytic and inflammatory activity in acute spontaneous ICH and is associated with functional improvement.
Our pilot study was a single-center study. All consecutive patients with acute ICH were eligible for inclusion if they were admitted to our hospital within 8 h of symptom onset. Recruitment started on August 9, 2018, and ended on September 30, 2019. ICH was defined as hemorrhage due to hypertension and included putaminal, thalamic, brainstem (pontine), and cerebellar hemorrhage. The exclusion criteria were a Glasgow Coma Scale (GCS) score of ≤8; ICH secondary to thrombolysis, trauma, or a known underlying structural abnormality; patients for whom tranexamic acid was contraindicated; patients with a Modified Rankin Scale (mRS) score >4; patients undergoing surgical treatment; and multiple ICHs. The treatment window and exclusion criteria were based on the TICH-2 trial.[
As this study involved human subjects, it was approved by the Local Institutional Review Board (Hitoyoshi Medical Center, Approval No. 2018-12). The study was performed in accordance with the principles of good clinical practice and the Declaration of Helsinki. Clinical trial registration number of the study was UMIN000035584 (18/01/2019).
The target patients were administered 250 mg tranexamic acid intravenously or orally 3 times a day. The initial intervention, tranexamic acid, was administered as quickly as possible after diagnosis. Tranexamic acid was continuously administered for 2 weeks from the time of admission. This was discontinued if a serious complication occurred from drug administration, if another stroke occurred, or if the patient died. The dose of tranexamic acid was based on a previous report of its daily administration for a chronic subdural hematoma.[
Baseline characteristic data were extracted at the time of admission from the patients’ medical records and their computed tomography (CT) scans. This data included the following: age, sex, ICH location, ICH size, intraventricular hemorrhage (IVH), pre-onset mRS score, GCS score at admission, and antithrombotic drug history. The target patients were reviewed on the day after admission, day 7, on the day of death or hospital discharge, and on day 90 to gather information on changes in ICH size, GCS score, and mRS score. This information was obtained through the transferred hospital report, on the outpatient visit, or through a direct phone interview.
For all target patients, CT was conducted at admission. A second CT was conducted on the day after admission to assess hematoma expansion. The first author evaluated all CT images. ICH location and size and IVH severity were also examined. The formula ABC/2 was used to measure ICH size.[
The primary outcome was mRS score on day 90. The secondary outcomes included hematoma expansion on the day after admission, GCS score on day 7, and mRS score on the day of death or hospital discharge (whichever came first). We hypothesized that 2 weeks administration of tranexamic acid would improve these outcomes. Whether tranexamic acid inhibited fibrinolytic and inflammatory activity in ICH was difficult to evaluate using CT. Therefore, we focused on clinical improvement, not imaging improvement.
Safety outcomes were thromboembolic complications (myocardial infarction, stroke, pulmonary embolism). These outcomes were recorded if they occurred while the patient was still in our hospital.
Our study was a prospective and single-arm pilot study with historical controls. Since this was a pilot study, the sample size was not calculated before the start of the study. First, a univariate analysis was performed for each baseline and outcome parameter. We analyzed the mRS score as a binary outcome (dichotomized at mRS scores 0–3 vs. 4–6). Continuous data were reported as the mean and standard deviation or as the median with the corresponding interquartile range and compared using the t-test or Wilcoxon rank-sum test. Categorical data were reported as numbers and percentages and compared using the Chi-squared test. Because of the bias caused by potentially confounding factors, a logistic regression model was used to calculate the adjusted odds ratio (OR) with a 95% confidence interval (CI) for 2 weeks administration of tranexamic acid associated with mRS score on day 90. Furthermore, all outcomes were compared after adjusting for baseline characteristics using propensity score matching. A multivariable logistic regression model was used to predict patients’ propensity scores. One-to-one nearest neighbor matching was performed (caliper width, 20%). After matching, continuous data were compared using the corresponding t-test, and categorical data were compared using the McNemar test. All P < 0.05 were considered statistically significant. No adjustment was made for testing multiplicity. There was no missing data in this trial, except in the case of one patient, for whom the mRS score on day 90 could not be obtained. The full analysis set was performed in accordance with the intention-to-treat principle. All analyses were performed using the JMP software (SAS Institute Inc., Cary, NC, USA).
A total of 35 patients were recruited and received tranexamic acid. Furthermore, we identified 90 historical control patients who had presented between January 2016 and September 2018.
Univariate analysis showed that the primary outcome (mRS score on day 90) was better in the administration group (P = 0.0095). The secondary outcomes of hematoma expansion and GCS score on day 7 were not significantly different between the two groups (P = 0.6762, P = 0.1182). mRS score on the day of death or discharge suggested a favorable effect of tranexamic acid treatment (P = 0.0678) [
Moreover, the primary outcome and other outcomes, such as hematoma expansion, GCS on day 7, and mRS score on the day of death or discharge were compared after adjusting for baseline characteristics by propensity score matching. Only two characteristics, ICH size and history of antithrombotic drugs, were selected as Matched predictor variables to reduce the risk of overfitting. Multivariate logistic analysis was performed to calculate the propensity scores, which were balanced between the two groups [
We did not detect adverse events that occurred from drug administration, such as thromboembolic complications (myocardial infarction, stroke, and pulmonary embolism) in the study.
Our study showed that 2 weeks administration of tranexamic acid might have a positive impact on the functional prognosis of patients with ICH in multivariable logistic regression. At present, the only treatment for functional improvement in patients with ICH is early intensive blood pressure control.[
Along with compression of the surrounding brain tissue by a hematoma, various cellular and molecular components of inflammation are associated with ICH-induced brain injury.[
We hypothesized that 2 weeks administration of tranexamic acid might inhibit the increase in vascular permeability seen in ICH, which would reduce cellular damage, although this was difficult to evaluate using CT. Therefore, the multivariable logistic regression showed that the treatment was associated with good mRS scores on day 90. After propensity score matching, however, there was no difference in the outcomes between the two groups. The reason for this result may be that ICH size was a much stronger prognostic factor[
Nausea and diarrhea are the most common adverse events associated with tranexamic acid.[
Our study had several limitations. First, selection bias was possible due to the nature of the study design, as this was a single center, single-arm pilot study with a small sample size. However, we used multivariable logistic regression and propensity score matching to balance the patient baselines to minimize its influence as much as possible. Second, this study included only Japanese patients. The same results cannot always be obtained when this treatment is administered to patients of other ethnicities. Third, the administration group represented mild ICH patients with a median GCS of 15 and a median ICH volume <10 mL. This limited the generalizability of this trial. Fourth, we hypothesized that this treatment might reduce cellular damage; however, we did not collect image data that supported the hypothesis such as magnetic resonance imaging. This is a subject for future research. Finally, the dose of tranexamic acid was based on a previous report of its daily administration for a chronic subdural hematoma,[
We surveyed the effect of 2 weeks administration of tranexamic acid for acute ICH. The outcomes did not differ between the two groups after matching; however, this pilot study suggested that this treatment is at least safe and feasible. This treatment might have anti-inflammatory effects, which could reduce cellular damage. Therefore, this treatment may have positive effects, such as the early introduction of rehabilitation, which may improve the functional prognosis of patients with ICH. The study may provide future directions on the treatment of ICH; however, a larger and adequately powered trial is needed because the study had many limitations including study size.
The authors certify that they have obtained all appropriate patient consent.
There are no conflicts of interest.
The views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Journal or its management. The information contained in this article should not be considered to be medical advice; patients should consult their own physicians for advice as to their specific medical needs.
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