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

BackgroundTranexamic acid (TXA) reduces death due to bleeding after trauma and post-partum haemorrhage. The aim was to assess if tranexamic acid reduces haematoma expansion and improves outcome in adults with stroke due to intracerebral 6 haemorrhage (ICH). MethodsWe undertook an international, randomised placebo-controlled trial in adults with intracerebral haemorrhage. Participants received 1g intravenous tranexamic acid bolus followed by an 8 hour 1g infusion, or matching placebo, within 8 hours of symptom onset. The primary outcome was functional status at day 90, measured by shift in the modified Rankin Scale (mRS), using ordinal logistic regression, with adjustment for stratification and minimisation criteria. All analyses were performed on an intention to treat basis. This trial is registered as ISRCTN93732214.FindingsWe recruited 2,325 participants (TXA 1161, placebo 1164) from 124 hospitals in 12 countries between 2013 and 2017. Treatment groups were well balanced at baseline. The primary outcome was determined for 2307 (99·2%) participants. There was no statistically significant difference between the groups for the primary outcome of functional status at day 90 (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 TXA group (aOR 0·73, 95% CI 0·53-0·99, p=0·0406), 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). There were fewer serious adverse events after TXA vs. placebo by days 2 (p=0·0272), 7 (p=0·0200) and 90 (p=0·0393).InterpretationThere was no significant difference in functional status 90 days after intracerebral haemorrhage with tranexamic acid, despite a reduction in early deaths and serious adverse events. Larger randomised trials are needed to confirm or refute a clinically significant treatment effect

Feasibility of progesterone treatment for ischaemic stroke

Two multi-centre phase III clinical trials examining the protective potential of progesterone following traumatic brain injury have recently failed to demonstrate any improvement in outcome. Thus, it is timely to consider how this impacts on the translational potential of progesterone treatment for ischaemic stroke. A wealth of experimental evidence supports the neuroprotective properties of progesterone, and associated metabolites, following various types of central nervous system injury. In particular, for ischaemic stroke, studies have also begun to reveal possible mechanisms of such neuroprotection. However, the results in traumatic brain injury now question whether further clinical development of progesterone for ischaemic stroke is relevant

Consent as an ethical consideration in the conduct of prehospital ambulance randomised controlled clinical trials: a systematic review

Background: Clinical trials in the ambulance setting are essential for providing the basis for evidence based healthcare in the prehospital environment. As the number and complexity of ambulance trials increases the ethical issues involved in such trials. We sought to understand the main ethical considerations when conducting clinical trials in the prehospital ambulance based setting. Methods: We conducted a systematic review of ethical issues considered in randomised controlled trials in ambulance settings. A search of eight databases identified ethical issues discussed in published studies involving recruitment of ambulance service users. Four independent authors undertook abstract and full-text reviews to determine eligibility and then extracted relevant data. The data extraction concentrated on ethical considerations, with any discussion of ethics being included for further analysis. The resultant data were combined to form a narrative synthesis.Results: In all, 56 papers were identified as meeting the inclusion criteria. Issues relating to consent were the most significant theme identified. Several consent models were used ranging from informed consent to exception from informed consent (also termed waiver of consent). Type of consent differed depending on the clinical condition or the intervention being studied. The country in which the research took place did not appear to influence the type of consent, apart from the USA where exception from informed consent appeared to be most commonly used. Many studies cited international guidelines as informing their choice of consent model and diverse and sometimes confused terms were used to describe these models.Conclusions: Consent was the main ethical consideration in published ambulance based research. A wide range of terms was used to describe consent and terms were sometimes confused or used inconsistently. This suggests that standardisation of consent models and the terminology used to describe them may be helpful for researchers, ethics committees and research participants.</p

Baseline characteristics by treatment groups.

<p>Data are shown as mean (standard deviation) and number (%).</p

Recruitment flow chart.

<p>Recruitment flow chart.</p

Serious Adverse Events, by group and time to event in days; includes all SAEs up to day 90, and any fatal SAEs post day 90.

<p>Serious Adverse Events, by group and time to event in days; includes all SAEs up to day 90, and any fatal SAEs post day 90.</p

Recovery outcome measures by treatment group (bars represent the standard error).

<p>a) Rivermead Motor Assessment (RMA) by G-CSF vs. placebo. b) Quality of life (EQ-5D) by G-CSF vs. placebo. c) Rivermead Motor Assessment (RMA) by physiotherapy vs. control. d) Quality of life (EQ-5D) by physiotherapy vs. control.</p

Relationship between nitrate headache and outcome in patients with acute stroke: results from the efficacy of nitric oxide in stroke (ENOS) trial

Introduction Nitrate-induced headache is common and may signify responsive cerebral vasculature. We assessed the relationship between nitrate headache and outcome in patients with acute stroke. Materials and methods Patients were those randomised to glyceryl trinitrate (GTN) versus no GTN in the efficacy of nitric oxide in stroke trial. Development of headache by end of treatment (day 7), and functional outcome (modified Rankin Scale, primary outcome) at day 90, were assessed. Analyses are adjusted for baseline prognostic factors and give OR and mean difference (MD) with 95% CI. Results In 4011 patients, headache was more common in GTN than control (360, 18.0% vs 170, 8.5%; p Discussion and conclusion Development of a nitrate headache by day 7 after stroke may be associated with improved activities of daily living and cognitive impairment at day 90, which was not seen with non-nitrate headache.</p

CONSORT flow diagram of patient randomisation, follow up, outcome, and withdrawals.

<p>Screening for eligibility was not collected routinely. Data are number/Number (%).</p

Clinical characteristics at randomisation, by intensive vs guideline blood pressure and lipid lowering.

<p>Clinical characteristics at randomisation, by intensive vs guideline blood pressure and lipid lowering.</p