Study Selection and Characteristics
We found a total of 1704 results, and 1307 records remained after the removal of duplicates. 1285 records were excluded after screening the title/abstracts. After assessing 22 full-text for eligibility, we excluded 15 because 1) do not contain outcome of interest (n=1), 2) specific on subdural and epidural hematoma (n=1), 3) observational studies (n=2), 4) in general trauma patients (n=1), 5.) unspecified location of injury (n=1), 6) study protocol (n=4), 7) analysis derived from an already included CRASH-3/CRASH-2 Trials (n=3), 8) animal study (n=1), 9) compliance of TXA use (observational) (n=1). We included 7 studies in qualitative synthesis and 6 in meta-analysis. (Figure 1) There were a total of 30.522 patients from 7 studies.9–15 The TXA protocol was mostly 1 g TXA infused over 10 minutes, followed by IV infusion of 1 g over 8 h. There was 1 study that gave bolus initially and another study that gave initial dose over 30 minutes. Matching placebo was specified in four studies, excluding Chakroun-Walha et al. and Jokar et al. Patients were around 30-40 years old and predominantly male. Time from injury to enrolment differs across studies. [Table 1]
Efficacy
Meta-analysis showed that TXA was associated with reduced mortality (RR 0.92 [0.88, 0.97], p=0.002; I2: 0%, p=0.70) [Figure 2A]. The rate of hemorrhagic expansion was lower in TXA group (RR 0.79 [0.64, 0.97], p=0.03; I2: 0%, p=0.83) [Figure 2B]. Both TXA and control group has a similar need for neurosurgical intervention (RR 0.99 [0.92, 1.07], p=0.87; I2: 0%, p=0.43). The unfavourable GOS on follow-up was similar in both groups (RR 0.93 [0.72, 1.21], p=0.59; I2: 20%, p=0.29).
Complications
The rate for vascular occlusive events were similar in both TXA and placebo groups (RR 0.85 [0.71, 1.02], p=0.09; I2: 21%, p= 0.22) [Figure 2C]. The risk for DVT subgroup (RR 0.82 [0.60, 1.13], p=0.23; I2: 0%, p=0.45), PE subgroup (RR 1.00 [0.60, 1.66], p=1; I2: 51%, p=0.11), stroke subgroup (RR 0.83 [0.54, 1.27], p=0.38; I2: 41%, p=0.16), and MI subgroup (RR 0.75 [0.50, 1.11], p=0.15; I2: 11%, p=0.32) were similar in both TXA and placebo group.
Risk of Bias Assessment
Risk of bias assessment using the Cochrane risk-of-bias tool for randomized trials showed two trial (Chakroun-Walha et al. and Jokar et al.) has a high risk of bias [Figure 3A]. The remaining 5 trials have a low risk of bias. The funnel-plot analysis showed a relatively symmetrical shape for mortality [Figure 3B] and symmetrical shape for hemorrhagic expansion [Figure 3C]. Regression-based Harbord’s test for small-study effects was not statistically significant for all outcomes [Table 2].
Subgroup Analysis for Randomized Controlled Trials with Low Risk of Bias
In this subgroup analysis, Chakroun-Walha et al. and Jokar et al. were excluded due to high risk of bias. Meta-analysis showed that TXA was associated with reduced mortality (RR 0.92 [0.87, 0.97], p=0.001; I2: 0%, p=0.80) [Figure 4A]. The rate of hemorrhagic expansion was lower in TXA group (RR 0.79 [0.64, 0.97], p=0.03; I2: 0%, p=0.83) [Figure 4B]. Both TXA and control group has a similar need for neurosurgical intervention (RR 0.99 [0.89, 1.12], p=0.93; I2: 5%, p=0.37). The unfavourable Glasgow outcome scale on follow-up was similar in both groups (RR 0.93 [0.72, 1.21], p=0.59; I2: 20%, p=0.29). The rate for vascular occlusive events were lower in TXA group (RR 0.85 [0.73, 0.99], p=0.04; I2: 4%, p= 0.40) [Figure 4C]. The risk for DVT subgroup (RR 0.79 [0.53, 1.19], p=0.26; I2: 25%, p=0.27), PE subgroup (RR 0.91 [0.70, 1.20], p=0.52; I2: 0%, p=0.51), stroke subgroup (RR 0.83 [0.54, 1.27], p=0.38; I2: 41%, p=0.16), and MI subgroup (RR 0.75 [0.50, 1.11], p=0.15; I2: 11%, p=0.32) were similar in both TXA and placebo group.
GRADE Approach
Grading of Recommendations Assessment, Development, and Evaluation (GRADE) were performed for the RCT with low risk of bias subgroup, it showed a high certainty of the evidence for lower mortality, less hemorrhage expansion, and a similar need for neurosurgical intervention in TXA group compared to the placebo group. The certainty of evidence was moderate for the similar unfavorable GOS, less vascular occlusive events, a similar rate of DVT, and a similar rate of MI in the TXA group compared to the placebo group. (Table 3)