METHODS: Among participants with ICH enrolled in the TICH-2 (Tranexamic Acid for Hyperacute Primary Intracerebral Haemorrhage) trial, we assessed baseline scans for hematoma location and presence of cerebral amyloid angiopathy (CAA) using computed tomography (CT, simplified Edinburgh criteria) and magnetic resonance imaging (MRI; Boston criteria) and categorized ICH as lobar CAA, lobar non-CAA, and nonlobar. The main outcomes were HE and favorable functional outcome. We constructed multivariate regression models and assessed treatment effects using interaction terms.
RESULTS: A total of 2,298 out of 2,325 participants were included with available CT (98.8%; median age = 71 years, interquartile range = 60-80 years; 1,014 female). Additional MRI was available in 219 patients (9.5%). Overall, 1,637 participants (71.2%) had nonlobar ICH; the remaining 661 participants (28.8%) had lobar ICH, of whom 202 patients had lobar CAA-ICH (8.8%, 173 participants according to Edinburgh and 29 participants according to Boston criteria) and 459 did not (lobar non-CAA, 20.0%). For HE, we found a significant interaction of lobar CAA ICH with time from onset to randomization (increasing risk with time, pinteraction
METHODS: TICH-2 was an international prospective double-blind placebo-controlled randomised trial evaluating intravenous tranexamic acid in patients with acute spontaneous intracerebral haemorrhage (ICH). Prerandomisation baseline SBP was split into predefined ≤170 and >170 mm Hg groups. The primary outcome at day 90 was the modified Rankin Scale (mRS), a measure of dependency, analysed using ordinal logistic regression. Haematoma expansion was defined as an increase in haematoma volume of >33% or >6 mL from baseline to 24 hours. Data are OR or common OR (cOR) with 95% CIs, with significance at p<0.05.
RESULTS: Of 2325 participants in TICH-2, 1152 had baseline SBP≤170 mm Hg and were older, had larger lobar haematomas and were randomised later than 1173 with baseline SBP>170 mm Hg. Tranexamic acid was associated with a favourable shift in mRS at day 90 in those with baseline SBP≤170 mm Hg (cOR 0.73, 95% CI 0.59 to 0.91, p=0.005), but not in those with baseline SBP>170 mm Hg (cOR 1.05, 95% CI 0.85 to 1.30, p=0.63). In those with baseline SBP≤170 mm Hg, tranexamic acid reduced haematoma expansion (OR 0.62, 95% CI 0.47 to 0.82, p=0.001), but not in those with baseline SBP>170 mm Hg (OR 1.02, 95% CI 0.77 to 1.35, p=0.90).
CONCLUSIONS: Tranexamic acid was associated with improved clinical and radiological outcomes in ICH patients with baseline SBP≤170 mm Hg. Further research is needed to establish whether certain subgroups may benefit from tranexamic acid in acute ICH.
TRIAL REGISTRATION NUMBER: ISRCTN93732214.
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 ANALYSIS: A systematic review will be undertaken according to the Preferred Reporting Items for Systematic review and Meta-Analysis of Individual Participant Data (IPD) guideline. A search of Cochrane Central Register of Controlled Trials, EMBASE and MEDLINE from inception will be conducted to identify randomised controlled trials of BP management in adults with acute spontaneous (non-traumatic) ICH enrolled within the first 7 days of symptom onset. Authors of studies that meet the inclusion criteria will be invited to share their IPD. The primary outcome will be functional outcome according to the modified Rankin Scale. Safety outcomes will be early neurological deterioration, symptomatic hypotension and serious adverse events. Secondary outcomes will include death and neuroradiological and haemodynamic variables. Meta-analyses of pooled IPD using the intention-to-treat dataset of included trials, including subgroup analyses to assess modification of the effects of BP lowering by time to treatment, treatment strategy and patient's demographic, clinical and prestroke neuroradiological characteristics.
ETHICS AND DISSEMINATION: No new patient data will be collected nor is there any deviation from the original purposes of each study where ethical approvals were granted; therefore, further ethical approval is not required. Results will be reported in international peer-reviewed journals.
PROSPERO REGISTRATION NUMBER: CRD42019141136.
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.
METHODS: Patients aged 30-75 years who had severe ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] score of 10-35) involving the MCA territory were recruited within 2 months of stroke onset. Using permuted block randomization, patients were assigned to receive 2 million BMMSCs per kilogram of body weight (treatment group) or standard medical care (control group). The primary outcomes were the NIHSS, modified Rankin Scale (mRS), Barthel Index (BI) and total infarct volume on brain magnetic resonance imaging (MRI) at 12 months. All outcome assessments were performed by blinded assessors. Per protocol, analyses were performed for between-group comparisons.
RESULTS: Seventeen patients were recruited. Nine were assigned to the treatment group, and eight were controls. All patients were severely disabled following their MCA infarct (median mRS = 4.0 [4.0-5.0], BI = 5.0 [5.0-25.0], NIHSS = 16.0 [11.5-21.0]). The baseline infarct volume on the MRI was larger in the treatment group (median, 71.7 [30.5-101.7] mL versus 26.7 [12.9-75.3] mL, P = 0.10). There were no between-group differences in median NIHSS score (7.0 versus 6.0, P = 0.96), mRS (2.0 versus 3.0, P = 0.38) or BI (95.0 versus 67.5, P = 0.33) at 12 months. At 12 months, there was significant improvement in absolute change in median infarct volume, but not in total infarct volume, from baseline in the treatment group (P = 0.027). No treatment-related adverse effects occurred in the BMMSC group.
CONCLUSIONS: Intravenous infusion of BMMSCs in patients with subacute MCA infarct was safe and well tolerated. Although there was no neurological recovery or functional outcome improvement at 12 months, there was improvement in absolute change in median infarct volume in the treatment group. Larger, well-designed studies are warranted to confirm this and the efficacy of BMMSCs in ischemic stroke.
Methods: We recruited independent patients with clinically confirmed lacunar ischaemic stroke without cognitive impairment to a prospective randomised clinical trial, LACunar Intervention-1 (LACI-1). We randomised patients using a central web-based system, 1:1:1:1 with minimisation, to masked ISMN 25 mg bd, cilostazol 100 mg bd, both ISMN and cilostazol started immediately, or both with start delayed. We escalated doses to target over two weeks, sustained for eight weeks. Primary outcome was the proportion achieving target dose. Secondary outcomes included symptoms, safety (haemorrhage, recurrent vascular events), cognition, haematology, vascular function, and neuroimaging. LACI-1 was powered (80%, alpha 0.05) to detect 35% (90% versus 55%) difference between the proportion reaching target dose on one versus both drugs at 55 patients. Registration ISRCTN12580546.
Findings: LACI-1 enrolled 57 participants between March 2016 and August 2017: 18 (32%) females, mean age 66 (SD 11, range 40-85) years, onset-randomisation 203 (range 6-920) days. Most achieved full (64%) or over half (87%) dose, with no difference between cilostazol vs ISMN, single vs dual drugs. Headache and palpitations increased initially then declined similarly with dual versus single drugs. There was no between-group difference in BP, pulse-wave velocity, haemoglobin or platelet function, but pulse rate was higher (mean difference, MD, 6.4, 95%CI 1.2-11.7, p = 0.02), platelet count higher (MD 35.7, 95%CI 2.8, 68.7, p = 0.03) and white matter hyperintensities reduced more (Chi-square p = 0.007) with cilostazol versus no cilostazol.
Interpretation: Cilostazol and ISMN are well tolerated when the dose is escalated, without safety concerns, in patients with lacunar stroke. Larger trials with longer term follow-up are justified.
Funding: Alzheimer's Society (AS-PG-14-033).
MATERIALS AND METHODS: Seven hundred fifty-four radiomics-based features were extracted from 1732 scans derived from the TICH-2 multicentre clinical trial. Features were harmonised and a correlation-based feature selection was applied. Different elastic-net parameterisations were tested to assess the predictive performance of the selected radiomics-based features using grid optimisation. For comparison, the same procedure was run using radiological signs and clinical factors separately. Models trained with radiomics-based features combined with radiological signs or clinical factors were tested. Predictive performance was evaluated using the area under the receiver operating characteristic curve (AUC) score.
RESULTS: The optimal radiomics-based model showed an AUC of 0.693 for haematoma expansion and an AUC of 0.783 for poor functional outcome. Models with radiological signs alone yielded substantial reductions in sensitivity. Combining radiomics-based features and radiological signs did not provide any improvement over radiomics-based features alone. Models with clinical factors had similar performance compared to using radiomics-based features, albeit with low sensitivity for haematoma expansion. Performance of radiomics-based features was boosted by incorporating clinical factors, with time from onset to scan and age being the most important contributors for haematoma expansion and poor functional outcome prediction, respectively.
CONCLUSION: Radiomics-based features perform better than radiological signs and similarly to clinical factors on the prediction of haematoma expansion and poor functional outcome. Moreover, combining radiomics-based features with clinical factors improves their performance.
KEY POINTS: • Linear models based on CT radiomics-based features perform better than radiological signs on the prediction of haematoma expansion and poor functional outcome in the context of intracerebral haemorrhage. • Linear models based on CT radiomics-based features perform similarly to clinical factors known to be good predictors. However, combining these clinical factors with radiomics-based features increases their predictive performance.
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.
Patients and methods: Seizures were reported prospectively up to day 90. Cox regression analyses were used to determine the predictors of seizures within 90 days and early seizures (≤7 days). We explored the effect of early seizures on day 90 outcomes.
Results: Of 2325 patients recruited, 193 (8.3%) had seizures including 163 (84.5%) early seizures and 30 (15.5%) late seizures (>7 days). Younger age (adjusted hazard ratio (aHR) 0.98 per year increase, 95% confidence interval (CI) 0.97-0.99; p = 0.008), lobar haematoma (aHR 5.84, 95%CI 3.58-9.52; p
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.