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 Unpublished information from three ongoing clinical trials was obtained.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.
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: 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.
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).
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.
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.
METHODS: A cross-sectional observational study of hospitalized COVID-19 patients was conducted. The neurological manifestations were divided into the self-reported central nervous system (CNS) symptoms, stroke associated symptoms, symptoms of encephalitis or encephalopathy and specific neurological complications. Multiple logistic regression was performed using demographic and clinical variables to determine the factors associated with outcome.
RESULTS: Of 156 hospitalized COVID-19 patients with mean age of 55.88 ± 6.11 (SD) years, 23.7% developed neurological complications, which included stroke, encephalitis and encephalopathy. Patients with neurological complications were more likely to have diabetes mellitus (p = 0.033), symptoms of stroke [limb weakness (p
METHODS: Data from 133 participants from the Rapid Intervention with Glyceryl Trinitrate in Hypertensive Stroke-2 Trial trial were analysed. Measures included ICHV (using ABC/2) and ICV (XYZ/2) (by independent observers); ICHV, ICV and CPV (semiautomated segmentation, SAS); atrophy (intercaudate distance, ICD, Sylvian fissure ratio, SFR); midline shift; leukoaraiosis and cistern effacement (visual assessment). The effects of these measures on death at day 4 and poor functional outcome at day 90 (modified Rankin scale, mRS of >3) was assessed.
RESULTS: ICV was significantly different between XYZ and SAS: mean (SD) of 1357 (219) vs 1420 (196), mean difference (MD) 62 mL (p<0.001). There was no significant difference in ICHV between ABC/2 and SAS. There was very good agreement for ICV measured by SAS, CPV, ICD, SFR, leukoaraiosis and cistern score (all interclass correlations, n=10: interobserver 0.72-0.99, intraobserver 0.73-1.00). ICHV/ICV and ICHV/CPV were significantly associated with mRS at day 90, death at day 4 and acute neurological deterioration (all p<0.05), similar to ICHV. Midline shift and cistern effacement at baseline were associated with poor functional outcome but old infarcts, leukoaraiosis and brain atrophy were not.
CONCLUSIONS: Intracranial compartment measures and visual estimates are reproducible. ICHV adjusted for ICH and CPV could be useful to prognosticate in acute stroke. The presence of midline shift and cistern effacement may predict outcome but the mechanisms need validation in larger studies.
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 pooled individual patient data from randomized controlled trials registered in the Blood Pressure in Acute Stroke Collaboration. Time was defined as time form symptom onset plus the time (hour) to first achieve and subsequently maintain SBP at 120 to 140 mm Hg over 24 hours. The primary outcome was functional status measured by the modified Rankin Scale at 90 to 180 days. A generalized linear mixed models was used, with adjustment for covariables and trial as a random effect.
RESULTS: A total of 5761 patients (mean age, 64.0 [SD, 13.0], 2120 [36.8%] females) were included in analyses. Earlier SBP control was associated with better functional outcomes (modified Rankin Scale score, 3-6; odds ratio, 0.98 [95% CI, 0.97-0.99]) and a significant lower risk of hematoma expansion (0.98, 0.96-1.00). This association was stronger in patients with bigger baseline hematoma volume (>10 mL) compared with those with baseline hematoma volume ≤10 mL (0.006 for interaction). Earlier SBP control was not associated with cardiac or renal adverse events.
CONCLUSIONS: Our study confirms a clear time relation between early versus later SBP control (120-140 mm Hg) and outcomes in the one-third of patients with intracerebral hemorrhage who attained sustained SBP levels within this range. These data provide further support for the value of early recognition, rapid transport, and prompt initiation of treatment of patients with intracerebral hemorrhage.
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