Influence of Time to Achieve Target Systolic Blood Pressure on Outcome After Intracerebral Hemorrhage: The Blood Pressure in Acute Stroke Collaboration.

OBJECTIVE: To investigate whether an earlier time to achieving and maintaining systolic blood pressure (SBP) at 120 to 140 mm Hg is associated with favorable outcomes in a cohort of patients with acute intracerebral hemorrhage. METHODS: We pooled individual patient data from randomized controlled trials registered in the Blood Pressure in Acute Stroke Collaboration. Time was defined as time form symptom onset plus the time (hour) to first achieve and subsequently maintain SBP at 120 to 140 mm Hg over 24 hours. The primary outcome was functional status measured by the modified Rankin Scale at 90 to 180 days. A generalized linear mixed models was used, with adjustment for covariables and trial as a random effect. RESULTS: A total of 5761 patients (mean age, 64.0 [SD, 13.0], 2120 [36.8%] females) were included in analyses. Earlier SBP control was associated with better functional outcomes (modified Rankin Scale score, 3-6; odds ratio, 0.98 [95% CI, 0.97-0.99]) and a significant lower risk of hematoma expansion (0.98, 0.96-1.00). This association was stronger in patients with bigger baseline hematoma volume (>10 mL) compared with those with baseline hematoma volume ≤10 mL (0.006 for interaction). Earlier SBP control was not associated with cardiac or renal adverse events. CONCLUSIONS: Our study confirms a clear time relation between early versus later SBP control (120-140 mm Hg) and outcomes in the one-third of patients with intracerebral hemorrhage who attained sustained SBP levels within this range. These data provide further support for the value of early recognition, rapid transport, and prompt initiation of treatment of patients with intracerebral hemorrhage.

Early lowering of blood pressure after acute intracerebral haemorrhage: a systematic review and meta-analysis of individual patient data.

OBJECTIVE: To summarise evidence of the effects of blood pressure (BP)-lowering interventions after acute spontaneous intracerebral haemorrhage (ICH). METHODS: A prespecified systematic review of the Cochrane Central Register of Controlled Trials, EMBASE and MEDLINE databases from inception to 23 June 2020 to identify randomised controlled trials that compared active BP-lowering agents versus placebo or intensive versus guideline BP-lowering targets for adults <7 days after ICH onset. The primary outcome was function (distribution of scores on the modified Rankin scale) 90 days after randomisation. Radiological outcomes were absolute (>6 mL) and proportional (>33%) haematoma growth at 24 hours. Meta-analysis used a one-stage approach, adjusted using generalised linear mixed models with prespecified covariables and trial as a random effect. RESULTS: Of 7094 studies identified, 50 trials involving 11 494 patients were eligible and 16 (32.0%) shared patient-level data from 6221 (54.1%) patients (mean age 64.2 [SD 12.9], 2266 [36.4%] females) with a median time from symptom onset to randomisation of 3.8 hours (IQR 2.6-5.3). Active/intensive BP-lowering interventions had no effect on the primary outcome compared with placebo/guideline treatment (adjusted OR for unfavourable shift in modified Rankin scale scores: 0.97, 95% CI 0.88 to 1.06; p=0.50), but there was significant heterogeneity by strategy (pinteraction=0.031) and agent (pinteraction<0.0001). Active/intensive BP-lowering interventions clearly reduced absolute (>6 ml, adjusted OR 0.75, 95%CI 0.60 to 0.92; p=0.0077) and relative (≥33%, adjusted OR 0.82, 95%CI 0.68 to 0.99; p=0.034) haematoma growth. INTERPRETATION: Overall, a broad range of interventions to lower BP within 7 days of ICH onset had no overall benefit on functional recovery, despite reducing bleeding. The treatment effect appeared to vary according to strategy and agent. PROSPERO REGISTRATION NUMBER: CRD42019141136.

Pre-hospital transdermal glyceryl trinitrate in patients with stroke mimics: data from the RIGHT-2 randomised-controlled ambulance trial.

BACKGROUND: Prehospital stroke trials will inevitably recruit patients with non-stroke conditions, so called stroke mimics. We undertook a pre-specified analysis to determine outcomes in patients with mimics in the second Rapid Intervention with Glyceryl trinitrate in Hypertensive stroke Trial (RIGHT-2). METHODS: RIGHT-2 was a prospective, multicentre, paramedic-delivered, ambulance-based, sham-controlled, participant-and outcome-blinded, randomised-controlled trial of transdermal glyceryl trinitrate (GTN) in adults with ultra-acute presumed stroke in the UK. Final diagnosis (intracerebral haemorrhage, ischaemic stroke, transient ischaemic attack, mimic) was determined by the hospital investigator. This pre-specified subgroup analysis assessed the safety and efficacy of transdermal GTN (5 mg daily for 4 days) versus sham patch among stroke mimic patients. The primary outcome was the 7-level modified Rankin Scale (mRS) at 90 days. RESULTS: Among 1149 participants in RIGHT-2, 297 (26%) had a final diagnosis of mimic (GTN 134, sham 163). The mimic group were younger, mean age 67 (SD: 18) vs 75 (SD: 13) years, had a longer interval from symptom onset to randomisation, median 75 [95% CI: 47,126] vs 70 [95% CI:45,108] minutes, less atrial fibrillation and a lower systolic blood pressure and Face-Arm-Speech-Time tool score than the stroke group. The three most common mimic diagnoses were seizure (17%), migraine or primary headache disorder (17%) and functional disorders (14%). At 90 days, the GTN group had a better mRS score as compared to the sham group (adjusted common odds ratio 0.54; 95% confidence intervals 0.34, 0.85; p = 0.008), a difference that persisted at 365 days. There was no difference in the proportion of patients who died in hospital, were discharged to a residential care facility, or suffered a serious adverse event. CONCLUSIONS: One-quarter of patients suspected by paramedics to have an ultra-acute stroke were subsequently diagnosed with a non-stroke condition. GTN was associated with unexplained improved functional outcome observed at 90 days and one year, a finding that may represent an undetected baseline imbalance, chance, or real efficacy. GTN was not associated with harm. TRIAL REGISTRATION: This trial is registered with International Standard Randomised Controlled Trials Number ISRCTN 26986053 .

Statistical reanalysis of vascular event outcomes in primary and secondary vascular prevention trials.

BACKGROUND: Vascular prevention trials typically use dichotomous event outcomes although this may be inefficient statistically and gives no indication of event severity. We assessed whether ordinal outcomes would be more efficient and how to best analyse them. METHODS: Chief investigators of vascular prevention randomised controlled trials that showed evidence of either benefit or harm, or were included in a systematic review that overall showed benefit or harm, shared individual participant data from their trials. Ordered categorical versions of vascular event outcomes (such as stroke and myocardial infarction) were analysed using 15 statistical techniques and their results then ranked, with the result with the smallest p-value given the smallest rank. Friedman and Duncan's multiple range tests were performed to assess differences between tests by comparing the average ranks for each statistical test. RESULTS: Data from 35 trials (254,223 participants) were shared with the collaboration. 13 trials had more than two treatment arms, resulting in 59 comparisons. Analysis approaches (Mann Whitney U, ordinal logistic regression, multiple regression, bootstrapping) that used ordinal outcome data had a smaller average rank and therefore appeared to be more efficient statistically than those that analysed the original binary outcomes. CONCLUSIONS: Ordinal vascular outcome measures appear to be more efficient statistically than binary outcomes and provide information on the severity of event. We suggest a potential role for using ordinal outcomes in vascular prevention trials.

Noncontrast Computed Tomography Signs as Predictors of Hematoma Expansion, Clinical Outcome, and Response to Tranexamic Acid in Acute Intracerebral Hemorrhage.

Background and Purpose- Blend, black hole, island signs, and hypodensities are reported to predict hematoma expansion in acute intracerebral hemorrhage. We explored the value of these noncontrast computed tomography signs in predicting hematoma expansion and functional outcome in our cohort of intracerebral hemorrhage. Methods- The TICH-2 (Tranexamic acid for IntraCerebral Hemorrhage-2) was a prospective randomized controlled trial exploring the efficacy and safety of tranexamic acid in acute intracerebral hemorrhage. Baseline and 24-hour computed tomography scans of trial participants were analyzed. Hematoma expansion was defined as an increase in hematoma volume of >33% or >6 mL on 24-hour computed tomography. Poor functional outcome was defined as modified Rankin Scale of 4 to 6 at day 90. Multivariable logistic regression was performed to identify predictors of hematoma expansion and poor functional outcome. Results- Of 2325 patients recruited, 2077 (89.3%) had valid baseline and 24-hour scans. Five hundred seventy patients (27.4%) had hematoma expansion while 1259 patients (54.6%) had poor functional outcome. The prevalence of noncontrast computed tomography signs was blend sign, 366 (16.1%); black hole sign, 414 (18.2%); island sign, 200 (8.8%); and hypodensities, 701 (30.2%). Blend sign (adjusted odds ratio [aOR] 1.53 [95% CI, 1.16-2.03]; P=0.003), black hole (aOR, 2.03 [1.34-3.08]; P=0.001), and hypodensities (aOR, 2.06 [1.48-2.89]; P<0.001) were independent predictors of hematoma expansion on multivariable analysis with adjustment for covariates. Black hole sign (aOR, 1.52 [1.10-2.11]; P=0.012), hypodensities (aOR, 1.37 [1.05-1.78]; P=0.019), and island sign (aOR, 2.59 [1.21-5.55]; P=0.014) were significant predictors of poor functional outcome. Tranexamic acid reduced the risk of hematoma expansion (aOR, 0.77 [0.63-0.94]; P=0.010), but there was no significant interaction between the presence of noncontrast computed tomography signs and benefit of tranexamic acid on hematoma expansion and functional outcome (P interaction all >0.05). Conclusions- Blend sign, black hole sign, and hypodensities predict hematoma expansion while black hole sign, hypodensities, and island signs predict poor functional outcome. Noncontrast computed tomography signs did not predict a better response to tranexamic acid. Clinical Trial Registration- URL: https://www.isrctn.com. Unique identifier: ISRCTN93732214.

Cost-benefit of outcome adjudication in nine randomised stroke trials.

BACKGROUND: Central adjudication of outcomes is common for randomised trials and should control for differential misclassification. However, few studies have estimated the cost of the adjudication process. METHODS: We estimated the cost of adjudicating the primary outcome in nine randomised stroke trials (25,436 participants). The costs included adjudicators' time, direct payments to adjudicators, and co-ordinating centre costs (e.g. uploading cranial scans and general set-up costs). The number of events corrected after adjudication was our measure of benefit. We calculated cost per corrected event for each trial and in total. RESULTS: The primary outcome in all nine trials was either stroke or a composite that included stroke. In total, the adjudication process associated with this primary outcome cost in excess of £100,000 for a third of the trials (3/9). Mean cost per event corrected by adjudication was £2295.10 (SD: £1482.42). CONCLUSIONS: Central adjudication is a time-consuming and potentially costly process. These costs need to be considered when designing a trial and should be evaluated alongside the potential benefits adjudication brings to determine whether they outweigh this expense.

Effect of Glyceryl Trinitrate on Hemodynamics in Acute Stroke.

Background and Purpose- Increased blood pressure (BP), heart rate, and their derivatives (variability, pulse pressure, rate-pressure product) are associated with poor clinical outcome in acute stroke. We assessed the effects of glyceryl trinitrate (GTN) on hemodynamic parameters and these on outcome in participants in the ENOS trial (Efficacy of Nitric Oxide in Stroke). Methods- Four thousand and eleven patients with acute stroke and raised BP were randomized within 48 hours of onset to transdermal GTN or no GTN for 7 days. Peripheral hemodynamics were measured at baseline (3 measures) and daily (2 measures) during treatment. Between-visit BP variability over days 1 to 7 (as SD) was assessed in quintiles. Functional outcome was assessed as modified Rankin Scale and cognition as telephone mini-mental state examination at day 90. Analyses were adjusted for baseline prognostic variables. Data are mean difference or odds ratios with 95% CI. Results- Increased baseline BP (diastolic, variability), heart rate, and rate-pressure product were each associated with unfavorable functional outcome at day 90. Increased between-visit systolic BP variability was associated with an unfavourable shift in modified Rankin Scale (highest quintile adjusted odds ratio, 1.65; 95% CI, 1.37-1.99), worse cognitive scores (telephone mini-mental state examination: highest quintile adjusted mean difference, -2.03; 95% CI, -2.84 to -1.22), and increased odds of death at day 90 (highest quintile adjusted odds ratio, 1.57; 95% CI, 1.12-2.19). GTN lowered BP and rate-pressure product and increased heart rate at day 1 and reduced between-visit systolic BP variability. Conclusions- Increased between-visit BP variability was associated with poor functional and cognitive outcomes and increased death 90 days after acute stroke. In addition to lowering BP and rate-pressure product, GTN reduced between-visit systolic BP variability. Agents that lower BP variability in acute stroke require further study.

Prehospital Transdermal Glyceryl Trinitrate for Ultra-Acute Intracerebral Hemorrhage: Data From the RIGHT-2 Trial.

Background and Purpose- Pilot trials suggest that glyceryl trinitrate (GTN; nitroglycerin) may improve outcome when administered early after stroke onset. Methods- We undertook a multicentre, paramedic-delivered, ambulance-based, prospective randomized, sham-controlled, blinded-end point trial in adults with presumed stroke within 4 hours of ictus. Participants received transdermal GTN (5 mg) or a sham dressing (1:1) in the ambulance and then daily for three days in hospital. The primary outcome was the 7-level modified Rankin Scale at 90 days assessed by central telephone treatment-blinded follow-up. This prespecified subgroup analysis focuses on participants with an intracerebral hemorrhage as their index event. Analyses are intention-to-treat. Results- Of 1149 participants with presumed stroke, 145 (13%; GTN, 74; sham, 71) had an intracerebral hemorrhage: time from onset to randomization median, 74 minutes (interquartile range, 45-110). By admission to hospital, blood pressure tended to be lower with GTN as compared with sham: mean, 4.4/3.5 mm Hg. The modified Rankin Scale score at 90 days was nonsignificantly higher in the GTN group: adjusted common odds ratio for poor outcome, 1.87 (95% CI, 0.98-3.57). A prespecified global analysis of 5 clinical outcomes (dependency, disability, cognition, quality of life, and mood) was worse with GTN; Mann-Whitney difference, 0.18 (95% CI, 0.01-0.35; Wei-Lachin test). GTN was associated with larger hematoma and growth, and more mass effect and midline shift on neuroimaging, and altered use of hospital resources. Death in hospital but not at day 90 was increased with GTN. There were no significant between-group differences in serious adverse events. Conclusions- Prehospital treatment with GTN worsened outcomes in patients with intracerebral hemorrhage. Since these results could relate to the play of chance, confounding, or a true effect of GTN, further randomized evidence on the use of vasodilators in ultra-acute intracerebral hemorrhage is needed. Clinical Trial Registration- URL: http://www.controlled-trials.com. Unique identifier: ISRCTN26986053.

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.

Glyceryl Trinitrate for Acute Intracerebral Hemorrhage: Results From the Efficacy of Nitric Oxide in Stroke (ENOS) Trial, a Subgroup Analysis.

BACKGROUND AND PURPOSE: The Efficacy of Nitric Oxide in Stroke (ENOS) trial found that transdermal glyceryl trinitrate (GTN, a nitric oxide donor) lowered blood pressure but did not improve functional outcome in patients with acute stroke. However, GTN was associated with improved outcome if patients were randomized within 6 hours of stroke onset. METHODS: In this prespecified subgroup analysis, the effect of GTN (5 mg/d for 7 days) versus no GTN was studied in 629 patients with intracerebral hemorrhage presenting within 48 hours and with systolic blood pressure ≥140 mm Hg. The primary outcome was the modified Rankin Scale at 90 days. RESULTS: Mean blood pressure at baseline was 172/93 mm Hg and significantly lower (difference -7.5/-4.2 mm Hg; both P≤0.05) on day 1 in 310 patients allocated to GTN when compared with 319 randomized to no GTN. No difference in the modified Rankin Scale was observed between those receiving GTN versus no GTN (adjusted odds ratio for worse outcome with GTN, 1.04; 95% confidence interval, 0.78-1.37; P=0.84). In the subgroup of 61 patients randomized within 6 hours, GTN improved functional outcome with a shift in the modified Rankin Scale (odds ratio, 0.22; 95% confidence interval, 0.07-0.69; P=0.001). There was no significant difference in the rates of serious adverse events between GTN and no GTN. CONCLUSIONS: In patients with intracerebral hemorrhage within 48 hours of onset, GTN lowered blood pressure was safe but did not improve functional outcome. Very early treatment might be beneficial but needs assessment in further studies. CLINICAL TRIAL REGISTRATION: URL: http://www.isrctn.com/ISRCTN99414122. Unique identifier: 99414122.

Continuing versus Stopping Prestroke Antihypertensive Therapy in Acute Intracerebral Hemorrhage: A Subgroup Analysis of the Efficacy of Nitric Oxide in Stroke Trial.

BACKGROUND AND PURPOSE: More than 50% of patients with acute intracerebral hemorrhage (ICH) are taking antihypertensive drugs before ictus. Although antihypertensive therapy should be given long term for secondary prevention, whether to continue or stop such treatment during the acute phase of ICH remains unclear, a question that was addressed in the Efficacy of Nitric Oxide in Stroke (ENOS) trial. METHODS: ENOS was an international multicenter, prospective, randomized, blinded endpoint trial. Among 629 patients with ICH and systolic blood pressure between 140 and 220 mmHg, 246 patients who were taking antihypertensive drugs were assigned to continue (n = 119) or to stop (n = 127) taking drugs temporarily for 7 days. The primary outcome was the modified Rankin Score at 90 days. Secondary outcomes included death, length of stay in hospital, discharge destination, activities of daily living, mood, cognition, and quality of life. RESULTS: Blood pressure level (baseline 171/92 mmHg) fell in both groups but was significantly lower at 7 days in those patients assigned to continue antihypertensive drugs (difference 9.4/3.5 mmHg, P < .01). At 90 days, the primary outcome did not differ between the groups; the adjusted common odds ratio (OR) for worse outcome with continue versus stop drugs was .92 (95% confidence interval, .45-1.89; P = .83). There was no difference between the treatment groups for any secondary outcome measure, or rates of death or serious adverse events. CONCLUSIONS: Among patients with acute ICH, immediate continuation of antihypertensive drugs during the first week did not reduce death or major disability in comparison to stopping treatment temporarily.

Effect of Hyperacute Administration (Within 6 Hours) of Transdermal Glyceryl Trinitrate, a Nitric Oxide Donor, on Outcome After Stroke: Subgroup Analysis of the Efficacy of Nitric Oxide in Stroke (ENOS) Trial.

BACKGROUND AND PURPOSE: Nitric oxide donors are candidate treatments for acute stroke, potentially through hemodynamic, reperfusion, and neuroprotectant effects, especially if given early. Although the large Efficacy of Nitric Oxide in Stroke (ENOS) trial of transdermal glyceryl trinitrate (GTN) was neutral, a prespecified subgroup suggested that GTN improved functional outcome if administered early after stroke onset. METHODS: Prospective analysis of subgroup of patients randomized into the ENOS trial within 6 hours of stroke onset. Safety and efficacy of GTN versus no GTN were assessed using data on early and late outcomes. RESULTS: Two hundred seventy-three patients were randomized within 6 hours of ictus: mean (SD) age, 69.9 (12.7) years; men, 154 (56.4%); ischemic stroke, 208 (76.2%); Scandinavian Stroke Scale, 32.1 (11.9); and total anterior circulation syndrome, 86 (31.5%). When compared with no GTN, the first dose of GTN lowered blood pressure by 9.4/3.3 mm Hg (P<0.01, P=0.064) and shifted the modified Rankin Scale to a better outcome by day 90, adjusted common odds ratio, 0.51 (95% confidence interval, 0.32-0.80). Significant beneficial effects were also seen with GTN for disability (Barthel Index), quality of life (EuroQol-Visual Analogue Scale), cognition (telephone Mini-Mental State Examination), and mood (Zung Depression Scale). GTN was safe to administer with less serious adverse events by day 90 (GTN 18.8% versus no GTN 34.1%) and death (hazard ratio, 0.44; 95% confidence interval, 0.20-0.99; P=0.047). CONCLUSIONS: In a subgroup analysis of the large ENOS trial, transdermal GTN was safe to administer and associated with improved functional outcome and fewer deaths when administered within 6 hours of stroke onset. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00989716.

Design of trials in lacunar stroke and cerebral small vessel disease: review and experience with the LACunar Intervention Trial 2 (LACI-2).

Cerebral small vessel disease (cSVD) causes lacunar stroke (25% of ischaemic strokes), haemorrhage, dementia, physical frailty, or is 'covert', but has no specific treatment. Uncertainties about the design of clinical trials in cSVD, which patients to include or outcomes to assess, may have delayed progress. Based on experience in recent cSVD trials, we reviewed ways to facilitate future trials in patients with cSVD.We assessed the literature and the LACunar Intervention Trial 2 (LACI-2) for data to inform choice of Participant, Intervention, Comparator, Outcome, including clinical versus intermediary endpoints, potential interventions, effect of outcome on missing data, methods to aid retention and reduce data loss. We modelled risk of missing outcomes by baseline prognostic variables in LACI-2 using binary logistic regression.Imaging versus clinical outcomes led to larger proportions of missing data. We present reasons for and against broad versus narrow entry criteria. We identified numerous repurposable drugs with relevant modes of action to test in various cSVD subtypes. Cognitive impairment is the most common clinical outcome after lacunar ischaemic stroke but was missing more frequently than dependency, quality of life or vascular events in LACI-2. Assessing cognitive status using Diagnostic and Statistical Manual for Mental Disorders Fifth Edition can use cognitive data from multiple sources and may help reduce data losses.Trials in patients with all cSVD subtypes are urgently needed and should use broad entry criteria and clinical outcomes and focus on ways to maximise collection of cognitive outcomes to avoid missing data.

Ninety-Day Stroke Recurrence in Minor Stroke: Systematic Review and Meta-Analysis of Trials and Observational Studies.

BACKGROUND: Risk of recurrence after minor ischemic stroke is usually reported with transient ischemic attack. No previous meta-analysis has focused on minor ischemic stroke alone. The objective was to evaluate the pooled proportion of 90-day stroke recurrence for minor ischemic stroke, defined as a National Institutes of Health Stroke Scale severity score of ≤5. METHODS AND RESULTS: Published papers found on PubMed from 2000 to January 12, 2021, reference lists of relevant articles, and experts in the field were involved in identifying relevant studies. Randomized controlled trials and observational studies describing minor stroke cohort with reported 90-day stroke recurrence were selected by 2 independent reviewers. Altogether 14 of 432 (3.2%) studies met inclusion criteria. Multilevel random-effects meta-analysis was performed. A total of 6 randomized controlled trials and 8 observational studies totaling 45 462 patients were included. The pooled 90-day stroke recurrence was 8.6% (95% CI, 6.5-10.7), reducing by 0.60% (95% CI, 0.09-1.1; P=0.02) with each subsequent year of publication. Recurrence was lowest in dual antiplatelet trial arms (6.3%, 95% CI, 4.5-8.0) when compared with non-dual antiplatelet trial arms (7.2%, 95% CI, 4.7-9.6) and observational studies 10.6% (95% CI, 7.0-14.2). Age, hypertension, diabetes, ischemic heart disease, or known atrial fibrillation had no significant association with outcome. Defining minor stroke with a lower National Institutes of Health Stroke Scale threshold made no difference - score ≤3: 8.6% (95% CI, 6.0-11.1), score ≤4: 8.4% (95% CI, 6.1-10.6), as did excluding studies with n<500%-7.3% (95% CI, 5.5-9.0). CONCLUSIONS: The risk of recurrence after minor ischemic stroke is declining over time but remains important.

The Effect of Tranexamic Acid on Neurosurgical Intervention in Spontaneous Intracerebral Hematoma: Data From 121 Surgically Treated Participants From the Tranexamic Acid in IntraCerebral Hemorrhage-2 Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: An important proportion of patients with spontaneous intracerebral hemorrhage (ICH) undergo neurosurgical intervention to reduce mass effect from large hematomas and control the complications of bleeding, including hematoma expansion and hydrocephalus. The Tranexamic acid (TXA) for hyperacute primary IntraCerebral Hemorrhage (TICH-2) trial demonstrated that tranexamic acid (TXA) reduces the risk of hematoma expansion. We hypothesized that TXA would reduce the frequency of surgery (primary outcome) and improve functional outcome at 90 days in surgically treated patients in the TICH-2 data set. METHODS: Participants enrolled in TICH-2 were randomized to placebo or TXA. Participants randomized to either TXA or placebo were analyzed for whether they received neurosurgery within 7 days and their characteristics, outcomes, hematoma volumes (HVs) were compared. Characteristics and outcomes of participants who received surgery were also compared with those who did not. RESULTS: Neurosurgery was performed in 5.2% of participants (121/2325), including craniotomy (57%), hematoma drainage (33%), and external ventricular drainage (21%). The number of patients receiving surgery who received TXA vs placebo were similar at 4.9% (57/1153) and 5.5% (64/1163), respectively (odds ratio [OR] 0.893; 95% CI 0.619-1.289; P-value = .545). TXA did not improve outcome compared with placebo in either surgically treated participants (OR 0.79; 95% CI 0.30-2.09; P = .64) or those undergoing hematoma evacuation by drainage or craniotomy (OR 1.19 95% 0.51-2.78; P-value = .69). Postoperative HV was not reduced by TXA (mean difference -8.97 95% CI -23.77, 5.82; P-value = .45). CONCLUSION: TXA was not associated with less neurosurgical intervention, reduced HV, or improved outcomes after surgery.

Prehospital transdermal glyceryl trinitrate for ultra-acute ischaemic stroke: data from the RIGHT-2 randomised sham-controlled ambulance trial.

BACKGROUND: The effect of transdermal glyceryl trinitrate (GTN, a nitrovasodilator) on clinical outcome when administered before hospital admission in suspected stroke patients is unclear. Here, we assess the safety and efficacy of GTN in the prespecified subgroup of patients who had an ischaemic stroke within the Rapid Intervention with Glyceryl trinitrate in Hypertensive stroke Trial-2 (RIGHT-2). METHODS: RIGHT-2 was an ambulance-based multicentre sham-controlled blinded-endpoint study with patients randomised within 4 hours of onset. The primary outcome was a shift in scores on the modified Rankin scale (mRS) at day 90. Secondary outcomes included death; a global analysis (Wei-Lachin test) containing Barthel Index, EuroQol-5D, mRS, telephone interview for cognitive status-modified and Zung depression scale; and neuroimaging-determined 'brain frailty' markers. Data were reported as n (%), mean (SD), median [IQR], adjusted common OR (acOR), mean difference or Mann-Whitney difference (MWD) with 95% CI. RESULTS: 597 of 1149 (52%) patients had a final diagnosis of ischaemic stroke; age 75 (12) years, premorbid mRS>2 107 (18%), Glasgow Coma Scale 14 (2) and time from onset to randomisation 67 [45, 108] min. Neuroimaging 'brain frailty' was common: median score 2 [2, 3] (range 0-3). At day 90, GTN did not influence the primary outcome (acOR for increased disability 1.15, 95% CI 0.85 to 1.54), death or global analysis (MWD 0.00, 95% CI -0.10 to 0.09). In subgroup analyses, there were non-significant interactions suggesting GTN may be associated with more death and dependency in participants randomised within 1 hour of symptom onset and in those with more severe stroke. CONCLUSIONS: In patients who had an ischaemic stroke, ultra-acute administration of transdermal GTN in the ambulance did not improve clinical outcomes in a population with more clinical and radiological frailty than seen in previous in-hospital trials.

Prevention of infections and fever to improve outcome in older patients with acute stroke (PRECIOUS): a randomised, open, phase III, multifactorial, clinical trial with blinded outcome assessment.

Background: Infections and fever after stroke are associated with poor functional outcome or death. We assessed whether prophylactic treatment with anti-emetic, antibiotic, or antipyretic medication would improve functional outcome in older patients with acute stroke. Methods: We conducted an international, 2∗2∗2-factorial, randomised, controlled, open-label trial with blinded outcome assessment in patients aged 66 years or older with acute ischaemic stroke or intracerebral haemorrhage and a score on the National Institutes of Health Stroke Scale ≥ 6. Patients were randomly allocated (1:1) to metoclopramide (oral, rectal, or intravenous; 10 mg thrice daily) vs. no metoclopramide, ceftriaxone (intravenous; 2000 mg once daily) vs. no ceftriaxone, and paracetamol (oral, rectal, or intravenous; 1000 mg four times daily) vs. no paracetamol, started within 24 h after symptom onset and continued for four days. All participants received standard of care. The target sample size was 3800 patients. The primary outcome was the score on the modified Rankin Scale (mRS) at 90 days analysed with ordinal logistic regression and reported as an adjusted common odds ratio (an acOR < 1 suggests benefit and an acOR > 1 harm). This trial is registered (ISRCTN82217627). Findings: From April 2016 through June 2022, 1493 patients from 67 European sites were randomised to metoclopramide (n = 704) or no metoclopramide (n = 709), ceftriaxone (n = 594) or no ceftriaxone (n = 482), and paracetamol (n = 706) or no paracetamol (n = 739), of whom 1471 were included in the intention-to-treat analysis. Prophylactic use of study medication did not significantly alter the primary outcome at 90 days: metoclopramide vs. no metoclopramide (adjusted common odds ratio [acOR], 1.01; 95% CI 0.81-1.25), ceftriaxone vs. no ceftriaxone (acOR 0.99; 95% CI 0.77-1.27), paracetamol vs. no paracetamol (acOR 1.19; 95% CI 0.96-1.47). The study drugs were safe and not associated with an increased incidence of serious adverse events. Interpretation: We observed no sign of benefit of prophylactic use of metoclopramide, ceftriaxone, or paracetamol during four days in older patients with a moderately severe to severe acute stroke. Funding: This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No: 634809.

Optimising the analysis of vascular prevention trials: Re-Assessment of the TARDIS trial, the first prevention trial to adopt an ordinal primary outcome measure.

Background: Ordinalised vascular outcomes incorporating event severity are more informative than binary outcomes that just include event numbers. The TARDIS trial was the first vascular prevention study to use an ordinalised vascular outcome as its primary efficacy and safety measures and collected severity information for other vascular events. Methods: TARDIS was an international prospective randomised open-label blinded-endpoint trial assessing one month of intensive versus guideline antiplatelet therapy in patients with acute non-cardioembolic stroke or TIA. Vascular events and their severity were recorded up to final follow-up at 90 days post randomisation. For each outcome, statistical techniques compared ordinal/continuous (10 models) and dichotomous (5 models) analyses; results were then ranked with the smallest p-value being given the smallest rank. Outcomes were also assessed within the pre-defined subgroup of participants with mild stroke (NIHSS≤3), or TIA recruited within 24 h. Results: Ordinal versions of vascular event outcomes were created in 3096 participants for stroke, myocardial infarction, major cardiac events, bleeding events, serious adverse events and venous thromboembolism (VTE), with 32 outcomes being created overall (29 in the subgroup population due to the absence of VTE events). Overall, the tests run on ordinal outcomes tended to rank higher than tests performed on binary outcomes. 764 (24.7%) participants were recruited within 24 h of a mild stroke/TIA; again, tests run on ordinal outcomes ranked higher. Conclusions: In TARDIS, tests performed on ordinal vascular outcomes tended to attain a higher rank than those performed on binary outcomes. Trial registration: ISRCTN47823388.

Cilostazol and isosorbide mononitrate for the prevention of progression of cerebral small vessel disease: baseline data and statistical analysis plan for the Lacunar Intervention Trial-2 (LACI-2) (ISRCTN14911850).

BACKGROUND: Cerebral small vessel disease (SVD) causes lacunar strokes (25% of all ischaemic strokes), physical frailty and cognitive impairment and vascular and mixed dementia. There is no specific treatment to prevent progression of SVD. METHODS: The LACunar Intervention Trial-2 is an investigator-initiated prospective randomised open-label blinded-endpoint phase II feasibility study assessing cilostazol and isosorbide mononitrate for preventing SVD progression. We aimed to recruit 400 patients with clinically evident lacunar ischaemic stroke and randomised to cilostazol, isosorbide mononitrate, both or neither, in addition to guideline secondary ischaemic stroke prevention, in a partial factorial design. The primary outcome is feasibility of recruitment and adherence to medication; key secondary outcomes include: drug tolerability; recurrent vascular events, cognition and function at 1 year after randomisation; and safety (bleeding, falls, death). Data are number (%) and median (IQR). RESULTS: The trial commenced on 5 February 2018 and ceased recruitment on 31 May 2021 with 363 patients randomised, with the following baseline characteristics: average age 64 (56.0, 72.0) years, female 112 (30.9%), stroke onset to randomisation 79.0 (27.0, 244.0) days, hypertension 267 (73.6%), median blood pressures 143.0 (130.0, 157.0)/83.0 (75.0, 90.0) mm Hg, current smokers 67 (18.5%), educationally achieved end of school examinations (A-level) or higher 118 (32.5%), modified Rankin scale 1.0 (0.0, 1.0), National Institutes Health stroke scale 1.0 (1.4), Montreal Cognitive Assessment 26.0 (23.0, 28.0) and total SVD score on brain imaging 1.0 (0.0, 2.0). This publication summarises the baseline data and presents the statistical analysis plan. SUMMARY: The trial is currently in follow-up which will complete on 31 May 2022 with results expected in October 2022. TRIAL REGISTRATION NUMBER: ISRCTN14911850.

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.