Protocol: The Lacunar Intervention Trial 2 (LACI-2). A trial of two repurposed licenced drugs to prevent progression of cerebral small vessel disease.

BACKGROUND: Small vessel disease causes a quarter of ischaemic strokes (lacunar subtype), up to 45% of dementia either as vascular or mixed types, cognitive impairment and physical frailty. However, there is no specific treatment to prevent progression of small vessel disease. AIM: We designed the LACunar Intervention Trial-2 (LACI-2) to test feasibility of a large trial testing cilostazol and/or isosorbide mononitrate (ISMN) by demonstrating adequate participant recruitment and retention in follow-up, drug tolerability, safety and confirm outcome event rates required to power a phase 3 trial. METHODS AND DESIGN: LACI-2 is an investigator-initiated, prospective randomised open label blinded endpoint (PROBE) trial aiming to recruit 400 patients with prior lacunar syndrome due to a small subcortical infarct. We randomise participants to cilostazol v no cilostazol and ISMN or no ISMN, minimising on key prognostic factors. All patients receive guideline-based best medical therapy. Patients commence trial drug at low dose, increment to full dose over 2-4 weeks, continuing on full dose for a year. We follow-up participants to one year for symptoms, tablet compliance, safety, recurrent vascular events, cognition and functional outcomes, Trails B and brain MRI. LACI-2 is registered ISRCTN 14911850, EudraCT 2016-002277-35.Trial outcome: Primary outcome is feasibility of recruitment and compliance; secondary outcomes include safety (cerebral or systemic bleeding, falls, death), efficacy (recurrent cerebral and cardiac vascular events, cognition on TICS, Trails B) and tolerability. SUMMARY: LACI-2 will determine feasibility, tolerability and provide outcome rates to power a large phase 3 trial to prevent progression of cerebral small vessel disease.

Impact of hydration status on haemodynamics, effects of acute blood pressure-lowering treatment, and prognosis after stroke.

AIMS: Although high blood pressure (BP) is common in acute stroke and associated with poor outcome, the Efficacy of Nitric Oxide in Stroke (ENOS) trial showed no beneficial effect of antihypertensive treatment in this situation. Antihypertensive agents have accentuated effects in dehydrated patients. We assessed the impact of dehydration on haemodynamics, the effects of antihypertensive treatment, and prognosis in the ENOS trial. METHODS: ENOS randomized 4011 patients with acute stroke and raised systolic BP to a glyceryl trinitrate (GTN) patch or no GTN patch, and to continue or to stop existing antihypertensive treatment within 48 h of onset. The primary outcome was functional outcome (modified Rankin Scale, mRS) at day 90. Blood markers of dehydration at baseline were collected at two sites (n = 310) and their relationship with haemodynamics and outcome was assessed. RESULTS: There were no significant associations between dehydration markers and fall in blood pressure from baseline to day 1, and no significant interaction with allocated treatment. Overall, increasing urea was associated with an unfavourable shift in mRS [odds ratio 3.43, 95% confidence interval (CI) 1.42, 8.32; P = 0.006] and increased risk of death at day 90 (hazard ratio 4.55, 95% CI 1.51, 13.66; P = 0.007). CONCLUSIONS: Blood pressure-lowering treatment was safe in dehydrated patients, with no precipitous changes in BP, thus supporting its use in acute stroke prior to blood markers of dehydration becoming available. Increased baseline urea was associated with poor prognosis after stroke.

Inhibition of TNF-α protects in vitro brain barrier from ischaemic damage.

Cerebral ischaemia, associated with neuroinflammation and oxidative stress, is known to perturb blood-brain barrier (BBB) integrity and promote brain oedema formation. Using an in vitro model of human BBB composed of brain microvascular endothelial cells and astrocytes, this study examined whether suppression of TNF-α, a potent pro-inflammatory cytokine, might attenuate ischaemia-mediated cerebral barrier damage. Radical decreases in transendothelial electrical resistance and concomitant increases in paracellular flux across co-cultures exposed to increasing periods of oxygen-glucose deprivation alone (0.5-20 h) or followed by 20 h of reperfusion (OGD ± R) confirmed the deleterious effects of ischaemic injury on cerebral barrier integrity and function which concurred with reductions in tight junction protein (claudin-5 and occludin) expressions. OGD ± R elevated TNF-α secretion, NADPH oxidase activity, O2(-) production, actin stress fibre formation, MMP-2/9 activities and apoptosis in both endothelial cells and astrocytes. Increases in MMP-2 activity were confined to its extracellular isoform and treatments with OGD+R in astrocytes where MMP-9 could not be detected at all. Co-exposure of individual cell lines or co-cultures to an anti-TNF-α antibody dramatically diminished the extent of OGD ± R-evoked oxidative stress, morphological changes, apoptosis, MMP-2/9 activities while improving the barrier function through upregulation of tight junction protein expressions. In conclusion, vitiation of the exaggerated release of TNF-α may be an important therapeutic strategy in preserving cerebral integrity and function during and following a cerebral ischaemic attack.

Rationale, design, and progress of the ENhanced Control of Hypertension ANd Thrombolysis strokE stuDy (ENCHANTED) trial: An international multicenter 2 × 2 quasi-factorial randomized controlled trial of low- vs. standard-dose rt-PA and early intensive vs. guideline-recommended blood pressure lowering in patients with acute ischaemic stroke eligible for thrombolysis treatment.

RATIONALE: Controversy exists over the optimal dose of intravenous (i.v.) recombinant tissue plasminogen activator (rt-PA) and degree of blood pressure (BP) control in acute ischaemic stroke (AIS). Asian studies suggest low-dose (0·6 mg/kg) is more efficacious than standard-dose (0·9 mg/kg) i.v. rt-PA, and guidelines recommend reducing systolic BP to <185 mmHg before and <180 mmHg after use of i.v. rt-PA, despite observational studies indicating better outcomes at much lower (<140 mmHg) systolic BP levels in this patient group. AIMS: The study aims to assess in thrombolysis-eligible AIS patients whether: (i) low-dose (0·6 mg/kg body weight; maximum 60 mg) i.v. rt-PA has non-inferior efficacy and lower risk of symptomatic intracerebral haemorrhage (sICH) compared to standard-dose (0·9 mg/kg body weight; maximum 90 mg) i.v. rt-PA; and (ii) early intensive BP lowering (systolic target 130-140 mmHg) has superior efficacy and lower risk of any ICH compared to guideline-recommended BP control (systolic target < 180 mmHg). DESIGN: The ENhanced Control of Hypertension And Thrombolysis strokE stuDy (ENCHANTED) trial is an independent,2 × 2 quasi-factorial, active-comparison, prospective, randomized, open blinded endpoint (PROBE), clinical trial that is evaluating Arm [A] 'rt-PA dose' and/or Arm [B] 'BP control', using central Internet randomization and data collection in patients fulfilling local criteria for thrombolysis and clinician uncertainty over the study treatments. The treatment arms will be analyzed separately. STUDY OUTCOMES: The primary study outcome in both trial Arms is death or disability according to the modified Rankin scale (mRS, scores 2-6) assessed at 90 days. Secondary outcomes include sICH, any ICH, a shift ('improvement') in function across mRS scores, separately on death and disability, early neurological deterioration, recurrent major vascular events, health-related quality of life, length of hospital stay, need for permanent residential care, and health care costs. RESULTS: Following launch of the trial in February 2012, the study has recruited more than 2500 patients across a global network of approximately 100 sites in 15 countries. The required sample sizes are 3300 for Arm [A] and 2300 for Arm [B], which will provide >90% power to detect non-inferiority of low-dose i.v. rt-PA and superiority of intensive BP lowering on the primary clinical outcome, respectively. CONCLUSIONS: Low-dose i.v. rt-PA and early intensive BP lowering could provide more affordable and safer use of thrombolysis treatment for patients with AIS worldwide.

Effects of candesartan in acute stroke on vascular events during long-term follow-up: results from the Scandinavian Candesartan Acute Stroke Trial (SCAST).

BACKGROUND: Randomized-controlled trials have shown no beneficial short-term effects of blood pressure lowering treatment in the acute phase of stroke. AIM: We aimed to see whether blood pressure lowering treatment with candesartan in the acute phase can lead to benefits that become apparent over a longer period of follow-up. METHODS: The Scandinavian Candesartan Acute Stoke Trial was a randomized- and placebo-controlled trial of candesartan in 2,029 patients with acute stroke and systolic blood pressure ≥140 mmHg. Trial treatment was given for seven-days, and the primary follow-up period was six-months. We have used the national patient registries and the cause of death registries in the Scandinavian countries to collect data on vascular events and deaths up to three-years from randomization. The primary end-point was the composite of stroke, myocardial infarction, or vascular death, and we used Cox proportional hazards regression model for analysis. RESULTS: Long-term data were available for 1,256 of the 1,286 patients (98%) from Scandinavia. The risk of the primary composite end-point did not differ significantly between the groups (candesartan 178/632 events, placebo 203/624 events, hazard ratio = 0·87, 95% confidence interval 0·71-1·07). There were also no statistically significant differences for the secondary end-points stroke and all-cause death, or in any of the pre-specified subgroups. CONCLUSIONS: Treatment with candesartan in the acute phase of stroke was not associated with clear long-term clinical benefits. This result supports the conclusion from trials with short-term follow-up, that blood pressure lowering treatment with candesartan should not be given routinely to patients with acute stroke and raised blood pressure.

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.

Effects of blood pressure-lowering treatment in different subtypes of acute ischemic stroke.

BACKGROUND AND PURPOSE: The Scandinavian Candesartan Acute Stroke Trial (SCAST) found no benefits of blood pressure-lowering treatment with candesartan in acute stroke. We have investigated whether the effect of treatment is different in different subtypes of ischemic stroke. METHODS: SCAST was a randomized- and placebo-controlled trial of candesartan in 2029 patients presenting within 30 hours of ischemic or hemorrhagic stroke and systolic blood pressure ≥140 mm Hg. Ischemic stroke subtype was categorized by the Oxfordshire Community Stroke Project classification. There were 2 primary effect variables: the composite vascular end point of vascular death, myocardial infarction, or stroke during the first 6 months and functional outcome at 6 months. RESULTS: A total of 1733 patients with ischemic stroke were included: total anterior circulation infarcts in 129, partial anterior in 850, posterior in 236, and lacunar in 510 patients. For functional outcome there was a significant trend toward a better effect of candesartan in patients with larger infarcts (total anterior circulation or partial anterior circulation) than in patients with smaller infarcts (lacunar infarction; P=0.02). For the composite vascular end point, there were no differences in treatment effect. CONCLUSIONS: The results suggest that the effect of blood pressure-lowering treatment with candesartan may differ according to different types of acute ischemic stroke, but this needs to be confirmed in future trials. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00120003.

Regulation and governance of multinational drug trials in stroke: barriers and possibilities.

Over the last 10 years, there has been stagnation in the number of multinational drug trials in stroke in Europe. One important cause of this is probably the increased burden of laws and regulations that came with the European Union Clinical Trials Directive. The main objective of research regulation and governance should be to protect research participants, their tissues, and data, but the approval systems are complex, regulation is variably interpreted and enforced, and the assessment of studies is often not proportionate to the risk of the research to participants. Such unnecessary barriers should be reduced by simplifying, centralizing, and harmonizing the application process, and by applying regulatory and governance requirements in a way that is proportionate to the potential harms to the patients. The traditional functions of a regulator (in setting, monitoring, and enforcing quality standards) could also be supplemented with an aim to actively help researchers achieve these standards, for example, by giving advice, and ultimately with an aim to facilitate and promote research, for example, by integrating research in everyday clinical practice. Research networks offer one way of integrating research and clinical practice across multiple centers, and can streamline research delivery by supporting researchers deal professionally and efficiently with the regulations and governance requirements.

Performance characteristics of methods for quantifying spontaneous intracerebral haemorrhage: data from the Efficacy of Nitric Oxide in Stroke (ENOS) trial.

BACKGROUND: Poor prognosis after intracerebral haemorrhage (ICH) is related to haemorrhage characteristics. Along with developing therapeutic interventions, we sought to understand the performance of haemorrhage descriptors in large clinical trials. METHODS: Clinical and neuroimaging data were obtained for 548 participants with ICH from the Efficacy of Nitric Oxide in Stroke (ENOS) trial. Independent observers performed visual categorisation of the largest diameter, measured volume using ABC/2, modified ABC/2, semiautomated segmentation (SAS), fully automatic measurement methods; shape, density and intraventricular haemorrhage were also assessed. Intraobserver and interobserver reliability were determined for these measures. RESULTS: ICH volume was significantly different among standard ABC/2, modified ABC/2 and SAS: (mean) 12.8 (SD 16.3), 8.9 (9.2), 12.8 (13.1) cm(3), respectively (p<0.0001). There was excellent agreement for haemorrhage volume (n=193): ABC/2 intraobserver intraclass correlation coefficient (ICC) 0.96-0.97, interobserver ICC 0.88; modified ABC/2 intraobserver ICC 0.95-0.97, interobserver ICC 0.91; SAS intraobserver ICC 0.95-0.99, interobserver ICC 0.93; largest diameter: (visual) interadjudicator ICC 0.82, (visual vs measured) adjudicator vs observer ICC 0.71; shape intraobserver ICC 0.88 interobserver ICC 0.75; density intraobserver ICC 0.86, interobserver ICC 0.73. Graeb score (mean 3.53) and modified Graeb (5.22) scores were highly correlated. Using modified ABC/2, ICH volume was underestimated in regular (by 2.2-2.5 cm(3), p<0.0001) and irregular-shaped haemorrhages (by 4.8-4.9 cm(3), p<0.0001). Fully automated measurement of haemorrhage volume was possible in only 5% of cases. CONCLUSIONS: Formal measurement of haemorrhage characteristics and visual estimates are reproducible. The standard ABC/2 method is superior to the modified ABC/2 method for quantifying ICH volume. CLINICAL TRIAL REGISTRATION: ISRCTN9941422.

Effects of blood pressure lowering in patients with acute ischemic stroke and carotid artery stenosis.

BACKGROUND: The Scandinavian Candesartan Acute Stroke Trial (SCAST) showed no beneficial clinical effects of blood pressure lowering with the angiotensin receptor blocker candesartan in the acute phase of stroke. In the present analysis we wanted to see if the effects of blood pressure lowering are harmful in the subgroup of patients with carotid artery stenosis. METHODS: SCAST was a randomized- and placebo-controlled, double-masked trial of 2029 patients with acute stroke and high systolic blood pressure (≥ 140 mmHg). Of 1733 patients with ischemic stroke 993 underwent carotid artery imaging, and the degree of stenosis was categorized as no/insignificant (0-49%, n = 806), moderate (50-69%, n = 97) or severe (≥ 70%, n = 90). The trial's two co-primary effect variables were the composite end-point of vascular death, stroke or myocardial infarction, and functional outcome at six-months, according to the modified Rankin Scale. RESULTS: Among patients with moderate or severe carotid artery stenosis the vascular end-point occurred in 9 of 87 patients (10.3%) treated with candesartan and in 17 of 100 controls (17.0%), and there was no evidence of a different risk in patients with severe stenosis (adjusted hazard ratio 0.74, 95% confidence interval 0.28-1.96, P = 0.54). For functional outcome there was also no clear difference, although in patients with severe stenosis the risk of a poor outcome was somewhat higher than in any of the other groups (adjusted odds ratio 2.24, 95% confidence interval 0.71-7.09, P = 0.16). Progressive stroke also occurred more often in patients with carotid artery stenosis treated with candesartan (10 of 87 patients (11.5%) vs. 4 of 100 patients (4.0%)), with a trend towards an increased risk with increasing severity of stenosis (P-value for linear trend = 0.04). CONCLUSIONS: There is no clear evidence that the effect of candesartan is qualitatively different in patients with carotid artery stenosis, but there are signals that patients with severe stenosis are at particularly high risk of stroke progression and poor functional outcome.

Evaluating the translational potential of progesterone treatment following transient cerebral ischaemia in male mice.

BACKGROUND: Progesterone is neuroprotective in numerous preclinical CNS injury models including cerebral ischaemia. The aim of this study was two-fold; firstly, we aimed to determine whether progesterone delivery via osmotic mini-pump would confer neuroprotective effects and whether such neuroprotection could be produced in co-morbid animals. RESULTS: Animals underwent transient middle cerebral artery occlusion. At the onset of reperfusion, mice were injected intraperitoneally with progesterone (8 mg/kg in dimethylsulfoxide). Adult and aged C57 Bl/6 mice were dosed additionally with subcutaneous infusion (1.0 µl/h of a 50 mg/ml progesterone solution) via implanted osmotic minipumps. Mice were allowed to survive for up to 7 days post-ischaemia and assessed for general well-being (mass loss and survival), neurological score, foot fault and t-maze performance. Progesterone reduced neurological deficit [F(1,2) = 5.38, P = 0.027] and number of contralateral foot-faults [F(1,2) = 7.36, P = 0.0108] in adult, but not aged animals, following ischaemia. In hypertensive animals, progesterone treatment lowered neurological deficit [F(1,6) = 18.31, P = 0.0001], reduced contralateral/ipsilateral alternation ratio % [F(1,2) = 17.05, P = 0.0006] and time taken to complete trials [F(1,2) = 15.92, P = 0.0009] for t-maze. CONCLUSION: Post-ischemic progesterone administration via mini-pump delivery is effective in conferring functional improvement in a transient MCAO model in adult mice. Preliminary data suggests such a treatment regimen was not effective in producing a protective effect in aged mice. However, in hypertensive mice, who received post-ischemic progesterone intraperitoneally at the onset of reperfusion had better functional outcomes than control hypertensive mice.

Interventions for deliberately altering blood pressure in acute stroke.

BACKGROUND: It is unclear whether blood pressure should be altered actively during the acute phase of stroke. This is an update of a Cochrane review first published in 1997, and previously updated in 2001 and 2008. OBJECTIVES: To assess the clinical effectiveness of altering blood pressure in people with acute stroke, and the effect of different vasoactive drugs on blood pressure in acute stroke. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (last searched in February 2014), the Cochrane Database of Systematic reviews (CDSR) and the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2014, Issue 2), MEDLINE (Ovid) (1966 to May 2014), EMBASE (Ovid) (1974 to May 2014), Science Citation Index (ISI, Web of Science, 1981 to May 2014) and the Stroke Trials Registry (searched May 2014). SELECTION CRITERIA: Randomised controlled trials of interventions that aimed to alter blood pressure compared with control in participants within one week of acute ischaemic or haemorrhagic stroke. DATA COLLECTION AND ANALYSIS: Two review authors independently applied the inclusion criteria, assessed trial quality and extracted data. The review authors cross-checked data and resolved discrepancies by discussion to reach consensus. We obtained published and unpublished data where available. MAIN RESULTS: We included 26 trials involving 17,011 participants (8497 participants were assigned active therapy and 8514 participants received placebo/control). Not all trials contributed to each outcome. Most data came from trials that had a wide time window for recruitment; four trials gave treatment within six hours and one trial within eight hours. The trials tested alpha-2 adrenergic agonists (A2AA), angiotensin converting enzyme inhibitors (ACEI), angiotensin receptor antagonists (ARA), calcium channel blockers (CCBs), nitric oxide (NO) donors, thiazide-like diuretics, and target-driven blood pressure lowering. One trial tested phenylephrine.At 24 hours after randomisation oral ACEIs reduced systolic blood pressure (SBP, mean difference (MD) -8 mmHg, 95% confidence interval (CI) -17 to 1) and diastolic blood pressure (DBP, MD -3 mmHg, 95% CI -9 to 2), sublingual ACEIs reduced SBP (MD -12.00 mm Hg, 95% CI -26 to 2) and DBP (MD -2, 95%CI -10 to 6), oral ARA reduced SBP (MD -1 mm Hg, 95% CI -3 to 2) and DBP (MD -1 mm Hg, 95% CI -3 to 1), oral beta blockers reduced SBP (MD -14 mm Hg; 95% CI -27 to -1) and DBP (MD -1 mm Hg, 95% CI -9 to 7), intravenous (iv) beta blockers reduced SBP (MD -5 mm Hg, 95% CI -18 to 8) and DBP (-5 mm Hg, 95% CI -13 to 3), oral CCBs reduced SBP (MD -13 mmHg, 95% CI -43 to 17) and DBP (MD -6 mmHg, 95% CI -14 to 2), iv CCBs reduced SBP (MD -32 mmHg, 95% CI -65 to 1) and DBP (MD -13, 95% CI -31 to 6), NO donors reduced SBP (MD -12 mmHg, 95% CI -19 to -5) and DBP (MD -3, 95% CI -4 to -2) while phenylephrine, non-significantly increased SBP (MD 21 mmHg, 95% CI -13 to 55) and DBP (MD 1 mmHg, 95% CI -15 to 16).Blood pressure lowering did not reduce death or dependency either by drug class (OR 0.98, 95% CI 0.92 to 1.05), stroke type (OR 0.98, 95% CI 0.92 to 1.05) or time to treatment (OR 0.98, 95% CI 0.92 to 1.05). Treatment within six hours of stroke appeared effective in reducing death or dependency (OR 0.86, 95% CI 0.76 to 0.99) but not death (OR 0.70, 95% CI 0.38 to 1.26) at the end of the trial. Although death or dependency did not differ between people who continued pre-stroke antihypertensive treatment versus those who stopped it temporarily (worse outcome with continuing treatment, OR 1.06, 95% CI 0.91 to 1.24), disability scores at the end of the trial were worse in participants randomised to continue treatment (Barthel Index, MD -3.2, 95% CI -5.8, -0.6). AUTHORS' CONCLUSIONS: There is insufficient evidence that lowering blood pressure during the acute phase of stroke improves functional outcome. It is reasonable to withhold blood pressure-lowering drugs until patients are medically and neurologically stable, and have suitable oral or enteral access, after which drugs can than be reintroduced. In people with acute stroke, CCBs, ACEI, ARA, beta blockers and NO donors each lower blood pressure while phenylephrine probably increases blood pressure. Further trials are needed to identify which people are most likely to benefit from early treatment, in particular whether treatment started very early is beneficial.

Blood pressure-lowering treatment with candesartan in patients with acute hemorrhagic stroke.

BACKGROUND AND PURPOSE: Early and intensive blood pressure-lowering treatment seems to be beneficial in patients with acute hemorrhagic stroke and high blood pressure. We wanted to see if similar benefits can be shown from a later and more gradual blood pressure lowering, using data from the Scandinavian Candesartan Acute Stroke Trial (SCAST). METHODS: SCAST was a randomized- and placebo-controlled, double-masked trial of candesartan given for 7 days, in 2029 patients with acute stroke and systolic blood pressure ≥140 mm Hg. We assessed the effects of candesartan in the 274 patients with hemorrhagic stroke, using the trial's 2 coprimary effect variables: the composite vascular end point of vascular death, stroke or myocardial infarction, and functional outcome at 6 months, according to the modified Rankin Scale. We used Cox proportional hazards models and ordinal regression for analysis and adjusted for key, predefined prognostic variables. RESULTS: There was no association between treatment with candesartan and risk of vascular events (17 of 144 [11.8%] versus 13 of 130 [10.0%]; hazard ratio, 1.36; 95% confidence interval, 0.65-2.83; P=0.41). For functional outcome we found evidence of a negative effect of candesartan (common odds ratio, 1.61; 95% confidence interval, 1.03-2.50; P=0.036). CONCLUSIONS: There was no evidence that blood pressure-lowering treatment with candesartan is beneficial during the first week of hemorrhagic stroke. Instead, there were signs that such treatment may be harmful, but this needs to be verified in larger studies. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00120003.

Relationship between poststroke cognition, baseline factors, and functional outcome: data from "efficacy of nitric oxide in stroke" trial.

BACKGROUND: Poststroke cognitive impairment is common and identification of prognostic factors associated with it and its relationship with other functional outcomes may help in developing preventative strategies. METHODS: Previously independent patients with acute stroke, enrolled into the ongoing "Efficacy of Nitric Oxide in Stroke" trial, were assessed by telephone on day 90 for cognitive impairment using modified versions of "Mini Mental State Examination" (MMSE-M) and "Telephone Instrument for Cognitive Status" (TICS-M) scales and category fluency. The relationship of cognitive impairment with baseline prognostic factors and other functional outcomes at day 90 were studied. RESULTS: The analysis included 1572 patients, mean age 69 years (standard deviation, 12), and female 40%. By 90 days, 246 patients had died, and cognitive impairment was present in 38%. Increasing age, stroke severity, heart rate, and presence of cerebral atrophy on baseline neuroimaging were associated with cognitive impairment (all P < .001). Hypertension and atrial fibrillation were also associated with category fluency and MMSE-M, respectively. Cognition was significantly related to other functional outcomes, TICS-M with dependency (modified Rankin Scale, rs = -.562, P < .001); disability (Barthel Index, rs = .577, P < .001); mood (Zung Depression Score, rs = -.542, P < .001); and quality of life (Euro Quality of life-5 Descriptor, rs = .519, P < .001). CONCLUSIONS: In previously independent individuals, cognitive impairment was common 3 months after stroke and related to increasing age, stroke severity, hypertension, atrial fibrillation, and cerebral atrophy on brain scanning. Cognition was related to dependency, disability, low mood, and quality of life. Hence, treatment directed toward reducing dependency might also reduce cognitive impairment.

EuroHYP-1: European multicenter, randomized, phase III clinical trial of therapeutic hypothermia plus best medical treatment vs. best medical treatment alone for acute ischemic stroke.

RATIONALE: Cooling reduced infarct size and improved neurological outcomes in animal studies modeling ischemic stroke, and also improved outcome in randomized clinical trials in patients with hypoxic-ischemic brain injury after cardiac arrest. Cooling awake patients with ischemic stroke has been shown feasible in phase II clinical trials. PRIMARY AIM: To determine whether systemic cooling to a target body temperature between 34·0 and 35·0°C, started within six-hours of symptom onset and maintained for 24 h, improves functional outcome at three-months in patients with acute ischemic stroke. DESIGN: International, multicenter, phase III, randomized, open-label clinical trial with blinded outcome assessment in 1500 patients aged 18 years or older with acute ischemic stroke and a National Institutes of Health Stroke Scale score of 6 up to and including 18. In patients randomized to hypothermia, cooling to a target body temperature of 34-35°C will be started within six-hours after symptom onset with rapid intravenous infusion of refrigerated normal saline or a surface cooling technique and maintained for 24 h with a surface or endovascular technique. Patients randomized to hypothermia will receive pethidine and buspirone to prevent shivering and discomfort. PRIMARY OUTCOME: Score on the modified Rankin Scale at 91 days, as analyzed with ordinal logistic regression and expressed as a common odds ratio. DISCUSSION: With 750 patients per intervention group, this trial has 90% power to detect 7% absolute improvement at the 5% significance level. The full trial protocol is available at http://www.eurohyp1.eu. ClinicalTrials.gov Identifier: NCT01833312.

Tranexamic acid for spontaneous intracerebral hemorrhage: a randomized controlled pilot trial (ISRCTN50867461).

BACKGROUND: Spontaneous intracerebral hemorrhage (ICH) can be devastating, particularly if hematoma expansion (HE) occurs. Tranexamic acid (TA), an antifibrinolytic drug, significantly reduced mortality in bleeding patients after trauma in the large CRASH-2 trial. The CRASH-2 ICH substudy found that TA nonsignificantly reduced mortality and dependency in traumatic ICH. The aim of this study was to assess the feasibility of performing a randomized controlled trial of tranexamic acid in spontaneous ICH, ahead of a definitive study. METHODS: We performed a single-center, prospective, randomized (2:1), double-blind, placebo-controlled blinded endpoint trial of TA (intravenous 1 g bolus, 1 g infusion/8 h) in acute (<24 hours) spontaneous ICH. The primary objective was to test the feasibility of recruiting to the trial. Other objectives included tolerability (adverse events) and the effect of TA on HE and death and dependency. RESULTS: The trial was feasible, with 24 patients enrolled (TA, n=16; placebo, n=8) between March 2011 and March 2012, and acceptable-only 3 patients declined to participate. All patients received the correct randomized treatment; 1 patient in the TA group did not complete the infusion because of neurologic deterioration. There were no significant differences in secondary outcomes including adverse events, HE, death, and dependency. One patient in the TA group had a deep vein thrombosis . CONCLUSIONS: This, the first randomized controlled trial of TA in ICH, found that the protocol could be delivered on schedule (2 patients/mo) and was feasible. Larger studies are needed to assess safety and efficacy of TA in ICH.

Views of paramedics on their role in an out-of-hospital ambulance-based trial in ultra-acute stroke: qualitative data from the Rapid Intervention With Glyceryl Trinitrate in Hypertensive Stroke Trial (RIGHT).

STUDY OBJECTIVE: Optimal practices for recruiting, consenting, and randomizing patients, and delivering treatment in out-of-hospital ultra-acute stroke trials, remain unclear. We aim to identify key barriers and facilitators relevant to the design and conduct of ambulance-based stroke trials and to formulate preliminary recommendations for the design of future trials. METHODS: Using semistructured interviews, we investigated the experiences and challenges faced by paramedics who took part in a randomized controlled trial in suspected ultra-acute stroke, the Rapid Intervention With Glyceryl Trinitrate in Hypertensive Stroke Trial (RIGHT), in which recruitment, consent, randomization, assessment, and treatment were delivered by paramedics before hospitalization. RESULTS: We purposively selected a diversity sample of 14 of the 78 paramedics who participated in RIGHT. We identified 13 themes (7 facilitators and 6 barriers to out-of-hospital stroke research). A simple stroke diagnostic tool, use of proxy consent on behalf of patients, and straightforward trial processes were identified as the main facilitators. Recruitment became easier with each new randomization attempt. Key barriers reported were informed consent in the emergency setting, lack of institutional support for research, learning curve and rarity (each paramedic treats only a few eligible patients), and difficulty in attending training sessions. Interviewed paramedics were motivated to participate in research. CONCLUSION: Ultra-acute stroke research in the out-of-hospital environment is feasible, but important barriers need to be addressed. Proxy consent by paramedics addresses some of the difficulties with the consent process in the out-of-hospital setting.

Blood pressure measurement reliability among different racial-ethnic groups in a stroke prevention study.

OBJECTIVE: High blood pressure (BP) is commonly not diagnosed, and patients do not achieve target values when treated. Among 20,000 patients encompassing most races-ethnicities, we evaluated BP measurements and treatment response in a stroke prevention trial. Our goal was to identify BP measurement differences between clinical trial and patient determinations and among the racial-ethnic groups. MATERIALS AND METHODS: A total of 20,332 patients with ischemic stroke were randomized to receive antiplatelet treatment and 80 mg of telmisartan versus placebo. BP measurements were obtained at the first clinic visit and then 1 and 3 months later and every 6 months thereafter. One week after the first clinic visit, patients were requested to report a BP measurement obtained elsewhere. Measurements at the trial clinics were obtained with the same electronic device. Statistical analysis was used to detect significant differences. RESULTS: The mean patient age was 66 years; 36% were women, and race-ethnicity comprised 58% Whites, 33% Asian, 4.9% Hispanic, and 4% Black. Overall, 74% of patients were hypertensive. BP varied between the race-ethnicity groups, being highest in Hispanics (145/85) and lowest in Blacks (144/82). BP at visits clinic 1, nonclinic 1A, and clinic 2 were, respectively, 144/84, 137/80, and 139/81 mmHg, with the difference between visits 1-2 and visit 1A being significant. BPs were normal in 42% of the cases at visit 1A, and of these, only 44% were normal at visit 1 and 57.6% were normal on visit 2. Similar findings were noted for all race-ethnicity groups. CONCLUSION: BP values varied among race-ethnicities and showed differences between clinic and patient measurements. This finding questions the reliability of self-reported BP and has implications for BP management in daily clinical practice.

Statistical analysis plan for the 'Efficacy of Nitric Oxide in Stroke' (ENOS) trial.

High blood pressure is common during the acute phase of stroke and is associated with a poor outcome. However, the management of high blood pressure remains unclear. The 'Efficacy of Nitric Oxide in Stroke' trial tested whether transdermal glyceryl trinitrate, a nitric oxide donor that lowers blood pressure, is safe and effective in improving outcome after acute stroke. Efficacy of Nitric Oxide in Stroke is an international multicenter, prospective, randomized, single-blind, blinded endpoint trial, with funding from the U.K. Medical Research Council. Patients with acute ischemic stroke or intracerebral hemorrhage and systolic blood pressure 140-220 mmHg were randomized to glyceryl trinitrate or no glyceryl trinitrate and, where relevant, to continue or stop prestroke antihypertensive therapy. The primary outcome is shift in modified Rankin Scale at three-months. Patients or relatives gave written informed (proxy) consent, and all sites had research ethics approval. Analyses will be done by intention to treat. This paper and attachment describe the trial's statistical analysis plan, developed prior to unblinding of date. The statistical analysis plan contains design and methods for analyses, and unpopulated tables and figures for the two primary publications and some secondary publications. The database will be locked in late February 2014 in preparation for presentation of the results in May 2014. The data from the trial will improve the precision of the estimates of the overall treatment effects (efficacy and safety) of results from completed trials of blood pressure management in acute stroke, and provide the first large-scale randomized evidence on transdermal glyceryl trinitrate, and of continuing (vs. stopping) prestroke antihypertensive medications, in acute stroke.