Tranexamic Acid in Aneurysmal Subarachnoid Hemorrhage: A Meta-analysis of Randomized Controlled Trials


 BackgroundTranexamic acid, as a hemostatic drug, is widely used to treat or prevent excessive blood loss. The efficacy of tranexamic acid in promoting good clinical outcomes, reducing mortality, and the occurrence of adverse events during treatment of aneurysmal subarachnoid hemorrhage remains unclear.MethodsPubMed, Web of Science, Embase, and The Cochrane Library were searched for randomized-controlled trials (from1980 to 2021) following strict inclusion and exclusion criteria. We performed STATA 16.0 and RevMan 5.3 for statistical analysis. Fixed-effect model (M-H method) and effect size RR (95% CI) were used as a pooled measure to combine the heterogeneous data. We also performed post hoc sensitivity analyses and conducted subgroup analyses to evaluate each outcome with low heterogeneity results.ResultsMeta-analysis showed that tranexamic acid was associated with reduced rebleeding(RR 0.72 [0.59, 0.87], p= 0.0008; I2:0%, p = 0.51). Tranexamic acid probably has no effect on good clinical outcome or mortality (RR 0.98 [0.92,1.04], p = 0.51; I2: 0%, p = 0.60; RR 1.01 [0.88,1.15], p=0.91; I2:0%, p = 0.51).TXA was associated with increased hydrocephalus (RR 1.13 [1.02, 1.24], p = 0.02; I2:0%, p = 0.61), DCI (RR 1.70 [1.34, 2.16], p < 0.0001; I2: 0%, p= 0.84) and seizure (RR 1.46 [1.00, 2.14], p= 0.05),The rate for thromboembolic complications were similar in both groups(RR 0.91 [0.63, 1.31], p = 0.62;I2: 0%, p = 0.73). There was significant drug related overall adverse events (RR 1.21 [1.11, 1.32], p < 0.0001; I2: 29%, p = 0.14).Conclusions﻿In patients with aneurysmal subarachnoid hemorrhage, these findings indicate that it does not support the routine use of TXA.


Introduction
Aneurysmal subarachnoid hemorrhage(SAH) is a signi cant cause of mortality and disability worldwide, especially in the relatively young population. Over the past 30 years, the case fatality rate declined by 17%, and the incidence remained relatively stable at 9 cases per 100,000 patients per year [1]. Due to the acute onset, approximately 33% of patients died because they did not get to the hospital in time [2].
Rebleeding was closely related to the prognosis of patients with aneurysmal SAH. The earlier the rebleeding occurs, the worse the prognosis [3]. Of those who survive effective treatment, up to one in ve will experience rebleeding, reducing the survival rate by 50% [4]. Tranexamic acid (TXA) is a hemostatic drug with anti-brinolytic activity, usually used to prevent or treat ruptured aneurysm rebleeding. In 2003, a Cochrane Review demonstrated that TXA showed a bene cial effect on reducing rebleeding but failed to show good clinical outcomes, possibly because the bene t was offset by an increase in adverse events due to cerebral ischemia [5].TXA with concomitant treatment strategies to prevent cerebral ischemia also showed a bene cial effect on reducing rebleeding; nonetheless, the effect of tranexamic acid on good clinical outcomes remained unclear [6]. Recently, the ULTRA, a multicenter prospective, randomized, controlled, open-label trial with 955 participants from 8 treatment centers and 16 referring hospitals, assessed the effects of ultra-early tranexamic acid for aneurysmal SAH and showed a slight reduction in mortality but not in rebleeding after randomization and before aneurysm treatment as well as in the improvement of clinical outcome at 6 months [7]. Some comments suggest that it might be associated with increased incidence of hydrocephalus and epilepsy [8,9]. Aiming to emphasize relevant curative effects previously missed because of small samples and to better focus on adverse events during the disease treatment course, we conducted a meta-analysis to evaluate the e cacy and safety of tranexamic acid in the treatment of aneurysmal SAH.

Search strategy
We conducted a comprehensive search of PubMed, Web of Science, Embase, The Cochrane Library from January 01, 1980, until June 01, 2021, for RCTs investigating the role of TXA in patients with aneurysmal SAH. We performed the search strategy with the assistance of an expert medical librarian and included three search terms: "Tranexamic acid," "aneurysmal subarachnoid hemorrhage," and "Randomized Controlled Trials." Two researchers (H.D and T.L) independently performed an initial search; discrepancies were resolved by discussion (see supplementary appendix for search string).
A Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) owchart of the literature search and selection strategy of studies was presented in Fig. 1. The protocol for this systematic review was registered on PROSPERO (CRD42021251142)

Inclusion and exclusion criteria
The inclusion criteria for the systematic review and meta-analysis were as follows: (1) RCT, (2) included patients who were diagnosed with aneurysmal subarachnoid hemorrhage, (3) compared the e cacy of tranexamic acid and matching placebo, and (4) involved >25 patients,(5) the studies were published from January 1, 1980, to June 01, 2021.
The exclusion criteria were as follows: (1) studies that did not include relevant outcomes information such as mortality, good functional outcomes, or adverse events; (2) studies that were not placebocontrolled; (3) non-RCTs, such as cohort studies, reviews, or case reports.

Data extraction
According to the inclusion and exclusion criteria, Data extraction was performed by two independent authors (H.D and T.L) using standardized extraction form, which includes authors, year of publication, study design, intervention, length of TXA treatment, time from symptom onset to treatment, TXA patients/ placebo patients, key results, good clinical outcomes, rebleeding, mortality, hydrocephalus, delayed cerebral ischemia, thromboembolic complications, seizure.
The primary outcomes were good clinical outcomes, rebleeding, mortality. The mRS score was dichotomized into good clinical outcome (mRS score 0-3 [good recovery, no signi cant disability, slight disability, moderate disability]) or poor outcome ([mRS score 4-6 moderately severe disability, severe disability, or death]).
The secondary outcomes were adverse events de ned as hydrocephalus, delayed cerebral ischemia, thromboembolic complications, seizure. Thromboembolic complications include deep venous thrombosis and pulmonary embolism.

Statistical analysis
We used STATA 16.0 (StataCorp LP) and RevMan version 5.3 software (Cochrane Collaboration) to perform the meta-analysis. We used the xed-effect model (M-H method) and effect size RR (95% CI) as a pooled measure. Inconsistent index (I2) test, which ranges from 0 to 100%, was used for assessing homogeneity among the studies, and both P≥0.1 and I2≤50% were considered no heterogeneity among the studies. Two independent reviews adopted the Cochrane risk of bias tool to assess the risk of bias for RCTs [10]. Risk of bias tool refers: random sequence generation(A); allocation concealment(B); blinding of participants and personnel(C); blinding of outcome assessments(D); incomplete outcome data addressed(E); selective outcome reporting(F); other potential threats(G), respectively.
A small study effect was tested using a regression-based test (Harbord test) for binary outcomes.
Regression-based Egger's test was also performed for the risk of publication bias. We also performed post hoc sensitivity analyses and conducted subgroup analyses to evaluate each outcome with low heterogeneity results. All p values were two-tailed with a statistical signi cance at 0.05 or below.

Description of included studies
A total of 537 studies were identi ed by searching the database. After the deletion of duplicates, reviews, and irrelevant studies, 348 studies met the criteria. By evaluating titles and abstracts, 167 studies were excluded. After assessing 22 full-text for eligibility, we excluded 15 because 1)no control group(n=7), 2)case report, 3)non-RCT studies (n=7). Therefore, seven articles were included in the qualitative synthesis [7,[11][12][13][14][15][16]. A total of 2917 patients from 7 RCTs were randomly assigned to TXA treatment (n = 1403) or placebo (n = 1514) for meta-analysis. Each group included 29 to 480 patients. The largest RCT population was a multicenter study published in 2021 [7]. Three studies were open-label RCTs [7,11,16], while the remaining four were double-blind RCTs [12][13][14][15]. The subjects were all adults. Time from symptom onset to treatment varied among studies: within 72 hours in 4 trials [11,[13][14][15], within 96 hours in 1 trial [12], in the latest trial, TXA was given within 24 hours after symptom onset [7], and another was not reported [16]. The length of TXA treatment also varied, ranging from 24 hours to 6 weeks. Baseline characteristics of included trials are summarized in Table 1. Details of the risk of bias summary were presented in Fig. 2 and Fig. 3. Table 1 Characteristics of the included studies Subgroup analysis for randomized controlled trials with low heterogeneity In this pooled analysis with low heterogeneity, Part of the studies were excluded due to a higher heterogeneity. Meta-analysis showed that TXA was associated with decreased rebleeding (RR 0.72 [0.59, 0.87], p = 0.0008; I 2 : 0%, p = 0.51; Fig. 1A Fig. 2C).

Discussion
Our study provides a comprehensive overview to clarify the e cacy and safety of TXA administration compared to that of placebo in aneurysmal SAH patients. Although previous systematic reviews of TXA treatment in aneurysmal SAH patients have been published, however, in these meta-analyses, the largest randomized controlled trial, the ULTRA-trial, was not included in the literature search. Our results demonstrate that TXA probably has a signi cant effect on rebleeding and an uncertain effect on good clinical outcomes and mortality when administered to patients with aneurysmal SAH. The prevalence rates of adverse events among aneurysmal SAH patients showed a signi cant difference, except thromboembolic complications. TXA treatment demonstrated a tendency to increase the risk of adverse events such as hydrocephalus, DCI, seizure in the aneurysmal SAH population. Overall, our study might help acquaint the e cacy and safety of TXA on aneurysmal SAH.
Rebleeding is the leading cause of death for intracranial aneurysms patients, with an incidence of 10-22%; the onset appeared in the rst 24 h, peaking in the rst 3-6 h after the event [17,18]. Many RCTs have shown that TXA treatment could considerably reduce the risk of rebleeding [11-13, 15, 16], the curative effect is closely related to its pharmacological action [19,20]. TXA can inhibit brinolysis by replacing plasminogen from brin and also inhibits enzymatic degradation by plasmin [21,22]. Nevertheless, in the recent publication of the ULTRA, rebleeding after randomization and before aneurysm treatment occurred in the tranexamic acid and control group did not reach the prede ned threshold for statistical signi cance, perhaps because half of the rebleeding occurred within 3 hours, in this trial, the median interval time from symptomatic onset to treatment was 3 hours, a considerable proportion of rebleeds had occurred. Another factor may be that the usual practice is to eliminate the aneurysm as early as possible, preferably within 24 hours [23]. The average time from diagnosis to treatment of the aneurysm in this trial was 14 hours. This early aneurysm treatment may be more critical than TXA in reducing rebleeding compared to previous trials.
The e cacy of TXA in reducing rebleeding has been proven, and studies also reported that TXA might have anti-in ammatory and healing effects [24,25]. Theoretically, these polytropic effects might lead to good clinical outcomes, but they do not. Although previous trials investigating long-term (throughout the hospital admission) or short-term TXA treatment in patients with SAH showed a reduction in rebleeding, they failed to show a bene cial effect on clinical outcome [6,14,18]. Conversely, the combination with chlorpromazine or using higher doses can lead to worse outcomes [16,26]. In the ULTRA trial, TXA was associated with a lower rate of excellent clinical outcome (mRS 0-2 at 6 months), although it did not positively affect good clinical outcomes (mRS 0-3 at 6 months). Fortunately, there was no difference in all-cause mortality at 30 days and 6 months between the two groups [7]. In 2002, Hillman et al. showed a signi cant reduction in mortality rate due to rebleeding by 80% upon TXA treatment [11]. Nonetheless, the mortality of TXA in patients with aneurysmal SAH is controversial, with con icting trial results [7,[12][13][14][15][16]18]. Thus, we hypothesize that not-prede ned adverse events, e.g., hydrocephalus or other complications, might have played a role in contributing to poor outcomes, either alone or in combination.
Whether the harm might outweigh the potential bene ts of TXA remains controversial [5,6]. Roos et al. presented evidence that clinical outcome was offset by an increase in poor outcomes caused by cerebral ischemia [5]. An updated review showed that TXA should not be routinely used to treat aneurysmal SAH, even in patients who had concomitant treatment strategy to prevent DCI, and no su cient evidence concluded that TXA reduced the risk of either cerebral ischemia or hydrocephalus [6]. Studies have suggested an increased cerebral ischemia rate or cerebral infarctions when using TXA [27][28][29][30]. Therefore, the current European guideline reached no international consensus on the use of TXA following SAH [31].
In contrast, comparing TXA-treated nontraumatic SAH patients with controls, Thorkil et al. demonstrated no substantial indication of increased risk of ischemic lesions [32]. American guidelines found it reasonable to use a short-term(<72 hours) TXA in aneurysmal SAH patients [23]. However, the e cacy of reducing the risk of rebleeding was reduced [7,14]. Hydrocephalus is a common adverse event after aneurysmal SAH [33,34]. In cases of clinical deterioration because of acute hydrocephalus, ultra-early treatment might improve clinical symptoms but increase the risk of a poor prognosis [35,36]. Mainly because the most frequent adverse events after ventricular drainage were rebleeding [37,38]. In our metaanalysis, the con dence intervals of hydrocephalus indicate that TXA exerts potential harm on aneurysmal SAH patients.
Contrary to other RCTs [39][40][41][42], Chakroun et al. demonstrated that TXA increased the incidence of pulmonary embolism in patients with traumatic brain injury [43]. Another retrospective study of 687 wounded soldiers showed that TXA did increase the risk of venous thrombosis [44]. In contrast, a metaanalysis of 30,522 patients in 7 clinical RCTs showed that, despite no statistical difference, the incidence of vascular occlusion in the TXA group was lower than that in the control group [45]. Shoji et al. con rmed that although thromboembolic complications such as pulmonary embolism and deep vein thrombosis may occur, the probability is relatively low [46]. Our study also found no difference in the incidence of Thromboembolic complications between the two groups.
During the rst few days following subarachnoid hemorrhage, cisternal blood may have an irritative effect on the cerebral cortex, leading to a seizure; rebleeding was also associated with epileptic seizures [47,48]. However, the mechanism between TXA and epileptic seizures is still not precise; some studies suggested that it might be the direct effect of TXA on the central nervous system; for example, TXA applied to the cortex or injected into the cisterna magna could cause grand mal epilepsy [48][49][50]. It also suggested that TXA increases the excitability of the central nervous system by inhibiting Gammaaminobutyric acid A receptors [51]. Hisato et al. found that TXA was associated with a 4.1-fold increase in epileptic seizure risk in adult cardiac surgery patients compared to controls [52]. Susan et al. reported in 2020 that 2gTXA increased the risk of epilepsy in patients with moderate to severe TBI by 2.5 times compared with the control group; in patients with moderate to severe traumatic brain injury without parenchymal bleeding, the risk of epilepsy increased by 3 times. However, there was no statistical difference [53]. Only one study reported the incidence of epilepsy; the study showed a statistically signi cant difference in epilepsy [7]. Therefore, when TXA is applied, the occurrence of epilepsy should be vigilant, and the electroencephalogram should be perfected if necessary.
This meta-analysis has some strengths. First, we implemented comprehensive search strategies in different databases; meanwhile, our study provides a comprehensive overview to clarify the e cacy and safety of TXA administration in aneurysmal SAH patients. Second, in summarizing all of the published data on rebleeding, good clinical outcomes, mortality, delayed cerebral ischemia, we further investigated whether TXA use is associated with increased incidences of hydrocephalus and seizures. Third, we conducted a sensitivity analysis to carry out subgroup analysis for RCTs, strengthening our metaanalysis.
This study also has several limitations. First, our broad inclusion criteria led to a heterogeneous population with a range of reasons for the length of TXA treatment, Intervention dose, time from symptom onset to treatment, and disease severities, which might lead to potential bias when evaluating the e cacy and safety of TXA. Second, the ULTRA trial study population represents nearly a third of the included population in our meta-analysis, which can be considered an overrepresentation. Third, different prognostic indicators were used (mRS, GOS), there was relative uncertainty regarding all the estimates. Finally, the inherent limitations of meta-analysis, such as publication bias, cannot be ignored.

Conclusion
This meta-analysis of 7 RCTs demonstrates that TXA can reduce rebleeding but a similar effect on good clinical outcomes and mortality in aneurysmal SAH patients. Meanwhile, this treatment conveys an increased risk of hydrocephalus, delayed cerebral ischemia, and seizure, which limits the value of its clinical application, but the incidence of thromboembolic complications was similar in both TXA and placebo groups. These ndings indicate that it does not support the routine use of TXA in the patients with aneurysmal SAH.  Literature search and study selection strategy.

Figure 2
Forest plot comparing the rebleeding(A), good clinical outcomes( B), and all-cause mortality (C) between the TXA and placebo groups.