OBJECTIVE: The objective of this study is to determine the efficacy of high-dose versus low-dose tranexamic acid (TXA) in adolescent idiopathic scoliosis (AIS) corrective surgery.

SUMMARY OF BACKGROUND DATA: Corrective surgery for AIS is associated with significant blood loss. Evidence on the optimum TXA dose to reduce bleeding in pediatric population is scarce.

METHODS: A total of 166 AIS patients aged between 10 and 21 years, of American Society of Anesthesiologists (ASA) physical status I and II, preoperative hemoglobin >10 g/dL, platelet count >150,000 cells/L and Cobb angle of >45° scheduled for elective single-stage posterior spinal fusion (PSF) surgery by two attending surgeons were included between March 2017 and November 2018. Patients were randomized into Group A (High Dose, 30 mg/kg TXA loading dose followed by 10 mg/kg/h infusion) and Group B (Low Dose, 10 mg/kg TXA loading dose followed by 1 mg/kg/h infusion). The primary outcome was total surgical blood loss between both groups. Secondary outcomes were transfusion requirement, perioperative changes in hemoglobin and coagulation profiles, adverse events, and factors that influence total blood loss.

RESULTS: The mean total surgical blood loss between the two groups was not significant (Group A: 928.8 ± 406.1 mL [range: 348-1857 mL]; Group B: 918.1 ± 406.2 mL [range: 271-2000 mL], P = 0.865). The median duration of surgery was 120 minutes. One patient in each group received allogenic blood transfusion during the perioperative period. There were no significant changes in hemoglobin and coagulation profile at pre-operation, post-operation 0 hour and 48 hours. Sex, number of vertebral levels fused, and duration of surgery were independently associated with total surgical blood loss. No adverse events were observed perioperatively.

METHODS AND DESIGN: TICH-2 is a pragmatic, phase III, prospective, double-blind, randomised placebo-controlled trial. Two thousand adult (aged ≥ 18 years) patients with an acute SICH, within 8 h of stroke onset, will be randomised to receive TXA or the placebo control. The primary outcome is ordinal shift of modified Rankin Scale score at day 90. Analyses will be performed using intention-to-treat.

RESULTS: This paper and its attached appendices describe the statistical analysis plan (SAP) for the trial and were developed and published prior to database lock and unblinding to treatment allocation. The SAP includes details of analyses to be undertaken and unpopulated tables which will be reported in the primary and key secondary publications. The database will be locked in early 2018, ready for publication of the results later in the same year.

DISCUSSION: The SAP details the analyses that will be done to avoid bias arising from prior knowledge of the study findings. The trial will determine whether TXA can improve outcome after SICH, which currently has no definitive therapy.

Method: We searched MEDLINE, EMBASE, CENTRAL and clinical trial registers for studies using search strategies incorporating the terms 'intracerebral haemorrhage', 'tranexamic acid' and 'antifibrinolytic'. Authors of ongoing clinical trials were contacted for further details.

Findings: We screened 268 publications and retrieved 17 articles after screening. Unpublished information from three ongoing clinical trials was obtained. We found five completed studies. Of these, two randomised controlled trials (RCTs) comparing intravenous tranexamic acid to placebo (n = 54) reported no significant difference in death or dependency. Three observational studies (n = 281) suggested less haematoma growth with rapid tranexamic acid infusion. There are six ongoing RCTs (n = 3089) with different clinical exclusions, imaging selection criteria (spot sign and haematoma volume), time window for recruitment and dosing of tranexamic acid.

Discussion: Despite their heterogeneity, the ongoing trials will provide key evidence on the effects of tranexamic acid on ICH. There are uncertainties of whether patients with negative spot sign, large haematoma, intraventricular haemorrhage, or poor Glasgow Coma Scale should be recruited. The time window for optimal effect of haemostatic therapy in ICH is yet to be established.

METHODS: The CRASH-3 trial randomised 9202 patients within 3 h of injury with a GCS score ≤ 12 or intracranial bleeding on CT scan and no significant extracranial bleeding to receive TXA or placebo. We conducted an exploratory analysis of the effects of TXA on all-cause mortality within 24 h of injury and within 28 days, excluding patients with a GCS score of 3 or bilateral unreactive pupils, stratified by severity and country income. We pool data from the CRASH-2 and CRASH-3 trials in a one-step fixed effects individual patient data meta-analysis.

RESULTS: There were 7637 patients for analysis after excluding patients with a GCS score of 3 or bilateral unreactive pupils. Of 1112 deaths, 23.3% were within 24 h of injury (early deaths). The risk of early death was reduced with TXA (112 (2.9%) TXA group vs 147 (3.9%) placebo group; risk ratio [RR] RR 0.74, 95% CI 0.58-0.94). There was no evidence of heterogeneity by severity (p = 0.64) or country income (p = 0.68). The risk of death beyond 24 h of injury was similar in the TXA and placebo groups (432 (11.5%) TXA group vs 421 (11.7%) placebo group; RR 0.98, 95% CI 0.69-1.12). The risk of death at 28 days was 14.0% in the TXA group versus 15.1% in the placebo group (544 vs 568 events; RR 0.93, 95% CI 0.83-1.03). When the CRASH-2 and CRASH-3 trial data were pooled, TXA reduced early death (RR 0.78, 95% CI 0.70-0.87) and death within 28 days (RR 0.88, 95% CI 0.82-0.94).

CONCLUSIONS: Tranexamic acid reduces early deaths in non-moribund TBI patients regardless of TBI severity or country income. The effect of tranexamic acid in patients with isolated TBI is similar to that in polytrauma. Treatment is safe and even severely injured patients appear to benefit when treated soon after injury.

DESIGN: MRI substudy nested within the double-blind randomised controlled Tranexamic Acid for Hyperacute Primary Intracerebral Haemorrhage (TICH)-2 trial (ISRCTN93732214).

SETTING: International multicentre hospital-based study.

PARTICIPANTS: Eligible adults consented and randomised in the TICH-2 trial who were also able to undergo MRI scanning. To address the primary hypothesis, a sample size of n=280 will allow detection of a 10% relative increase in prevalence of diffusion-weighted imaging (DWI) hyperintense lesions in the TXA group with 5% significance, 80% power and 5% imaging data rejection.

INTERVENTIONS: TICH-2 MRI substudy participants will undergo MRI scanning using a standardised protocol at day ~5 and day ~90 after randomisation. Clinical assessments, randomisation to TXA or placebo and participant follow-up will be performed as per the TICH-2 trial protocol.

CONCLUSION: The TICH-2 MRI substudy will test whether TXA increases the incidence of new DWI-defined ischaemic lesions or reduces perihaematomal oedema or final ICH lesion volume in the context of SICH.

ETHICS AND DISSEMINATION: The TICH-2 trial obtained ethical approval from East Midlands - Nottingham 2 Research Ethics Committee (12/EM/0369) and an amendment to allow the TICH-2 MRI sub study was approved in April 2015 (amendment number SA02/15). All findings will be published in peer-reviewed journals. The primary outcome results will also be presented at a relevant scientific meeting.

DATA SOURCES: EMBASE, MEDLINE, CENTRAL, and ISI Web of Science were systematically searched from their inception until May 31, 2019.

REVIEW METHODS: Parallel-arm randomized controlled trials were included.

RESULTS: Seventy-one trials (7539 participants: orthopedics 5450 vs nonorthopedics 1909) were included for quantitative meta-analysis. In comparison to placebo, topical TXA significantly reduced intraoperative blood loss [mean difference (MD) -36.83 mL, 95% confidence interval (CI) -54.77 to -18.88, P < 0.001], total blood loss (MD -319.55 mL, 95% CI -387.42 to -251.69, P < 0.001), and incidence of blood transfusion [odds ratio (OR) 0.30, 95% CI 0.26-0.34, P < 0.001]. Patients who received topical TXA were associated with a shorter length of hospital stay (MD -0.28 days, 95% CI -0.47 to -0.08, P = 0.006). No adverse events associated with the use of topical TXA were observed, namely mortality (OR 0.78, 95% CI 0.45-1.36, P = 0.39), pulmonary embolism (OR 0.73, 95% CI 0.27-1.93, P = 0.52), deep vein thrombosis (OR 1.07, 95% CI 0.65-1.77, P = 0.79), myocardial infarction (OR 0.79, 95% CI 0.21-2.99, P = 0.73), and stroke (OR 0.85, 95% CI 0.28-2.57, P = 0.77). Of all included studies, the risk of bias assessment was "low" for 20 studies, "unclear" for 26 studies and "high" for 25 studies.

CONCLUSIONS: In the meta-analysis of 71 trials (7539 patients), topical TXA reduced the incidence of blood transfusion without any notable adverse events associated with TXA in adults undergoing surgery.

METHODS: This is a prospective substudy nested within the CRASH-3 trial, a randomised placebo-controlled trial of TXA (loading dose 1 g over 10 min, then 1 g infusion over 8 hours) in patients with isolated head injury. CRASH-3 trial patients were recruited between July 2012 and January 2019. Participants in the current substudy were a subset of trial patients enrolled at 10 hospitals in the UK and 4 in Malaysia, who had at least one CT head scan performed as part of the routine clinical practice within 28 days of randomisation. The primary outcome was the volume of intraparenchymal haemorrhage (ie, contusion) measured on a CT scan done after randomisation. Secondary outcomes were progressive intracranial haemorrhage (post-randomisation CT shows >25% of volume seen on pre-randomisation CT), new intracranial haemorrhage (any haemorrhage seen on post-randomisation CT but not on pre-randomisation CT), cerebral infarction (any infarction seen on any type of brain scan done post-randomisation, excluding infarction seen pre-randomisation) and intracranial haemorrhage volume (intraparenchymal + intraventricular + subdural + epidural) in those who underwent neurosurgical haemorrhage evacuation. We planned to conduct sensitivity analyses excluding patients who were severely injured at baseline. Dichotomous outcomes were analysed using relative risks (RR) or hazard ratios (HR), and continuous outcomes using a linear mixed model.

RESULTS: 1767 patients were included in this substudy. One-third of the patients had a baseline GCS (Glasgow Coma Score) of 3 (n=579) and 24% had unilateral or bilateral unreactive pupils. 46% of patients were scanned pre-randomisation and post-randomisation (n=812/1767), 19% were scanned only pre-randomisation (n=341/1767) and 35% were scanned only post-randomisation (n=614/1767). In all patients, there was no evidence that TXA prevents intraparenchymal haemorrhage expansion (estimate=1.09, 95% CI 0.81 to 1.45) or intracranial haemorrhage expansion in patients who underwent neurosurgical haemorrhage evacuation (n=363) (estimate=0.79, 95% CI 0.57 to 1.11). In patients scanned pre-randomisation and post-randomisation (n=812), there was no evidence that TXA reduces progressive haemorrhage (adjusted RR=0.91, 95% CI 0.74 to 1.13) and new haemorrhage (adjusted RR=0.85, 95% CI 0.72 to 1.01). When patients with unreactive pupils at baseline were excluded, there was evidence that TXA prevents new haemorrhage (adjusted RR=0.80, 95% CI 0.66 to 0.98). In patients scanned post-randomisation (n=1431), there was no evidence of an increase in infarction with TXA (adjusted HR=1.28, 95% CI 0.93 to 1.76). A larger proportion of patients without (vs with) a post-randomisation scan died from head injury (38% vs 19%: RR=1.97, 95% CI 1.66 to 2.34, p<0.0001).

CONCLUSION: TXA may prevent new haemorrhage in patients with reactive pupils at baseline. This is consistent with the results of the CRASH-3 trial which found that TXA reduced head injury death in patients with at least one reactive pupil at baseline. However, the large number of patients without post-randomisation scans and the possibility that the availability of scan data depends on whether a patient received TXA, challenges the validity of inferences made using routinely collected scan data. This study highlights the limitations of using routinely collected scan data to examine the effects of TBI treatments.

OBJECTIVE: The aim of the study was to assess if tranexamic acid is safe, reduces haematoma expansion and improves outcomes in adults with spontaneous intracerebral haemorrhage (ICH).

DESIGN: The TICH-2 (Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage) study was a pragmatic, Phase III, prospective, double-blind, randomised placebo-controlled trial.

SETTING: Acute stroke services at 124 hospitals in 12 countries (Denmark, Georgia, Hungary, Ireland, Italy, Malaysia, Poland, Spain, Sweden, Switzerland, Turkey and the UK).

PARTICIPANTS: Adult patients (aged ≥ 18 years) with ICH within 8 hours of onset.

EXCLUSION CRITERIA: Exclusion criteria were ICH secondary to anticoagulation, thrombolysis, trauma or a known underlying structural abnormality; patients for whom tranexamic acid was thought to be contraindicated; prestroke dependence (i.e. patients with a modified Rankin Scale [mRS] score > 4); life expectancy  4.5 hours after stroke onset. Pragmatic inclusion criteria led to a heterogeneous population of participants, some of whom had very large strokes. Although 12 countries enrolled participants, the majority (82.1%) were from the UK.

CONCLUSIONS: Tranexamic acid did not affect a patient's functional status at 90 days after ICH, despite there being significant modest reductions in early death (by 7 days), haematoma expansion and SAEs, which is consistent with an antifibrinolytic effect. Tranexamic acid was safe, with no increase in thromboembolic events.

FUTURE WORK: Future work should focus on enrolling and treating patients early after stroke and identify which participants are most likely to benefit from haemostatic therapy. Large randomised trials are needed.

TRIAL REGISTRATION: Current Controlled Trials ISRCTN93732214.

METHODS: TICH-2 trial (Tranexamic Acid for Hyperacute Primary Intracerebral Haemorrhage) was a randomized, placebo-controlled clinical trial recruiting acutely hospitalized participants with intracerebral hemorrhage within 8 hours after symptom onset. Local investigators randomized participants to 2 grams of intravenous tranexamic acid or matching placebo (1:1). All participants underwent computed tomography scan on admission and on day 2 (24±12 hours) after randomization. In this sub group analysis, we included all participants from the main trial population with imaging allowing adjudication of spot sign status.

RESULTS: Of the 2325 TICH-2 participants, 254 (10.9%) had imaging allowing for spot-sign adjudication. Of these participants, 64 (25.2%) were spot-sign positive. Median (interquartile range) time from symptom onset to administration of the intervention was 225.0 (169.0 to 310.0) minutes. The adjusted percent difference in absolute day-2 hematoma volume between participants allocated to tranexamic versus placebo was 3.7% (95% CI, -12.8% to 23.4%) for spot-sign positive and 1.7% (95% CI, -8.4% to 12.8%) for spot-sign negative participants (Pheterogenity=0.85). No difference was observed in significant hematoma progression (dichotomous composite outcome) between participants allocated to tranexamic versus placebo among spot-sign positive (odds ratio, 0.85 [95% CI, 0.29 to 2.46]) and negative (odds ratio, 0.77 [95% CI, 0.41 to 1.45]) participants (Pheterogenity=0.88).

METHODS: We did an international, randomised placebo-controlled trial in adults with intracerebral haemorrhage from acute stroke units at 124 hospital sites in 12 countries. Participants were randomly assigned (1:1) to receive 1 g intravenous tranexamic acid bolus followed by an 8 h infusion of 1 g tranexamic acid or a matching placebo, within 8 h of symptom onset. Randomisation was done centrally in real time via a secure website, with stratification by country and minimisation on key prognostic factors. Treatment allocation was concealed from patients, outcome assessors, and all other health-care workers involved in the trial. The primary outcome was functional status at day 90, measured by shift in the modified Rankin Scale, using ordinal logistic regression with adjustment for stratification and minimisation criteria. All analyses were done on an intention-to-treat basis. This trial is registered with the ISRCTN registry, number ISRCTN93732214.

FINDINGS: We recruited 2325 participants between March 1, 2013, and Sept 30, 2017. 1161 patients received tranexamic acid and 1164 received placebo; the treatment groups were well balanced at baseline. The primary outcome was assessed for 2307 (99%) participants. The primary outcome, functional status at day 90, did not differ significantly between the groups (adjusted odds ratio [aOR] 0·88, 95% CI 0·76-1·03, p=0·11). Although there were fewer deaths by day 7 in the tranexamic acid group (101 [9%] deaths in the tranexamic acid group vs 123 [11%] deaths in the placebo group; aOR 0·73, 0·53-0·99, p=0·0406), there was no difference in case fatality at 90 days (250 [22%] vs 249 [21%]; adjusted hazard ratio 0·92, 95% CI 0·77-1·10, p=0·37). Fewer patients had serious adverse events after tranexamic acid than after placebo by days 2 (379 [33%] patients vs 417 [36%] patients), 7 (456 [39%] vs 497 [43%]), and 90 (521 [45%] vs 556 [48%]).

INTERPRETATION: Functional status 90 days after intracerebral haemorrhage did not differ significantly between patients who received tranexamic acid and those who received placebo, despite a reduction in early deaths and serious adverse events. Larger randomised trials are needed to confirm or refute a clinically significant treatment effect.