
==== Front
Ann Indian Acad Neurol
Ann Indian Acad Neurol
AIAN
Ann Indian Acad Neurol
Annals of Indian Academy of Neurology
0972-2327
1998-3549
Wolters Kluwer - Medknow India

39196807
AIAN-27-358
10.4103/aian.aian_435_24
View Point
Current Status of Tranexamic Acid in Hyperacute Treatment of Intracerebral Hemorrhage
Philips Atul
Pandian Jeyaraj Durai 1
Department of Critical Care Medicine, University of Calgary, Calgary, Alberta, Canada
1 Department of Neurology, Christian Medical College, Ludhiana, Punjab, India
Address for correspondence: Dr. Jeyaraj Durai Pandian, Department of Neurology and Principal, Christian Medical College, Ludhiana - 141 008, Punjab, India. E-mail: jeyarajpandian@hotmail.com
Jul-Aug 2024
23 8 2024
27 4 358363
02 6 2024
20 6 2024
22 6 2024
Copyright: © 2024 Annals of Indian Academy of Neurology
2024
https://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.
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pmcINTRODUCTION

Intracerebral hemorrhage (ICH) takes place when the blood vessels rupture due to underlying hypertension or small vessel disease, resulting in collection of blood in the brain parenchyma causing brain injury.[1] According to 2019 study by Global Burden of Diseases, the incidence of ICH was 27.9% and ICH-related disability-adjusted life-years occurred in 68.57 [95% utility index (UI) 63.27–73.68] million people.[2] ICH is the most lethal among all stroke types having very high mortality rates between 30-40%.[3] The incidence of ICH in Southeast Asia region (SEAR) countries is substantially higher, ranging between 19% and 46%, compared to high-income countries.[4]

Various mechanisms contribute to brain injury in ICH: hematoma growth and perilesional edema leading to mass effect that occurs within a few hours; delayed (beyond 48 h) injury due to edema because of blood–brain barrier disruption and toxic inflammation from clot lysis releasing heme iron.[5] After ICH bleed, hyperfibrinolysis, which is an amplified physiologic process, tends to destabilize clot formation with consequential hematoma expansion (HE).[6]

HE has been a reliable predictor of death and poor functional outcomes in ICH. Studies have shown that early in the course of disease, every milliliter of growth in hematoma results in 37% increase in the risk of neurologic deterioration (defined as an increase in National Institutes of Health Stroke Scale [NIHSS] score by 4).[7] This is associated with a 7% greater likelihood of poor functional outcome in patients with ICH.[8]

HE is described as either an increase in absolute (6–12 ml) or relative (33%) growth of hematoma on computed tomography (CT) scan.[9] HE develops rapidly within 4 h of symptom onset in 26% of patients presenting with ICH. With time, the risk of expansion decreases and happens in 12% of the patients within 20 h from symptom onset.[10]

ICH is a heterogeneous disease; trajectory of its natural course and longer times to recovery are distinct from ischemic stroke.[11] The primary aim in treatment of ICH is to prevent death and mitigate primary and secondary brain injuries by providing the right intervention for the right patient. These broadly include but are not limited to hematoma growth restriction and surgical evacuation of clot in the hyperacute phase and targeted lowering of blood pressure (BP) in the acute phase. Complexities in conducting clinical trials and lack of standardized methodology have failed to ascertain clinically meaningful benefits of therapies for ICH.[12]

Among the limited options of medical therapy to restrict HE that are available, BP management remains the most effective treatment. Targeting rapid lowering of systolic blood pressure (SBP) to 130–140 mmHg early in the course of disease and avoiding BP variability enhance the restriction of HE with improved functional outcomes.[1314]

Using hemostatic therapies for limiting HE by normalizing coagulation has been a subject of long discourse in the last decade. Clinical trials done so far to evaluate the effectiveness of hemostatic therapies such as platelet transfusion, prothrombin rich concentrates, vitamin K and recombinant factor VIIa in ICH[1516] have not shown benefit due to inadequate reduction of hematoma volume with concomitant increase in adverse effects of these therapies.

Tranexamic acid (TXA) is a hemostatic drug (antifibrinolytic) commonly used for controlling bleeding in conditions like menorrhagia, cardiac surgery and orthopedic surgery and is proven to be beneficial in traumatic brain injury (TBI) also.[1718]

MECHANISM OF ACTION OF TXA

TXA is a lysine derivative that blocks plasminogen-binding sites and competitively inhibits the interaction between plasmin and fibrin.[19] This inhibits breakdown of fibrin clots by plasmin. TXA increases synthesis of collagen in fibrin clots, thereby making the clots more stable. Both in vitro and in vivo studies have shown that the effective dose of TXA to achieve 80% fibrinolysis inhibition is over 10 µg/ml.[20] This can be achieved with an approximate loading dose of 10–15 mg/kg to be followed by an infusion of 10-15 mg/kg/h.[21]

CLINICAL TRIALS ON USE OF TXA IN SPONTANEOUS ICH [TABLE 1]

One of the early trials performed in Malaysia by Arumugam et al.[22] was a single-center study which attempted to find an association between TXA treatment and hematoma growth in patients presenting within 8 h of symptom onset with acute ICH. The final analysis observed no difference in hematoma growth in the TXA group (10.64 ml at baseline to 10.94 ml at 24 h, P = 0.313), while the placebo group showed an increase in hematoma volume (14.53 to 17.59 ml, P = 0.001). However, this study with a sample size of 30 was underpowered to detect clinically important outcomes.

Table 1 Summary of clinical trials of tranexamic acid in ICH

	Arumugam et al.[22]	TICH-2[23]	STOP-AUST[26]	TRIAGE[25]	STOP-MSU[27]	
Design	Single center (2015)	Multicenter (2018)	Multicenter (2020)	Multicenter (2021)	Multicenter (2024)	
No. of participants	30	2325	100	171	201	
Enrolment time from symptom onset (hours)	8	8	4.5	6	2	
Baseline characteristics	
Age (in years)	53 (mean)	68.9 (20-101)	72 (55-79)	55.9 (± 11.6)	66 (55-77)	
GCS	14 (13-15)	14 (5-15)	14 (11-15)	14 (11-15)	15 (13-15)	
NIHSS	NS	13 (0-42)	13 (8-13)	11 (7-15)	13 (10-18)	
ICH volume (ml)	12.25	14.1 (5.9-32.4)	14.6 (7.9-32.7)	19.8 (11.0-31.5)	10.3 (4.3 - 23.0)	
IVH (%)	NS	32	20	33	25	
Location of bleed	
Cortical	70%	32%	30%	25%	17%	
Deep	30%	59%	69%	75%	83%	
Cerebellar	NS	6%	1%	NS	NS	
Spot Sign	NS	52 (out of 249 participants)	Yes	Yes	Yes	
Time from symptom onset to baseline CT scan (minutes)	330 (240-300)	NS	105 (75-171)	182.5 (112-209)	73 (53-88)	
Time from baseline CT to TXA (minutes)	30 (20-45)	NS	41.5 (75-171)	107.5 (73.0-161.0)	25 (18-35)	
SBP (mm-Hg) on arrival - (TXA vs placebo)	185 (172-205) (TXA group)	172 (27.5) vs 174 (26.8)	168 (25) vs 173 (25)	170.1 (24.8) vs 170.4 (32.8)	168.0 (152.0-185.0) vs 160.0 (150.0 - 178.0)	
Outcome	
Growth in HV (ml)	
TXA	0.2 ml (-2.41 to -2.07)	3.72 ml (15.9)	1.9 ml (0.2.9.5)	6.6 ml (16.5)	1.2 ml (0.1-9.3)	
Placebo	3.07 ml (0.74 to 13.79)	4.9 ml (16)	3.4 ml (0-16)	7.6 ml (15.6)	1.2 ml (0.2-7.6)	
Effect size (95% CI)	NS	-1.37 (-2.71 to -0.04)	-1.8 (-5.2 to 5.1)	NS	-0.1 (-1.5 to 1.3)	
Death (within 90 days)(%)	NS	22 vs 21	26 vs 16	7 vs 8	18 vs 15	
TXA vs Placebo		(P=0.37)	(P=0.19)	OR = 0.82 (0.28-2.37)	OR = 1.61 (0.65-3.98)	
Functional outcomes at 90 days (mRS 0-3) (%)
(TXA vs Placebo)	NS	45 vs 46
OR = 0.88 (0.76-1.03)	56 vs 46
(P=0.31)	55.7 vs 54	30 vs 32
0.77 (0.38-1.56)	
Comments	Glasgow Outcome Score on discharge were 4.4 in TXA group vs 3.6 placebo group	• Fewer deaths by Day 7 in TXA group (9%) vs placebo (11%)
• Most patients recruited beyond 3 hours of presentation	• Both groups showed same incidence of ICH growth being 1.2 ml	• Overall 30% patients showed a hematoma growth more than 6 ml.
• Participants treated before 4.5 hours showed a favorable treatment effect	Baseline ICH volumes were too low and increase in hematoma growth was small to show a treatment effect.	
All data are n (%), median (IQR) or mean (SD). MD=mean difference. CT=computed tomography, GCS=Glasgow Coma Scale, ICH=intracerebral hemorrhage, IQR=interquartile range, mRS=modified Rankin Scale, NIHSS=National Institutes of Health Stroke Scale, OR=odds ratio, SBP=systolic blood pressure, SD=standard deviation, TXA=tranexamic acid, HV=hematoma volume

TICH-2 (TXA for hyperacute primary ICH)[23] – TICH-2 is the largest multicentric study till date to study the effect of TXA in patients with spontaneous ICH (sICH) who presented within 8 h of symptom onset. This double-blinded, placebo-controlled Phase 3 trial recruited 2325 adult patients and noted small changes in hematoma volume from baseline to 24 h with TXA compared to placebo (3.72 ml in the TXA group vs. 4.90 ml in the placebo group; mean difference –1.37, [95% CI, -2.71 to -0.04], P = 0.0432). The incidence of HE was lower in the TXA group (25%) versus placebo group (29%).

TXA group showed a lower mortality by day 7 (adjusted odds ratio [OR] = 0.73 [95% CI, 0.53–0.99], P = 0.041) with fewer serious adverse events (SAEs) at 90 days (521 [45%] vs. 556 [48%], P = 0.039). Moreover, in a post hoc analysis, participants with hematoma volume between 30 and 60 ml had better neurologic outcomes in the TXA group (OR = 0.66, 95% CI, 0.44–0.98).

In a secondary analysis of the TICH-2 trial,[24] patients with baseline SBP of lesser than 170 mmHg randomized to TXA group had less HE (3.3 ml vs. 5.1 ml; OR −1.99, 95% CI, − 3.90 to 0.08) and a trend toward lower deaths and dependency (cOR 0.73, 95% CI, 0.59–0.9) compared to the placebo group. This was despite patients being older, randomized beyond 3 h, and having larger baseline hematoma volumes.

Thus, the results from TICH-2 trial favored TXA and found it to be effective in restriction of HE with a reduction in its incidence. Despite these moderate effects, no improvement in the long-term functional outcomes was seen.

The beneficial effect of TXA was seen in subsets of population presenting within 4.5 h, with lower baseline SBP and moderate ICH volumes. These factors should be taken into consideration to define more selective inclusion criteria for designing future trials.

TRAIGE (TXA for Acute ICH Growth prEdicted by Spot Sign)[25] – This was a multicenter, Phase 2, randomized, double-blind, placebo-controlled trial, which recruited patients with a positive spot sign on CT angiography, treated within 8 h from onset. No significant difference was observed in the incidence of HE between the two groups (TXA 40.4% vs. placebo 41.5%; OR = 0.96, 95% CI, 0.52–1.77, P = 0.89) or in other secondary outcomes that were reported. However, no improvement in mortality or long-term functional outcomes was seen in the TXA group compared to the placebo group. A statistically insignificant lower 90-day mortality was seen with TXA when given within 4.5 h. The trial recruited 85% of the target sample size, and the analysis was thus underpowered.

STOP-AUST (Spot Sign and TXA on Preventing ICH Growth- AUStralasia study)[26] – This was a multicenter, randomized, Phase 2 trial, which compared outcomes with TXA or matching placebo in adult patients with sICH, who had CT angiography evidence of contrast extravasation (i.e., positive spot sign) when presented within 4.5 h of symptom onset. Forty-four percent of patients in the TXA group compared to 52% patients in the placebo group had hematoma growth (effect size 0.72; 95% CI, 0.32–1.59, P = 0.41). The median hematoma growth over 24 h from baseline was 1.9 ml in TXA versus 3.4 ml in placebo (P = 0.81). This trial did not observe positive effects due to the slow recruitment rate, smaller sample size, and median delay of 40 min from baseline scan to treatment.

Spot sign is a marker of active bleeding and predictor of HE (seen on CT angiography) in ICH. STOP-AUST and TRAIGE trials recruited patients based on the criteria of spot sign, but failed to provide evidence that TXA prevented HE.

Unavailability of advanced imaging techniques in resource-limited settings and unfamiliarity with the protocols and techniques of CT angiography make its use challenging in an acute trial setting. Refusal of consent, preexisting renal disease, and contrast allergy may preclude CT angiography in clinical setting. Therefore, using early markers of active bleeding on noncontrast CT, such as black hole and blend sign, may be a justifiable criteria to identify patients with active bleeding who can benefit from early TXA therapy.[26]

STOP-MSU[27] (TXA vs. placebo in individuals with ICH treated within 2 h of symptom onset) – This is a recently concluded Phase 2 trial in a mobile stroke unit that recruited participants aged more than 18 years with acute sICH and treated with TXA or placebo within 2 h of stroke onset. This study did not find a difference in reduction of hematoma growth with TXA. Patients had low baseline ICH volumes (11.1 in placebo vs. 9.5 ml in TXA), and an average 60% of the study participants did not show hematoma growth. Due to low ICH volumes, the risk of HE was low and may have diluted any potential treatment effect of TXA.

In a prediction model study, larger ICH volumes (more than 60 ml) were associated with odds of hematoma growth (adjusted odds ratio [aOR] 2.10, 95% CI, 1.25–3.55).[28] Therefore, the beneficial effects of TXA in small ICH are uncertain.

TRIALS THAT HAVE SHOWN BENEFIT IN ICH TREATMENT

INTERACT-3[29] (The third Intensive Care Bundle with BP Reduction in Acute Cerebral Haemorrhage Trial) – This trial showed that following a protocoled, bundled approach including early lowering of SBP to 130–140 mm Hg, glycemic control, fever management, and reversal of coagulation in patients with sICH is associated with improved functional outcomes at 6 months.

In a post hoc exploratory analysis of ATTACH-2,[30] one-third of the trial population was targeted to be treated within 2 h of symptom onset with nicardipine and showed a significantly lower frequency of hematoma growth compared to the standard group (18.2% vs. 28.4%, P = 0.02).

In TICH-2, patients with 5% or more increase in SBP from baseline to day 2 and randomized to the placebo group were associated with increased SAEs at days 7 and 90.[24]

Thus, focusing on an ultra-early time window for reduction of BP combined with administration of TXA can be a novel therapeutic strategy in treatment of ICH.

ENRICH (Early miNimally invasive Removal of ICH) trial[31] – This is an innovative, adaptive trial design that demonstrated the benefit of minimally invasive parafascicular surgery (MIPS) for supratentorial ICH. Adult patients who presented with acute ICH with a volume of 30–80 ml within 24 h of symptom onset were treated with MIPS. The reduction in hemorrhagic volume was 43.9 ml in the surgical group versus 3.6 ml in the medical management group (P = 0.001). The mean time to surgery from symptom onset was 16.6 h. Moreover, 68% patients who were recruited had lobar hemorrhage. MIPS was associated with improved 30-day all-cause mortality (9.3%) versus medical management (18.1%) and with a shorter intensive care unit and hospital stay. Thus, the trial showed MIPS to be a safe procedure resulting in substantial reduction in clot burden with improved functional outcomes at 6 months. The caveat is that the surgical advantage demonstrated in the trial was limited to minimally invasive surgery for lobar hemorrhages. The trial did not compare MIPS to conventional craniotomy.

Nonetheless, combining early surgical clot evacuation with medical management can be a novel approach to manage ICH patients with better long-term favorable outcomes.

Deriving evidence from CRASH trials, which proved the efficacy of TXA in restricting HE, has been extrapolated in treatment of ICH. Several randomized controlled trials (RCTs) have evaluated the efficacy and safety of TXA in acute sICH in recent years. The trials have lacked consistency in methodology, differing in techniques to detect HE and in dosage and timing of administration of TXA. However, the existing RCTs and published systematic reviews have reported inconsistent and divergent results. Some studies have shown a benefit in restricting HE with lower early mortality, but failed to show improvement in functional outcome. The neutral results could be due to firstly, inclusion of patients who are at lower risk of hematoma growth with low baseline ICH volumes in which the therapeutic benefit is not significant; secondly, delayed initiation of treatment when the hematoma growth has completed and when probably surgical evacuation will be more beneficial; and thirdly, higher BPs during the study period and perilesional hematoma spread contributing to secondary brain injuries mitigating the beneficial effect of early hemostatic therapies. Thus, future trials should be designed to include patients for whom the therapy will be most effective.

To prove that TXA can be beneficial, inclusion criteria should include patients with evidence of active bleeding. In the recently concluded ANNEXA-4 study,[32] patients presenting with a lower Glasgow Coma Scale score at admission, shorter time to CT scans, higher SBP (mean 150 mmHg [standard deviation 24.1 mmHg]), multicompartment hemorrhage, and higher mean ICH volumes (29.3 ml) were associated with higher risk of HE. Male preponderance, low fibrinogen levels reflecting impaired hemostasis, and presence of active bleeding as evidenced by black hole and blend sign on noncontrast CT have shown association with increased risk of HE. Primary neuroimaging endpoints like ultra-early HE (i.e., baseline ICH volume divided by onset-to-CT time), spot sign, and high burden of intraventricular hemorrhage are useful metrics that should be assessed in clinical trials.[6]

Data from trials have shown that with active rehabilitation, the path to recovery in ICH patients is longer, but comparable to those with ischemic stroke.[33] Study investigators should factor in that measuring the functional outcome early (90 or 180 days) may not depict positive significant effects of the intervention for ICH. Therefore, primary end points used in ICH trial should consider early mortality outcome (day 7 or 30) and delayed functional outcomes (9–12 months).

Adaptive trial designs that allow for enrichment and modificication of the eligibilty criteria during the trial, based on pre-specified rules and information from accumulating data during the trial, have the potential to decide more effectively the subgroup of ICH patients who can benefit from TXA.[12]

ONGOING CLINICAL TRIALS [TABLE 2]

TICH-3 trial[34] – This is a large Phase 3 trial which will recruit 5500 participants presenting within 4·5 h of symptom onset to receive TXA or placebo. This study is being conducted by the TICH investigators, with a primary endpoint of mortality at 7 days based on the reduced early mortality observed in TICH-2 in the TXA group.

Table 2 Ongoing trials for Tranexamic acid in spontaneous ICH

Trial	INTRINSIC	TICH 3	
Start date	August 2022	January 2022	
Number recruited/target	1317/3400	710/5500	
TXA dose	2 grams over 45 minutes in 100 ml 0.9% saline.	1 gram loading dose given as 100 ml 0,9% saline infusion over 10 minutes, followed by 1 gram in 250 ms infused over 8 hours.	
Patient characteristics	
Age	≥18 years	≥18 years	
Premorbid mRS	<4	N/A	
GCS	>5	>5	
Time (hours)	4.5 hours of symptom onset	4.5 hours of symptom onset	
Haematoma location	None	None	
ICH volume	≥60 ml	≥60 ml	
Planned surgery within 24 hours	Will be included	NS	
Outcome	
Primary outocme	Death at Day 7	Death at Day 7	
Secondary outcome	1. Assess change in hematoma volume from baseline to the 24-hour scan
2. Measuring neurological impairment with the NIHSS at day 7 or upon discharge
3. Determining dependency levels with the seven-level mRS at day 90 and evaluating quality of life with the EQ-5D at day 90.	1. Assess the effect of TXA on dependency 6 months after ICH.
2. Death at day 2	
Funding	Indian Council of Medical Research	National Institute for Health and Care Research - Health Technology Assessment	
GCS=Glasgow Coma Scale, ICH=intracerebral hemorrhage, mRS=modified Rankin Scale, NIHSS=National Institutes of Health Stroke Scale, TXA=tranexamic acid, EQ-5D=EuroQol 5 dimension

INTRINSIC trial (Indian Trial of TXA in Spontaneous Intracerebral Haemorrhage)[35] (NCT05836831) is an ongoing multicenter, randomized, open-label, clinical trial which will include adult patients aged more than 18 years presenting with nontraumatic ICH within 4.5 h of symptom onset or when last seen well. The study participants will receive 2 g of TXA administered within 45 min, and control participants will receive standard of care. Intensive BP reduction as per the INTERACT 2 protocol[13] will be done in both groups. A total of 3400 patients will be recruited in the trial to study the effect of TXA on reduction in HE. The primary end points are similar to those of TICH-3 trial, including deaths at day 7 and dependency at day 90 compared to the nonintervention group.

CONCLUSIONS

The clinical trials have shown that the effect of TXA in ICH significantly reduces the expansion of hematoma growth in the brain, although no significant effect was detected on the recovery of neurologic function or long-term mortality. The reduction of hematoma growth with effective control of BP in the early phase of ICH is also associated with favorable outcomes, without which the resultant mechanical compression, increased inflammation, and cytotoxicity further increase secondary brain injury. Future trials should include patients who are likely to benefit from future trials should consider in their eligibilty criteria : ultra-early treatment window (witin 4.5 hours), moderate heamtoma volume at baseline (30-60ml), treayment with combiantion of tranexamic acid and tight BP control. Patients with very high ICH volumes (more than 60 ml), very low ICH volumes, large intraventricular extension, and in the older age group (>80 years) should be excluded from clinical trials.

A multimodality approach with timely hemostatic therapy, early surgical clot evacuation, and effective BP control to lessen secondary brain injury are potential methods to manage ICH.

INTRINSIC and TICH-3 are the two ongoing trials with similar inclusion criteria and will be able to elucidate and confirm parts of these hypotheses.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.
==== Refs
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