METHODS: Consent was provided by patients or by a relative or an independent doctor in incapacitated patients, using a 1-stage (full written consent) or 2-stage (initial brief consent followed by full written consent post-randomization) approach. The computed tomography-to-randomization time according to consent pathways was compared using the Kruskal-Wallis test. Multivariable logistic regression was performed to identify variables associated with onset-to-randomization time of ≤3 hours.

RESULTS: Of 2325 patients, 817 (35%) gave self-consent using 1-stage (557; 68%) or 2-stage consent (260; 32%). For 1507 (65%), consent was provided by a relative (1 stage, 996 [66%]; 2 stage, 323 [21%]) or a doctor (all 2-stage, 188 [12%]). One patient did not record prerandomization consent, with written consent obtained subsequently. The median (interquartile range) computed tomography-to-randomization time was 55 (38-93) minutes for doctor consent, 55 (37-95) minutes for 2-stage patient, 69 (43-110) minutes for 2-stage relative, 75 (48-124) minutes for 1-stage patient, and 90 (56-155) minutes for 1-stage relative consents (P<0.001). Two-stage consent was associated with onset-to-randomization time of ≤3 hours compared with 1-stage consent (adjusted odds ratio, 1.9 [95% CI, 1.5-2.4]). Doctor consent increased the odds (adjusted odds ratio, 2.3 [1.5-3.5]) while relative consent reduced the odds of randomization ≤3 hours (adjusted odds ratio, 0.10 [0.03-0.34]) compared with patient consent. Only 2 of 771 patients (0.3%) in the 2-stage pathways withdrew consent when full consent was sought later. Two-stage consent process did not result in higher withdrawal rates or loss to follow-up.

CONCLUSIONS: The use of initial brief consent was associated with shorter times to enrollment, while maintaining good participant retention. Seeking written consent from relatives was associated with significant delays.

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.

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.

OBJECTIVES: To examine 1. the effects of individual classes of haemostatic therapies, compared with placebo or open control, in adults with acute spontaneous ICH, and 2. the effects of each class of haemostatic therapy according to the use and type of antithrombotic drug before ICH onset.

SEARCH METHODS: We searched the Cochrane Stroke Trials Register, CENTRAL (2022, Issue 8), MEDLINE Ovid, and Embase Ovid on 12 September 2022. To identify further published, ongoing, and unpublished randomised controlled trials (RCTs), we scanned bibliographies of relevant articles and searched international registers of RCTs in September 2022.

SELECTION CRITERIA: We included RCTs of any haemostatic intervention (i.e. procoagulant treatments such as clotting factor concentrates, antifibrinolytic drugs, platelet transfusion, or agents to reverse the action of antithrombotic drugs) for acute spontaneous ICH, compared with placebo, open control, or an active comparator.

DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcome was death/dependence (modified Rankin Scale (mRS) 4 to 6) by day 90. Secondary outcomes were ICH expansion on brain imaging after 24 hours, all serious adverse events, thromboembolic adverse events, death from any cause, quality of life, mood, cognitive function, Barthel Index score, and death or dependence measured on the Extended Glasgow Outcome Scale by day 90.

MAIN RESULTS: We included 20 RCTs involving 4652 participants: nine RCTs of recombinant activated factor VII (rFVIIa) versus placebo/open control (1549 participants), eight RCTs of antifibrinolytic drugs versus placebo/open control (2866 participants), one RCT of platelet transfusion versus open control (190 participants), and two RCTs of prothrombin complex concentrates (PCC) versus fresh frozen plasma (FFP) (47 participants). Four (20%) RCTs were at low risk of bias in all criteria. For rFVIIa versus placebo/open control for spontaneous ICH with or without surgery there was little to no difference in death/dependence by day 90 (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.74 to 1.05; 7 RCTs, 1454 participants; low-certainty evidence). We found little to no difference in ICH expansion between groups (RR 0.81, 95% CI 0.56 to 1.16; 4 RCTs, 220 participants; low-certainty evidence). There was little to no difference in all serious adverse events and death from any cause between groups (all serious adverse events: RR 0.81, 95% CI 0.30 to 2.22; 2 RCTs, 87 participants; very low-certainty evidence; death from any cause: RR 0.78, 95% CI 0.56 to 1.08; 8 RCTs, 1544 participants; moderate-certainty evidence). For antifibrinolytic drugs versus placebo/open control for spontaneous ICH, there was no difference in death/dependence by day 90 (RR 1.00, 95% CI 0.93 to 1.07; 5 RCTs, 2683 participants; high-certainty evidence). We found a slight reduction in ICH expansion with antifibrinolytic drugs for spontaneous ICH compared to placebo/open control (RR 0.86, 95% CI 0.76 to 0.96; 8 RCTs, 2866 participants; high-certainty evidence). There was little to no difference in all serious adverse events and death from any cause between groups (all serious adverse events: RR 1.02, 95% CI 0.75 to 1.39; 4 RCTs, 2599 participants; high-certainty evidence; death from any cause: RR 1.02, 95% CI 0.89 to 1.18; 8 RCTs, 2866 participants; high-certainty evidence). There was little to no difference in quality of life, mood, or cognitive function (quality of life: mean difference (MD) 0, 95% CI -0.03 to 0.03; 2 RCTs, 2349 participants; mood: MD 0.30, 95% CI -1.98 to 2.57; 2 RCTs, 2349 participants; cognitive function: MD -0.37, 95% CI -1.40 to 0.66; 1 RCTs, 2325 participants; all high-certainty evidence). Platelet transfusion likely increases death/dependence by day 90 compared to open control for antiplatelet-associated ICH (RR 1.29, 95% CI 1.04 to 1.61; 1 RCT, 190 participants; moderate-certainty evidence). We found little to no difference in ICH expansion between groups (RR 1.32, 95% CI 0.91 to 1.92; 1 RCT, 153 participants; moderate-certainty evidence). There was little to no difference in all serious adverse events and death from any cause between groups (all serious adverse events: RR 1.46, 95% CI 0.98 to 2.16; 1 RCT, 190 participants; death from any cause: RR 1.42, 95% CI 0.88 to 2.28; 1 RCT, 190 participants; both moderate-certainty evidence). For PCC versus FFP for anticoagulant-associated ICH, the evidence was very uncertain about the effect on death/dependence by day 90, ICH expansion, all serious adverse events, and death from any cause between groups (death/dependence by day 90: RR 1.21, 95% CI 0.76 to 1.90; 1 RCT, 37 participants; ICH expansion: RR 0.54, 95% CI 0.23 to 1.22; 1 RCT, 36 participants; all serious adverse events: RR 0.27, 95% CI 0.02 to 3.74; 1 RCT, 5 participants; death from any cause: RR 0.49, 95% CI 0.16 to 1.56; 2 RCTs, 42 participants; all very low-certainty evidence).

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.

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.

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.