Our study provides a comprehensive description of the efficacy and safety of TXA in the treatment of patients with aneurysmal SAH. Although previous studies have also focused on this topic, the largest randomized controlled trials and the ULTRA trials were not included. Our results indicate that TXA may have an important influence on rebleeding in patients with aneurysmal SAH, but the effect on good clinical outcomes and mortality is uncertain. The prevalence rates of adverse events among aneurysmal SAH patients showed a significant difference, except for TC. TXA treatment has shown a tendency to raise the risk of adverse events, including hydrocephalus, DCI, seizure in the aneurysmal SAH population. Overall, our study may help acquaint the safety and efficacy of TXA on aneurysmal SAH.
Rebleeding is one of the leading death factors for intracranial aneurysms patients, with an incidence of 10–22%; the onset would appear in the first 24 h with a peak reaching after the first 3–6 h of the occurrence [17, 18]. Many RCTs have shown that TXA treatment could considerably decrease the risk of recurrent hemorrhage [11–13, 15, 16], and the curative effect is closely related to its pharmacological action [19, 20]. Generally, TXA could exert function through the inhibition of fibrinogenase activity [21, 22]. Nevertheless, in the recent publication of the ULTRA, the occurrence of recurrent hemorrhage after randomization and before aneurysm treatment in the TXA and control group did not show any statistical difference, perhaps because half of the rebleeding occurred within 3 hours. In this trial, the median interval from the occurrence of symptoms to treatment was 3 hours, a considerable proportion of rebleeds had occurred. It also might attribute to the timing of treatment to aneurysm, which was suggested to be within 24 hours, as early as possible . The average time from the diagnosis of the aneurysm to treatment in this trial was 14 hours. This early aneurysm treatment may be more critical than TXA in reducing rebleeding compared to previous trials.
The efficacy of TXA in reducing rebleeding has been proven, and studies also reported that TXA might have anti-inflammatory and healing effects [24, 25]. Numerous studies have shown that TAX could reduce pathological injury in traumatic brain injury by modulating the immune environment in vivo. A recent study in a mouse model of cerebral hemorrhage found that immediate administration of high doses (100 mg/kg) of TXA suppressed the inflammatory response to Th1 in severely shocked mice, as evidenced by significant reductions in interleukin-6 and tumor necrosis factor-α levels . It has also been reported that TXA reduced TNF-α levels and reduced damage and inflammatory responses in the small intestine and lung tissue . It is known that IL-6 and TNF-α are essential mediators involved in infectious diseases, so TXA may play an anti-inflammatory role and thus regulate the body's immune response. Theoretically, these polytropic effects might lead to good clinical outcomes, but they did not. Researchers observed decreased rebleeding in SAH patients with TXA treatment [6, 14, 18]. Conversely, the combination with chlorpromazine or using higher doses can lead to worse outcomes [16, 27]. In the ULTRA trial, although TXA was associated with a decrease in the incidence of good clinical outcomes (mRS 0–2 at 6 months), it did not have a positive effect on good clinical outcomes (mRS 0–3 at 6 months). Fortunately, there was no difference in the all-cause death rate between the two groups, whether at 30 days or six months . In 2002, Hillman et al. found a significant decrease in rebleeding-related mortality with the subjects who received TXA treatment . Nonetheless, the mortality of TXA in aneurysmal SAH patients was controversial, with conflicting trial results [7, 12–16, 18]. Thus, we hypothesize that not-predefined adverse events, e.g., hydrocephalus or other complications, might have exerted influence on poor outcomes, either alone or in combination.
Whether the harm exceeds the potential benefits of TXA remains controversial [5, 6]. The evidence provided by Ross et al. showed that adverse outcomes caused by cerebral ischemia increased, which offset the benefits . An updated review showed that TXA should not be routinely used to treat aneurysmal SAH; even in patients who had concomitant treatment strategies to prevent DCI, there is insufficient evidence that TXA can reduce the risk of hydrocephalus or cerebral ischemia . Studies have suggested an increased rate of cerebral infarctions or cerebral ischemia with the use of TXA [28–31]. Therefore, the current European guideline reached no agreement on the usage of TXA with SAH patients .
In contrast, Thorkil et al. observed no difference in risk of ischemic lesions between TXA-treated nontraumatic SAH group and controls . American guidelines suggested a short-term (< 72 hours) use of TXA in aneurysmal SAH patients . However, the efficacy of reducing the risk of rebleeding was decreased [7, 14]. Hydrocephalus is a common adverse event after aneurysmal SAH [34, 35]. In cases of clinical deterioration because of acute hydrocephalus, ultra-early treatment might improve clinical symptoms but increase the risk of a poor prognosis[36, 37]. Mainly because the most common adverse event after ventricular drainage was rebleeding [38, 39]. In our meta-analysis, the confidence intervals of hydrocephalus indicate that TXA exerts potential harm on aneurysmal SAH patients.
Contrary to other RCTs [40–43], Chakroun et al. demonstrated an increased incidence of pulmonary embolism with the use of TXA in subjects with traumatic brain injury . Another retrospective research of 687 wounded soldiers showed that TXA did increase the risk of venous thrombosis . In contrast, a meta-analysis of 30,522 patients in 7 clinical RCTs showed that, despite no statistical difference, the incidence of vascular occlusion appeared lower with the TXA-treated group when compared with the control group . Shoji et al. confirmed that although TC such as deep vein thrombosis and pulmonary embolism might occur, the probability was relatively low . Our study also did not show any significant differences in the incidence of TC between the two groups.
The irritative effect of cisternal blood was one of the leading causes of seizures for subarachnoid hemorrhage patients; rebleeding was also associated with epileptic seizures [48, 49]. However, the mechanism between TXA and epileptic seizures is still not precise; some studies have suggested that it might be the direct effect of TXA on the central nervous system; for example, TXA injected into the cisterna magna or applied to the cortex could cause grand mal epilepsy [49–51]. It also suggested that TXA could enhance the excitability of the central nervous system by inhibiting Gamma-aminobutyric acid A receptors . Another study found that TXA was related to a 4.1-fold increase in epileptic seizure risk in adult cardiac surgery patients compared to controls . Susan et al. reported in 2020 that 2 g TXA increased the risk of epilepsy by 2.5 times compared with the control group; in subjects with moderate to severe traumatic brain injury but without parenchymal bleeding, the risk of epilepsy increased by three times. However, there was no statistical difference . Only one study reported the incidence of epilepsy; the study showed a statistically significant difference in epilepsy . 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 comprehensively searched different databases to find likely trials; meanwhile, our study provides a comprehensive overview to figure out the efficacy and safety of TXA administration in aneurysmal SAH subjects. Second, through analyzing the data of all the included RCTs on rebleeding, good clinical outcomes, mortality, DCI, we further investigated whether the usage of TXA is related to increased incidences of seizures and hydrocephalus. Third, a sensitivity analysis was performed to carry out subgroup analysis for RCTs.
Our study also has some limitations. Due to the length of TXA treatment, the intervention dose, the time from the onset of symptoms to treatment and the severity of the disease, our extensive inclusion criteria have led to population heterogeneity, which may lead to potential deviations in the evaluation of efficacy and safety of TXA. Coupled with the overrepresentation of the ULTRA trial study population as it represents nearly one-third of the included population in our meta-analysis. Furthermore, different prognostic indicators were used (mRS, GOS), there was relative uncertainty regarding all the estimates.