The ESCAPS study: a feasibility randomized controlled trial of early electrical stimulation to the wrist extensors and flexors to prevent post-stroke complications of pain and contractures in the paretic arm.

OBJECTIVE: To establish feasibility of initiating electrical stimulation treatment of wrist extensors and flexors in patients early after stroke to prevent muscle contractures and pain. DESIGN: Feasibility randomized controlled trial with economic evaluation. SETTING: A specialist stroke unit in Nottinghamshire. SUBJECTS: A total of 40 patients recruited within 72 hours post-stroke with arm hemiparesis. INTERVENTIONS: Participants were randomized to receive usual care or usual care and electrical stimulation to wrist flexors and extensors for 30 minutes, twice a day, five days a week for three months. Initial treatment was delivered by an occupational therapist or physiotherapist who trained participants to self-manage subsequent treatments. MEASURES: Measures of feasibility included recruitment and attrition rates, completion of treatment, and successful data collection. Outcome data on wrist range of motion, pain, arm function, independence, quality of life, and resource use were measured at 3-, 6-, and 12-months post-randomization. RESULTS: A total of 40 participants (of 215 potentially eligible) were recruited in 15 months (20 men; mean age: 72 (SD: 13.0)). Half the participants lacked mental capacity and were recruited by consultee consent. Attrition at three-month follow-up was 12.5% (death (n = 2), end-of-life care (n = 2), and unable to contact (n = 1)). Compliance varied (mean: 65 (SD: 53)) and ranged from 10 to 166 treatments per patient (target dosage was 120). Data for a valid economic analysis can be adequately collected. CONCLUSION: Early initiation of electrical stimulation was acceptable and feasible. Data collection methods used were feasible and acceptable to participants. A large definitive study is needed to determine if electrical stimulation is efficacious and cost effective.

Tranexamic acid to improve functional status in adults with spontaneous intracerebral haemorrhage: the TICH-2 RCT.

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 < 3 months; and a Glasgow Coma Scale score of < 5. INTERVENTIONS: Participants, allocated by randomisation, received 1 g of an intravenous tranexamic acid bolus followed by an 8-hour 1-g infusion or matching placebo (i.e. 0.9% saline). MAIN OUTCOME MEASURE: The primary outcome was functional status (death or dependency) at day 90, which was measured by the shift in the mRS score, using ordinal logistic regression, with adjustment for stratification and minimisation criteria. RESULTS: A total of 2325 participants (tranexamic acid, n = 1161; placebo, n = 1164) were recruited from 124 hospitals in 12 countries between 2013 and 2017. Treatment groups were well balanced at baseline. The primary outcome was determined for 2307 participants (tranexamic acid, n = 1152; placebo, n = 1155). There was no statistically significant difference between the treatment groups for the primary outcome of functional status at day 90 [adjusted odds ratio (aOR) 0.88, 95% confidence interval (CI) 0.76 to 1.03; p = 0.11]. Although there were fewer deaths by day 7 in the tranexamic acid group (aOR 0.73, 95% CI 0.53 to 0.99; p = 0.041), there was no difference in case fatality at 90 days (adjusted hazard ratio 0.92, 95% CI 0.77 to 1.10; p = 0.37). Fewer patients experienced serious adverse events (SAEs) after treatment with tranexamic acid than with placebo by days 2 (p = 0.027), 7 (p = 0.020) and 90 (p = 0.039). There was no increase in thromboembolic events or seizures. LIMITATIONS: Despite attempts to enrol patients rapidly, the majority of participants were enrolled and treated > 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.

BACKGROUND: Stroke caused by bleeding in the brain [i.e. an intracerebral haemorrhage (ICH)] is a medical emergency. Around one-third of such strokes are complicated by continuing bleeding, which usually occurs within the first few hours after trauma and childbirth, and is associated with death or severe disability. Tranexamic acid is a drug that is seen to reduce death from bleeding after trauma and childbirth. METHODS: The study enrolled adults within 8 hours of an ICH into this large randomised trial. Half of the participants were given an injection of tranexamic acid and the other half placebo (in the form of salt water). The main aim of the trial was to measure changes in recovery by a telephone questionnaire on how much the person was able to do or needed help with 90 days after the stroke (i.e. functional status). Other measures included amount of brain bleeding, complications after stroke (serious adverse events), drug side effects and death within 7 days of stroke. RESULTS: A total of 2325 participants from 124 hospitals in 12 countries were enrolled between 2013 and 2017. Participants treated with tranexamic acid had no significant difference in functional status 90 days after stroke. There were small but significant reductions in brain bleeding, death in the first 7 days and complications after stroke, and tranexamic acid was safe with no increased side effects. CONCLUSION: Treatment with tranexamic acid did not result in a significant improvement in recovery at 90 days (i.e. functional status), despite small reductions in the number of early deaths, amount of brain bleeding and the number of complications. Larger trials are needed to confirm if these small benefits observed after treatment with tranexamic acid can significantly improve functional status after stroke due to bleeding in the brain (ICH).

Triple versus guideline antiplatelet therapy to prevent recurrence after acute ischaemic stroke or transient ischaemic attack: the TARDIS RCT.

BACKGROUND: Two antiplatelet agents are better than one for preventing recurrent stroke after acute ischaemic stroke or transient ischaemic attack (TIA). Therefore, intensive treatment with three agents might be better still, providing it does not cause undue bleeding. OBJECTIVE: To compare the safety and efficacy of intensive therapy with guideline antiplatelet therapy for acute ischaemic stroke and TIA. DESIGN: International prospective randomised open-label blinded end-point parallel-group superiority clinical trial. SETTING: Acute hospitals at 106 sites in four countries. PARTICIPANTS: Patients > 50 years of age with acute non-cardioembolic ischaemic stroke or TIA within 48 hours of ictus (stroke). INTERVENTIONS: Participants were allocated at random by computer to 1 month of intensive (combined aspirin, clopidogrel and dipyridamole) or guideline (combined aspirin and dipyridamole, or clopidogrel alone) antiplatelet agents, and followed for 90 days. MAIN OUTCOME MEASURES: The primary outcome was the incidence and severity of any recurrent stroke (ischaemic, haemorrhagic; assessed using the modified Rankin Scale) or TIA within 90 days by blinded telephone follow-up. Analysis using ordinal logistic regression was by intention to treat. Other outcomes included bleeding and its severity, death, myocardial infarction (MI), disability, mood, cognition and quality of life. RESULTS: The trial was stopped early on the recommendation of the Data Monitoring Committee after recruitment of 3096 participants (intensive, n = 1556; guideline, n = 1540) from 106 hospitals in four countries between April 2009 and March 2016. The incidence and severity of recurrent stroke or TIA did not differ between intensive and guideline therapy in 3070 (99.2%) participants with data [93 vs. 105 stroke/TIA events; adjusted common odds ratio 0.90, 95% confidence interval (CI) 0.67 to 1.20; p = 0.47]. Major (encompassing fatal) bleeding was increased with intensive as compared with guideline therapy [39 vs. 17 participants; adjusted hazard ratio (aHR) 2.23, 95% CI 1.25 to 3.96; p = 0.006]. There were no differences between the treatment groups in all-cause mortality, or the composite of death, stroke, MI and major bleeding (aHR 1.02, 95% CI 0.77 to 1.35; p = 0.88). LIMITATIONS: Patients and investigators were not blinded to treatment. The comparator group comprised two guideline strategies because of changes in national guidelines during the trial. The trial was stopped early, thereby reducing its statistical power. CONCLUSIONS: The use of three antiplatelet agents is associated with increased bleeding without any significant reduction in recurrence of stroke or TIA. FUTURE WORK: The safety and efficacy of dual antiplatelet therapy (combined aspirin and clopidogrel) versus aspirin remains to be defined. Further research is required on identifying individual patient response to antiplatelets, and the relationship between response and the subsequent risks of vascular recurrent events and bleeding complications. TRIAL REGISTRATION: Current Controlled Trials ISRCTN47823388. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 48. See the NIHR Journal Library website for further project information. The Triple Antiplatelets for Reducing Dependency after Ischaemic Stroke (TARDIS) vanguard phase was funded by the British Heart Foundation (grant PG/08/083/25779, from 1 April 2009 to 30 September 2012) and indirect funding was provided by the Stroke Association through its funding of the Stroke Trials Unit, Division of Clinical Neuroscience, University of Nottingham, Nottingham, UK. There was no commercial support for the trial and antiplatelet drugs were sourced locally at each site. The trial was sponsored by the University of Nottingham.

Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage (TICH-2): an international randomised, placebo-controlled, phase 3 superiority trial.

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.

Antiplatelet therapy with aspirin, clopidogrel, and dipyridamole versus clopidogrel alone or aspirin and dipyridamole in patients with acute cerebral ischaemia (TARDIS): a randomised, open-label, phase 3 superiority trial.

BACKGROUND: Intensive antiplatelet therapy with three agents might be more effective than guideline treatment for preventing recurrent events in patients with acute cerebral ischaemia. We aimed to compare the safety and efficacy of intensive antiplatelet therapy (combined aspirin, clopidogrel, and dipyridamole) with that of guideline-based antiplatelet therapy. METHODS: We did an international, prospective, randomised, open-label, blinded-endpoint trial in adult participants with ischaemic stroke or transient ischaemic attack (TIA) within 48 h of onset. Participants were assigned in a 1:1 ratio using computer randomisation to receive loading doses and then 30 days of intensive antiplatelet therapy (combined aspirin 75 mg, clopidogrel 75 mg, and dipyridamole 200 mg twice daily) or guideline-based therapy (comprising either clopidogrel alone or combined aspirin and dipyridamole). Randomisation was stratified by country and index event, and minimised with prognostic baseline factors, medication use, time to randomisation, stroke-related factors, and thrombolysis. The ordinal primary outcome was the combined incidence and severity of any recurrent stroke (ischaemic or haemorrhagic; assessed using the modified Rankin Scale) or TIA within 90 days, as assessed by central telephone follow-up with masking to treatment assignment, and analysed by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN47823388. FINDINGS: 3096 participants (1556 in the intensive antiplatelet therapy group, 1540 in the guideline antiplatelet therapy group) were recruited from 106 hospitals in four countries between April 7, 2009, and March 18, 2016. The trial was stopped early on the recommendation of the data monitoring committee. The incidence and severity of recurrent stroke or TIA did not differ between intensive and guideline therapy (93 [6%] participants vs 105 [7%]; adjusted common odds ratio [cOR] 0·90, 95% CI 0·67-1·20, p=0·47). By contrast, intensive antiplatelet therapy was associated with more, and more severe, bleeding (adjusted cOR 2·54, 95% CI 2·05-3·16, p<0·0001). INTERPRETATION: Among patients with recent cerebral ischaemia, intensive antiplatelet therapy did not reduce the incidence and severity of recurrent stroke or TIA, but did significantly increase the risk of major bleeding. Triple antiplatelet therapy should not be used in routine clinical practice. FUNDING: National Institutes of Health Research Health Technology Assessment Programme, British Heart Foundation.

Stroke in women - from evidence to inequalities.

Stroke is the second largest cause of disability-adjusted life-years lost worldwide. The prevalence of stroke in women is predicted to rise rapidly, owing to the increasing average age of the global female population. Vascular risk factors differ between women and men in terms of prevalence, and evidence increasingly supports the clinical importance of sex differences in stroke. The influence of some risk factors for stroke - including diabetes mellitus and atrial fibrillation - are stronger in women, and hypertensive disorders of pregnancy also affect the risk of stroke decades after pregnancy. However, in an era of evidence-based medicine, women are notably under-represented in clinical trials - despite governmental actions highlighting the need to include both men and women in clinical trials - resulting in a reduced generalizability of study results to women. The aim of this Review is to highlight new insights into specificities of stroke in women, to plan future research priorities, and to influence public health policies to decrease the worldwide burden of stroke in women.

Remote Assessment of Platelet Function in Patients with Acute Stroke or Transient Ischaemic Attack.

BACKGROUND: The TARDIS trial assessed the safety and efficacy of intensive versus guideline antiplatelet agents given for one month in patients with acute stroke or TIA. The aim of this substudy was to assess the effect of antiplatelet agents taken at baseline on platelet function reactivity and activation. METHODS: Platelet function, assessed by remotely measured surface expression of P-selectin, was assessed in patients at their time of randomisation. Data are median fluorescence values. RESULTS: The aspirin P-selectin test demonstrated that platelet expression was lower in 494 patients taking aspirin than in 162 patients not: mean 210 (SD 188) versus 570 (435), difference 360.3 (95% CI 312.2-408.4) (2p < 0.001). Aspirin did not suppress P-selectin levels below 500 units in 23 (4.7%) patients. The clopidogrel test showed that platelet reactivity was lower in 97 patients taking clopidogrel than in 585 patients not: 655 (296) versus 969 (315), difference 314.5 (95% CI 247.3-381.7) (2p < 0.001). Clopidogrel did not suppress P-selectin level below 860 units in 24 (24.7%) patients. CONCLUSIONS: Aspirin and clopidogrel suppress stimulated platelet P-selectin, although one-quarter of patients on clopidogrel have high on-treatment platelet reactivity. Platelet function testing may be performed remotely in the context of a large multicentre trial. Trial registration ISRCTN47823388.

ESCAPS study protocol: a feasibility randomised controlled trial of 'Early electrical stimulation to the wrist extensors and wrist flexors to prevent the post-stroke complications of pain and contractures in the paretic arm'.

INTRODUCTION: Approximately 70% of patients with stroke experience impaired arm function, which is persistent and disabling for an estimated 40%. Loss of function reduces independence in daily activities and impacts on quality of life. Muscles in those who do not recover functional movement in the stroke affected arm are at risk of atrophy and contractures, which can be established as early as 6 weeks following stroke. Pain is also common. This study aims to evaluate the feasibility of a randomised controlled trial to test the efficacy and cost-effectiveness of delivering early intensive electrical stimulation (ES) to prevent post-stroke complications in the paretic upper limb. METHODS AND ANALYSIS: This is a feasibility randomised controlled trial (n=40) with embedded qualitative studies (patient/carer interviews and therapist focus groups) and feasibility economic evaluation. Patients will be recruited from the Stroke Unit at the Nottingham University Hospitals National Health Service (NHS) Trust within 72 h after stroke. Participants will be randomised to receive usual care or usual care and early ES to the wrist flexors and extensors for 30 min twice a day, 5 days a week for 3 months. The initial treatment(s) will be delivered by an occupational therapist or physiotherapist who will then train the patient and/or their nominated carer to self-manage subsequent treatments. ETHICS AND DISSEMINATION: This study has been granted ethical approval by the National Research Ethics Service, East Midlands Nottingham1 Research Ethics Committee (ref: 15/EM/0006). To our knowledge, this is the first study of its kind of the early application (within 72 h post-stroke) of ES to both the wrist extensors and wrist flexors of stroke survivors with upper limb impairment. The results will inform the design of a definitive randomised controlled trial. Dissemination will include 2 peer-reviewed journal publications and presentations at national conferences. TRIAL REGISTRATION NUMBER: ISRCTN1648908; Pre-results. Clinicaltrials.gov ID: NCT02324634.

Statistical analysis plan for the 'Triple Antiplatelets for Reducing Dependency after Ischaemic Stroke' (TARDIS) trial.

RATIONALE: Antiplatelet agents such as aspirin, clopidogrel and dipyridamole are effective in reducing the risk of recurrence after a stroke. Importantly, the risk of recurrence is highest immediately after the index event while antiplatelets cause bleeding. AIMS AND/OR HYPOTHESIS: The 'Triple Antiplatelets for Reducing Dependency after Ischaemic Stroke' (TARDIS) trial is testing whether short-term intensive antiplatelet therapy is safe and effective in reducing the early risk of recurrence as compared with standard guideline-based therapy. DESIGN: TARDIS is an international multi-center prospective randomized open-label blinded-end-point trial, with funding from the UK Health Technology Assessment program. Patients with acute ischemic stroke or transient ischemic attack are randomized within 48 h to intensive/triple antiplatelet therapy or guideline antiplatelets taken for one-month. Patients or relatives give written informed (proxy) consent and all sites have research ethics approval. Analyses will be done by intention-to-treat. STUDY OUTCOME: The primary outcome is shift in stroke recurrent events and their severity, assessed using the modified Rankin Scale, at three-months. DISCUSSION: This paper and attachment describe the trial's statistical analysis plan, as developed from the protocol during recruitment and prior to unblinding of data. The statistical analysis plan contains design and methods for analyses, and unpopulated tables and figures for the primary and baseline publications. The data from the trial will provide the first large-scale randomized evidence for the use of intensive antiplatelet therapy for preventing recurrence after acute stroke and transient ischemic attack.