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.
FUNDING: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 35. See the NIHR Journals Library website for further project information. The project was also funded by the Pragmatic Trials, UK, funding call and the Swiss Heart Foundation in Switzerland.
METHODS: AIS patients treated with IV rt-PA from February 2012 to August 2016 were recruited. Demographic data, National Institutes of Health Stroke Scale (NIHSS) scores, timing and neuroradiological findings were recorded. Patients received a dose of 0.9 mg/kg IV rt-PA within 4.5 hours of symptom onset. mRS score was evaluated at discharge and three months, and good and poor clinical outcomes were defined as scores of 0-2 and 3-6, respectively. Baseline THRIVE scores were assessed.
RESULTS: 36 patients received IV rt-PA. 20 (55.6%) patients had an mRS score of 0-2 at three months. Based on THRIVE score, 86.1% had a good or moderately good prognosis. On univariate analysis, poor outcome was associated with NIHSS score before rt-PA (p = 0.03), THRIVE score (p = 0.02), stroke subtype (p = 0.049) and diabetes mellitus (DM; p = 0.06). Multiple logistic regression showed that outcome was significantly associated with NIHSS score before rt-PA (p = 0.032) and DM (p = 0.010).
CONCLUSION: Our newly developed Malaysian IV rt-PA service is safe, with similar outcomes to the published literature. Functional outcome after thrombolysis was associated with baseline NIHSS score and DM.
METHODS: We take advantage of improved contrast seen on magnetic resonance (MR) images of patients with acute and early subacute SICH and introduce an automated algorithm for haematoma and oedema segmentation from these images. To our knowledge, there is no previously proposed segmentation technique for SICH that utilises MR images directly. The method is based on shape and intensity analysis for haematoma segmentation and voxel-wise dynamic thresholding of hyper-intensities for oedema segmentation.
RESULTS: Using Dice scores to measure segmentation overlaps between labellings yielded by the proposed algorithm and five different expert raters on 18 patients, we observe that our technique achieves overlap scores that are very similar to those obtained by pairwise expert rater comparison. A further comparison between the proposed method and a state-of-the-art Deep Learning segmentation on a separate set of 32 manually annotated subjects confirms the proposed method can achieve comparable results with very mild computational burden and in a completely training-free and unsupervised way.
CONCLUSION: Our technique can be a computationally light and effective way to automatically delineate haematoma and oedema extent directly from MR images. Thus, with increasing use of MR images clinically after intracerebral haemorrhage this technique has the potential to inform clinical practice in the future.
RESULTS: Primary outcome will be the ability of tranexamic acid to limit absolute haematoma volume on computed tomography at 24 h (± 12 h) after randomisation among spot sign positive and spot sign negative participants, respectively. Within all outcome measures, the effect of tranexamic acid in spot sign positive/negative participants will be compared using tests of interaction. This sub-study will investigate the important clinical hypothesis that spot sign positive patients might benefit more from administration of tranexamic acid compared to spot sign negative patients. Trial registration ISRCTN93732214 ( http://www.isrctn.com ).
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.
FUNDING: National Institute of Health Research Health Technology Assessment Programme and Swiss Heart Foundation.
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.
TRIAL REGISTRATION NUMBER: ISRCTN93732214; Pre-results.
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.
TRIAL REGISTRATION: ISRCTN registry, ID: ISRCTN93732214 . Registered on 17 January 2013.
METHODS: This observational study was conducted at the Emergency Department of Sulaymaniyah General Teaching Hospital and Shar Hospital from September 1st, 2014 to August 31st, 2015. Fifty patients who developed acute spontaneous hypertensive intracerebral hemorrhage (ICH) and 50 patients who developed acute non-traumatic subarachnoid hemorrhage (SAH) were included in the study. All patients underwent resting 12-lead ECG within half an hour of admission. The QTc interval was calculated and analyzed in those 100 patients.
RESULTS: Females (62%) outnumbered males (38%) with a female to male ratio of 1.6:1. Forty percent of the patients were between 60-69 years of age. Hypertension was seen in 82% of patients while left ventricular hypertrophy was documented in 40% of patients. The QTc was prolonged in 38 patients (17 patients in the ICH group and 21 patients in the SAH group). In both groups, males demonstrated QTc prolongation more than females. However, there were no statistically significant gender difference between both groups and within the same group. There was a statistically significant association between SAH and QTc prolongation (p-value<0.001); the ICH group did not demonstrate any significant relationship with QTc prolongation.
CONCLUSION: Prolongation in the QTc interval was "statistically" associated with acute SAH only. No gender difference was noted; whether this observation is clinically significant or not, it needs further analytic studies.
METHODOLOGY: A prospective, descriptive and correlational study was conducted at Sarawak General Hospital (SGH) over the span of two years (April 2013-April 2015). Patients aged between 30 years and 75 years with supratentorial intracerebral bleed secondary to uncontrolled hypertension were recruited in this study. Data pertaining to the demography, clinical and radiological parameters, peripheral WBC count and CRP levels were obtained. Mortality and functional outcomes were determined at 6 months post ictus. Patients were recruited following the fulfilment of exclusion and inclusion criteria, and all obtained data were analysed with the Statistical Package for Social Sciences (SPSS) for Windows version 21.0.
RESULTS: A total of 60 patients with a mean age of 56 years were recruited in this study. We found that approximately 16 patients were less than or equal to 50 years old (26.7%) and that 44 patients belonged to the older age group of above 50 years (73.3%). The Glasgow Coma Scale (GCS) score on admission ranged from 9 to 14/15 with a median value of 11/15. The mean clot volume was 20.1 cm(3). The GCS score on admission and clot volume were significantly associated with the Glasgow Outcome Scale (GOS) at 6 months and overall survival (P < 0.05). The elevated WBC count and CRP level on admission and at 72 hours post admission were significantly associated with GOS at 6 months and overall survival (P < 0.05). Thus, the GCS score, clot volume, WBC count and CRP levels on admission and at 72 hours post admission can be used to predict functional outcome at 6 months and overall survival in patients with SICH.
CONCLUSION: We could conclude via this study that for patients with SICH, the main determinants or predictors of functional outcome at 6 months and overall survival were noted to be the GCS score on admission, clot size, WBC count and CRP levels on admission and at 72 hours post admission.
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.
Conclusion: Tranexamic acid is a promising haemostatic agent for ICH. We await the results of the trials before definite conclusions can be drawn.
METHODS: Patients who were 10-80 years old and presented with a Graeb score of more than six were randomised into endoscopic washout and EVD treatment groups. A CT brain was repeated on each patient within 24 hours after surgery, and if a patient's Graeb score was still more than six, a repeat endoscopic washout was performed to clear the remaining clots. All patients were monitored for shunt dependency at two weeks and three months, and clinical outcomes were measured at six months after the procedure.
RESULTS: A total of 39 patients were recruited; 19 patients were randomised into the endoscopic washout group, and 20 were randomised into the EVD group. However, three patients in the endoscopic group refused that treatment and opted for EVD insertion. Patients treated with endoscopic washout had significantly less drainage dependency at two weeks (P < 0.005) and at three months (P < 0.004) as compared to patients in the external ventricular drainage group. The reduction in Graeb scores was also significantly greater in the endoscopic washout group (P < 0.001). However, the functional outcome at six months measured via a modified Rankin scale score was no different in the two groups of patients. The difference in the functional outcome of the patients was mainly dependent on the initial pathology, with those presenting with a thalamic bleed with IVH showing a poor functional outcome. This parameter was also influenced by the Glasgow Coma Scale (GCS) score on admission, with those patients with a score of 12 or less having a poor functional outcome (MRS 5-6) at three and six months after the surgery.
CONCLUSIONS: The use of neuroendoscopy in patients with a massive IVH significantly reduced drainage dependency. However, it did not alter the final functional outcome.