Treatment of spontaneous intracerebral haemorrhage with tranexamic acid

Spontaneous intracerebral haemorrhage is a devastating condition with high morbidity and mortality. Haematoma expansion and subsequent secondary brain injuries lead to worse outcomes in intracerebral haemorrhage. Tranexamic acid is a promising haemostatic agent that may prevent haematoma expansion and improve outcomes. The current thesis explores the effects of tranexamic acid in intracerebral haemorrhage from clinical, radiological and biochemical aspects, based on data from the now completed Tranexamic acid in IntraCerebral Haemorrhage-2 (TICH-2) trial. Two systematic reviews explore available evidence on efficacy and safety of tranexamic acid and other haemostatic therapies in intracerebral haemorrhage. There was insufficient evidence to support the routine use of tranexamic acid or blood clotting factors in treating intracerebral haemorrhage. Platelet transfusion had been found to be harmful and should be avoided in intracerebral haemorrhage. Predictors of neurological deterioration and seizures and the effects of tranexamic acid on both were explored. Older age, more severe stroke, larger haematoma volume, intraventricular and subarachnoid extension, previous intracerebral haemorrhage and antiplatelet therapy independently predicted neurological deterioration. Tranexamic acid reduced early neurological deterioration occurring within 48 hours from symptom onset through a reduction in haematoma expansion, but had no significant effect on late neurological deterioration (48 hours to 7 days). Lobar location of haematoma was the strongest predictor of early (≤ 7 days) and late seizures (> 7 days). The risk of seizures in intracerebral haemorrhage was not increased in patients treated with tranexamic acid. The role of several noncontrast CT signs, namely blend sign, black hole sign, hypodensities and island sign, in predicting haematoma expansion and poor functional outcome was assessed. Blend sign, black hole sign and hypodensities independently predicted haematoma expansion while black hole sign, hypodensities and island sign predicted poor functional outcome (modified Rankin Scale of 4 to 6). Tranexamic acid reduced haematoma expansion but there was no benefit on functional outcome. There was no significant interaction between the presence of noncontrast CT signs and benefit from tranexamic acid in terms of reduction in haematoma expansion or improvement in functional outcome From a biochemical aspect, a range of plasma biomarkers involved in fibrinolysis and haemostasis were examined in a single-centre substudy of the TICH-2 trial involving 22 patients and 9 healthy volunteers. Patients with intracerebral haemorrhage had higher D-dimer and plasmin-alpha-2-antiplasmin complex levels compared to healthy controls. Elevated baseline tissue-type plasminogen activator and urokinase-type plasminogen activator, lower baseline plasminogen and elevated day 2 matrix metalloproteinase-9 levels were associated with haematoma progression. Tranexamic acid did not have significant effects on plasma biomarker levels. In summary, there were clinical and radiological signals that tranexamic acid may be beneficial in patients with spontaneous intracerebral haemorrhage. Plasma biomarker results suggest fibrinolysis may be a pathophysiological mechanism in intracerebral haemorrhage. There is a role for further trials of tranexamic acid in intracerebral haemorrhage

Elevated plasminogen activators are associated with hematoma progression in spontaneous intracerebral hemorrhage

Endogenous fibrinolysis might lead to hematoma progression in spontaneous intracerebral hemorrhage (ICH). We studied plasma biomarkers of fibrinolysis and hemostasis in twenty-two patients with ICH and nine healthy controls (HC) in a single-center study. Patients with ICH had significantly higher D-dimer and plasmin-alpha-2-antiplasmin complexes compared to HC. At baseline, patients with hematoma progression had higher urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA) and lower plasminogen levels, compared to those with no progression. 24-hour and day-7 matrix metalloproteinase-9 (MMP-9) was significantly increased in patients with hematoma progression

Results from the tranexamic acid for primary intracerebral haemorrhage-2 (TICH-2) trial

Background: Haematoma expansion leads to worse outcome in intracerebral haemorrhage (ICH). Tranexamic acid (TXA) is a promising haemostatic agent to prevent haematoma expansion and improve outcome after ICH. Methods: TICH-2 is a multicentre prospective double blind randomised controlled trial, which recruited patients presenting within 8 hours of primary ICH to receive intravenous TXA or placebo. Primary outcome is modified Rankin Scale at day 90 and will be analysed using ordinal logistic regression, adjusted for minimisation criteria. Secondary outcomes will be analysed using adjusted binary logistic regression and multiple linear regression; these include haematoma expansion at 24 hours, day 7 National Institute of Health Stroke Scale (NIHSS), day 90 Barthel Index, quality of life, cognition and mood. Results: A total of 2325 patients were recruited between 14th March 2013 and 30th September 2017, from 12 countries: United Kingdom (n= 1910), Italy, Georgia, Switzerland, Malaysia, Hungary, Poland, Ireland, Turkey, Sweden, Denmark and Spain. Randomisation characteristics included: age 68.9 (13.8) years; male 1301 (56.0%); time from onset to randomisation 3.6 hours [2.6, 5.0]; NIHSS 13 (7.5); Glasgow coma scale 13.4 (2.1); systolic blood pressure 172.6 (27.2) mmHg; intraventricular haemorrhage 745 (32.0%) and prior antiplatelet use 610 (26.2%). Conclusion: TICH-2 is the largest trial of TXA in spontaneous ICH and recruited over its original target of 2000 patients. The results will be available in May 2018 and will inform whether TXA should be recommended for the treatment of acute spontaneous ICH

Haemostatic therapies for acute spontaneous intracerebral haemorrhage

Background: Outcome after spontaneous (non-traumatic) intracerebral haemorrhage (ICH) is influenced by haematoma volume; up to one-third of ICHs enlarge within 24 hours of onset. Early haemostatic therapy might improve outcome by limiting haematoma growth. This is an update of a Cochrane Review first published in 2006, and last updated in 2009. Objectives: To examine 1) the effectiveness and safety of individual classes of haemostatic therapies, compared against placebo or open control, in adults with acute spontaneous intracerebral haemorrhage, and 2) the effects of each class of haemostatic therapy according to the type of antithrombotic drug taken immediately before ICH onset (i.e. anticoagulant, antiplatelet, or none). Search methods: We searched the Cochrane Stroke Trials Register, CENTRAL; 2017, Issue 11, MEDLINE Ovid, and Embase Ovid on 27 November 2017. In an effort to identify further published, ongoing, and unpublished randomised controlled trials (RCT), we scanned bibliographies of relevant articles and searched international registers of RCTs in November 2017. Selection criteria: We sought randomised controlled trials (RCTs) of any haemostatic intervention (i.e. pro-coagulant treatments such as coagulation factors, antifibrinolytic drugs, or platelet transfusion) for acute spontaneous ICH, compared with placebo, open control, or an active comparator, reporting relevant clinical outcome measures. Data collection and analysis: Two authors independently extracted data, assessed risk of bias, and contacted corresponding authors of eligible RCTs for specific data if they were not provided in the published report of an RCT. Main results: We included 12 RCTs involving 1732 participants. There were seven RCTs of blood clotting factors versus placebo or open control involving 1480 participants, three RCTs of antifibrinolytic drugs versus placebo or open control involving 57 participants, one RCT of platelet transfusion versus open control involving 190 participants, and one RCT of blood clotting factors versus fresh frozen plasma involving five participants. We were unable to include two eligible RCTs because they presented aggregate data for adults with ICH and other types of intracranial haemorrhage. We identified 10 ongoing RCTs. Across all seven criteria in the 12 included RCTs, the risk of bias was unclear in 37 (44%), high in 16 (19%), and low in 31 (37%). Only one RCT was at low risk of bias in all criteria. In one RCT of platelet transfusion versus open control for acute spontaneous ICH associated with antiplatelet drug use, there was a significant increase in death or dependence (modified Rankin Scale score 4 to 6) at day 90 (70/97 versus 52/93; risk ratio (RR) 1.29, 95% confidence interval (CI) 1.04 to 1.61, one trial, 190 participants, moderate-quality evidence). All findings were non-significant for blood clotting factors versus placebo or open control for acute spontaneous ICH with or without surgery (moderate-quality evidence), for antifibrinolytic drugs versus placebo (moderate-quality evidence) or open control for acute spontaneous ICH (moderate-quality evidence), and for clotting factors versus fresh frozen plasma for acute spontaneous ICH associated with anticoagulant drug use (no evidence). Authors' conclusions: Based on moderate-quality evidence from one trial, platelet transfusion seems hazardous in comparison to standard care for adults with antiplatelet-associated ICH. We were unable to draw firm conclusions about the efficacy and safety of blood clotting factors for acute spontaneous ICH with or without surgery, antifibrinolytic drugs for acute spontaneous ICH, and clotting factors versus fresh frozen plasma for acute spontaneous ICH associated with anticoagulant drug use

First Reported Case of Neuroleptospirosis Complicated With Anton's Syndrome

Leptospirosis is a spirochetal zoonotic disease with a wide clinical spectrum, often underdiagnosed especially when presented as an acute neurological manifestation. We report a case of a 24-year-old man with serologically positive leptospirosis, who presented with altered sensorium, seizures and subsequently developed cortical blindness. His brain MRI revealed bilateral occipital and later parietal lobe cerebritis

Predictors and outcomes of neurological deterioration in intracerebral hemorrhage: results from the TICH-2 randomised controlled trial

Neurological deterioration is common after intracerebral hemorrhage (ICH). We aimed to identify the predictors and effects of neurological deterioration and whether tranexamic acid reduced the risk of neurological deterioration. Data from the Tranexamic acid in IntraCerebral Hemorrhage-2 (TICH-2) randomized controlled trial were analyzed. Neurological deterioration was defined as an increase in National Institutes of Health Stroke Scale (NIHSS) of ≥ 4 or a decline in Glasgow Coma Scale of ≥ 2. Neurological deterioration was considered to be early if it started ≤ 48 h and late if commenced between 48 h and 7 days after onset. Logistic regression was used to identify predictors and effects of neurological deterioration and the effect of tranexamic acid on neurological deterioration. Of 2325 patients, 735 (31.7%) had neurological deterioration: 590 (80.3%) occurred early and 145 (19.7%) late. Predictors of early neurological deterioration included recruitment from the UK, previous ICH, higher admission systolic blood pressure, higher NIHSS, shorter onset-to-CT time, larger baseline hematoma, intraventricular hemorrhage, subarachnoid extension and antiplatelet therapy. Older age, male sex, higher NIHSS, previous ICH and larger baseline hematoma predicted late neurological deterioration. Neurological deterioration was independently associated with a modified Rankin Scale of > 3 (aOR 4.98, 3.70–6.70; p [less than] 0.001). Tranexamic acid reduced the risk of early (aOR 0.79, 0.63–0.99; p = 0.041) but not late neurological deterioration (aOR 0.76, 0.52–1.11; p = 0.15). Larger hematoma size, intraventricular and subarachnoid extension increased the risk of neurological deterioration. Neurological deterioration increased the risk of death and dependency at day 90. Tranexamic acid reduced the risk of early neurological deterioration and warrants further investigation in ICH

Measures of intracranial compartments in acute intracerebral haemorrhage: data from the Rapid Intervention with Glyceryl Trinitrate in Hypertensive Stroke-2 Trial (RIGHT-2)

Background and purpose: Intracerebral haemorrhage volume (ICHV) is prognostically important but does not account for intracranial volume (ICV) and cerebral parenchymal volume (CPV). We assessed measures of intracranial compartments in acute ICH using computerised tomography scans and whether ICHV/ICV and ICHV/CPV predict functional outcomes. We also assessed if cistern effacement, midline shift, old infarcts, leukoaraiosis and brain atrophy were associated with outcomes. 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

Platelet and haemoglobin levels in patients on isosorbide mononitrate and/or cilostazol with lacunar ischaemic stroke: data from the LACI-1 trial

Background: Cilostazol and isosorbide mononitrate (ISMN) have properties that may be of benefit in the context of cerebral small vessel disease and lacunar ischaemic stroke. As both drugs may influence platelet and haemoglobin levels, we sought to assess their effects using data from the lacunar intervention trial-1 (LACI-1). Methods: LACI-1 recruited 57 patients with lacunar ischaemic stroke and randomised them to ISMN or cilostazol in isolation, or combined for 9 weeks. One group received both drugs but with a delayed start. Full blood counts were taken at baseline, and weeks 3 and 8. Platelet function was assessed with remote measurement of surface expression of P-selectin (CD62P) using kits sensitive to aspirin or clopidogrel at the same timepoints. Differences in haemoglobin and platelet levels and platelet function were assessed by multiple linear regression with adjustment for baseline value. Results: Haemoglobin levels did not differ between the treatment groups at week 8 (Table), whilst platelet levels were slightly higher in those who received cilostazol compared with no cilostazol. No differences were noted in platelet function in unstimulated, aspirin or clopidogrel testing between groups. Conclusions: Cilostazol and isosorbide mononitrate have no clinically concerning effects on haemoglobin and platelet levels and function in the short to medium term. Further assessment of the safety and efficacy of these medications following lacunar ischaemic stroke is warranted