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  1. Flaherty K, Bath PM, Dineen R, Law Z, Scutt P, Pocock S, et al.
    Trials, 2017 Dec 20;18(1):607.
    PMID: 29262841 DOI: 10.1186/s13063-017-2341-5
    RATIONALE: Aside from blood pressure lowering, treatment options for intracerebral haemorrhage remain limited and a proportion of patients will undergo early haematoma expansion with resultant significant morbidity and mortality. Tranexamic acid (TXA), an anti-fibrinolytic drug, has been shown to significantly reduce mortality in patients, who are bleeding following trauma, when given rapidly. TICH-2 is testing whether TXA is effective at improving outcome in spontaneous intracerebral haemorrhage (SICH).

    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.

  2. Appleton JP, Blair GW, Flaherty K, Law ZK, May J, Woodhouse LJ, et al.
    Front Neurol, 2019;10:723.
    PMID: 31333572 DOI: 10.3389/fneur.2019.00723
    Background: Cilostazol and isosorbide mononitrate (ISMN) are candidate treatments for cerebral small vessel disease and lacunar ischaemic stroke. As both drugs may influence hemoglobin and platelet count, and hemodynamics, we sought to assess their effects in the lacunar intervention-1 (LACI-1) trial. Methods: Fifty-seven lacunar ischaemic stroke patients were randomized to immediate ISMN, cilostazol, or their combination for 9 weeks in addition to guideline stroke prevention. A fourth group received both drugs with a delayed start. Full blood count, platelet function, peripheral blood pressure (BP), heart rate and central hemodynamics (Augmentation index, Buckberg index) were measured at baseline, and weeks 3 and 8. Differences were assessed by multiple linear regression adjusted for baseline and key prognostic variables. Registration ISRCTN 12580546. Results: At week 8, platelet count was higher with cilostazol vs. no cilostazol (mean difference, MD 35.73, 95% confidence intervals, 95% CI 2.81-68.66, p = 0.033), but no significant differences were noted for hemoglobin levels or platelet function. At week 8, BP did not differ between the treatment groups, whilst heart rate was higher in those taking cilostazol vs. no cilostazol (MD 6.42, 95% CI 1.17-11.68, p = 0.017). Buckberg index (subendocardial perfusion) was lower in those randomized to cilostazol vs. no cilostazol and in those randomized to both drugs vs. either drug. Whilst ISMN significantly increased unadjusted augmentation index (arterial stiffness, MD 21.19, 95% CI 9.08-33.31, p = 0.001), in isolation both drugs non-significantly reduced augmentation index adjusted for heart rate. Conclusions: Cilostazol increased heart rate and platelet count, and reduced Buckberg index, whilst both drugs may individually reduce arterial stiffness adjusted for heart rate. Neither drug had clinically significant effects on hemoglobin or platelet function over 8 weeks. Further assessment of the safety and efficacy of these medications following lacunar ischaemic stroke is warranted.
  3. Ovesen C, Jakobsen JC, Gluud C, Steiner T, Law Z, Flaherty K, et al.
    BMC Res Notes, 2018 Jun 13;11(1):379.
    PMID: 29895329 DOI: 10.1186/s13104-018-3481-8
    OBJECTIVE: We present the statistical analysis plan of a prespecified Tranexamic Acid for Hyperacute Primary Intracerebral Haemorrhage (TICH)-2 sub-study aiming to investigate, if tranexamic acid has a different effect in intracerebral haemorrhage patients with the spot sign on admission compared to spot sign negative patients. The TICH-2 trial recruited above 2000 participants with intracerebral haemorrhage arriving in hospital within 8 h after symptom onset. They were included irrespective of radiological signs of on-going haematoma expansion. Participants were randomised to tranexamic acid versus matching placebo. In this subgroup analysis, we will include all participants in TICH-2 with a computed tomography angiography on admission allowing adjudication of the participants' spot sign status.

    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 ).

  4. Dineen RA, Pszczolkowski S, Flaherty K, Law ZK, Morgan PS, Roberts I, et al.
    BMJ Open, 2018 02 03;8(2):e019930.
    PMID: 29431141 DOI: 10.1136/bmjopen-2017-019930
    OBJECTIVES: To test whether administration of the antifibrinolytic drug tranexamic acid (TXA) in patients with spontaneous intracerebral haemorrhage (SICH) leads to increased prevalence of diffusion-weighted MRI-defined hyperintense ischaemic lesions (primary hypothesis) or reduced perihaematomal oedema volume, perihaematomal diffusion restriction and residual MRI-defined SICH-related tissue damage (secondary hypotheses).

    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.

  5. Ovesen C, Jakobsen JC, Gluud C, Steiner T, Law Z, Flaherty K, et al.
    Stroke, 2021 08;52(8):2629-2636.
    PMID: 34000834 DOI: 10.1161/STROKEAHA.120.032426
    BACKGROUND AND PURPOSE: The computed tomography angiography or contrast-enhanced computed tomography based spot sign has been proposed as a biomarker for identifying on-going hematoma expansion in patients with acute intracerebral hemorrhage. We investigated, if spot-sign positive participants benefit more from tranexamic acid versus placebo as compared to spot-sign negative participants.

    METHODS: TICH-2 trial (Tranexamic Acid for Hyperacute Primary Intracerebral Haemorrhage) was a randomized, placebo-controlled clinical trial recruiting acutely hospitalized participants with intracerebral hemorrhage within 8 hours after symptom onset. Local investigators randomized participants to 2 grams of intravenous tranexamic acid or matching placebo (1:1). All participants underwent computed tomography scan on admission and on day 2 (24±12 hours) after randomization. In this sub group analysis, we included all participants from the main trial population with imaging allowing adjudication of spot sign status.

    RESULTS: Of the 2325 TICH-2 participants, 254 (10.9%) had imaging allowing for spot-sign adjudication. Of these participants, 64 (25.2%) were spot-sign positive. Median (interquartile range) time from symptom onset to administration of the intervention was 225.0 (169.0 to 310.0) minutes. The adjusted percent difference in absolute day-2 hematoma volume between participants allocated to tranexamic versus placebo was 3.7% (95% CI, -12.8% to 23.4%) for spot-sign positive and 1.7% (95% CI, -8.4% to 12.8%) for spot-sign negative participants (Pheterogenity=0.85). No difference was observed in significant hematoma progression (dichotomous composite outcome) between participants allocated to tranexamic versus placebo among spot-sign positive (odds ratio, 0.85 [95% CI, 0.29 to 2.46]) and negative (odds ratio, 0.77 [95% CI, 0.41 to 1.45]) participants (Pheterogenity=0.88).

    CONCLUSIONS: Data from the TICH-2 trial do not support that admission spot sign status modifies the treatment effect of tranexamic acid versus placebo in patients with acute intracerebral hemorrhage. The results might have been affected by low statistical power as well as treatment delay. Registration: URL: http://www.controlled-trials.com; Unique identifier: ISRCTN93732214.

  6. Blair GW, Appleton JP, Flaherty K, Doubal F, Sprigg N, Dooley R, et al.
    EClinicalMedicine, 2019 04 24;11:34-43.
    PMID: 31317131 DOI: 10.1016/j.eclinm.2019.04.001
    Background: Lacunar stroke, a frequent clinical manifestation of small vessel disease (SVD), differs pathologically from other ischaemic stroke subtypes and has no specific long-term secondary prevention. Licenced drugs, isosorbide mononitrate (ISMN) and cilostazol, have relevant actions to prevent SVD progression.

    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).

  7. Blair GW, Appleton JP, Law ZK, Doubal F, Flaherty K, Dooley R, et al.
    Int J Stroke, 2018 07;13(5):530-538.
    PMID: 28906205 DOI: 10.1177/1747493017731947
    Rationale The pathophysiology of most lacunar stroke, a form of small vessel disease, is thought to differ from large artery atherothrombo- or cardio-embolic stroke. Licensed drugs, isosorbide mononitrate and cilostazol, have promising mechanisms of action to support their testing to prevent stroke recurrence, cognitive impairment, or radiological progression after lacunar stroke. Aim LACI-1 will assess the tolerability, safety, and efficacy, by dose, of isosorbide mononitrate and cilostazol, alone and in combination, in patients with ischemic lacunar stroke. Sample size A sample of 60 provides 80+% power (significance 0.05) to detect a difference of 35% (90% versus 55%) between those reaching target dose on one versus both drugs. Methods and design LACI-1 is a phase IIa partial factorial, dose-escalation, prospective, randomized, open label, blinded endpoint trial. Participants are randomized to isosorbide mononitrate and/or cilostazol for 11 weeks with dose escalation to target as tolerated in two centers (Edinburgh, Nottingham). At three visits, tolerability, safety, blood pressure, pulse wave velocity, and platelet function are assessed, plus magnetic resonance imaging to assess cerebrovascular reactivity in a subgroup. Study outcomes Primary: proportion of patients completing study achieving target maximum dose. Secondary symptoms whilst taking medications; safety (hemorrhage, recurrent vascular events, falls); blood pressure, platelet function, arterial stiffness, and cerebrovascular reactivity. Discussion This study will inform the design of a larger phase III trial of isosorbide mononitrate and cilostazol in lacunar stroke, whilst providing data on the drugs' effects on vascular and platelet function. Trial registration ISRCTN (ISRCTN12580546) and EudraCT (2015-001953-33).
  8. Sprigg N, Flaherty K, Appleton JP, Al-Shahi Salman R, Bereczki D, Beridze M, et al.
    Health Technol Assess, 2019 07;23(35):1-48.
    PMID: 31322116 DOI: 10.3310/hta23350
    BACKGROUND: Tranexamic acid reduces death due to bleeding after trauma and postpartum haemorrhage.

    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.

  9. Sprigg N, Flaherty K, Appleton JP, Al-Shahi Salman R, Bereczki D, Beridze M, et al.
    Lancet, 2018 May 26;391(10135):2107-2115.
    PMID: 29778325 DOI: 10.1016/S0140-6736(18)31033-X
    BACKGROUND: Tranexamic acid can prevent death due to bleeding after trauma and post-partum haemorrhage. We aimed to assess whether tranexamic acid reduces haematoma expansion and improves outcome in adults with stroke due to intracerebral haemorrhage.

    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.

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