Nikola Sprigg

Granulocyte-Colony–Stimulating Factor Mobilizes Bone Marrow Stem Cells in Patients With Subacute Ischemic Stroke: The Stem Cell Trial of Recovery EnhanceMent After Stroke (STEMS) Pilot Randomized, Controlled Trial (ISRCTN 16784092)

Background and Purpose— Loss of motor function is common after stroke and leads to significant chronic disability. Stem cells are capable of self-renewal and of differentiating into multiple cell types, including neurones, glia, and vascular cells. We assessed the safety of granulocyte-colony–stimulating factor (G-CSF) after stroke and its effect on circulating CD34+ stem cells. Methods— We performed a 2-center, dose-escalation, double-blind, randomized, placebo-controlled pilot trial (ISRCTN 16784092) of G-CSF (6 blocks of 1 to 10 &mgr;g/kg SC, 1 or 5 daily doses) in 36 patients with recent ischemic stroke. Circulating CD34+ stem cells were measured by flow cytometry; blood counts and measures of safety and functional outcome were also monitored. All measures were made blinded to treatment. Results— Thirty-six patients, whose mean±SD age was 76±8 years and of whom 50% were male, were recruited. G-CSF (5 days of 10 &mgr;g/kg) increased CD34+ count in a dose-dependent manner, from 2.5 to 37.7 at day 5 (area under curve, P=0.005). A dose-dependent rise in white cell count (P<0.001) was also seen. There was no difference between treatment groups in the number of patients with serious adverse events: G-CSF, 7/24 (29%) versus placebo 3/12 (25%), or in their dependence (modified Rankin Scale, median 4, interquartile range, 3 to 5) at 90 days. Conclusions— G-CSF is effective at mobilizing bone marrow CD34+ stem cells in patients with recent ischemic stroke. Administration is feasible and appears to be safe and well tolerated. The fate of mobilized cells and their effect on functional outcome remain to be determined.

Efficacy of nitric oxide, with or without continuing antihypertensive treatment, for management of high blood pressure in acute stroke (ENOS): a partial-factorial randomised controlled trial.

Summary Background High blood pressure is associated with poor outcome after stroke. Whether blood pressure should be lowered early after stroke, and whether to continue or temporarily withdraw existing antihypertensive drugs, is not known. We assessed outcomes after stroke in patients given drugs to lower their blood pressure. Methods In our multicentre, partial-factorial trial, we randomly assigned patients admitted to hospital with an acute ischaemic or haemorrhagic stroke and raised systolic blood pressure (systolic 140–220 mm Hg) to 7 days of transdermal glyceryl trinitrate (5 mg per day), started within 48 h of stroke onset, or to no glyceryl trinitrate (control group). A subset of patients who were taking antihypertensive drugs before their stroke were also randomly assigned to continue or stop taking these drugs. The primary outcome was function, assessed with the modified Rankin Scale at 90 days by observers masked to treatment assignment. This study is registered, number ISRCTN99414122. Findings Between July 20, 2001, and Oct 14, 2013, we enrolled 4011 patients. Mean blood pressure was 167 (SD 19) mm Hg/90 (13) mm Hg at baseline (median 26 h [16–37] after stroke onset), and was significantly reduced on day 1 in 2000 patients allocated to glyceryl trinitrate compared with 2011 controls (difference −7·0 [95% CI −8·5 to −5·6] mm Hg/–3·5 [–4·4 to −2·6] mm Hg; both p<0·0001), and on day 7 in 1053 patients allocated to continue antihypertensive drugs compared with 1044 patients randomised to stop them (difference −9·5 [95% CI −11·8 to −7·2] mm Hg/–5·0 [–6·4 to −3·7] mm Hg; both p<0·0001). Functional outcome at day 90 did not differ in either treatment comparison—the adjusted common odds ratio (OR) for worse outcome with glyceryl trinitrate versus no glyceryl trinitrate was 1·01 (95% CI 0·91–1·13; p=0·83), and with continue versus stop antihypertensive drugs OR was 1·05 (0·90–1·22; p=0·55). Interpretation In patients with acute stroke and high blood pressure, transdermal glyceryl trinitrate lowered blood pressure and had acceptable safety but did not improve functional outcome. We show no evidence to support continuing prestroke antihypertensive drugs in patients in the first few days after acute stroke. Funding UK Medical Research Council.

Sex Differences in Quality of Life in Stroke Survivors Data From the Tinzaparin in Acute Ischaemic Stroke Trial (TAIST)

Background and Purpose— Female sex is predictive of poor functional outcome in stroke, even after correction for prognostic factors. Poor quality of life (QoL) is observed in stroke survivors with lower scores seen in the most disabled patients. We used data from the Tinzaparin in Acute Ischaemic Stroke Trial (TAIST) to assess the relationship between sex and QoL after ischemic stroke. Methods— TAIST was a randomized, controlled trial assessing the safety and efficacy of tinzaparin versus aspirin in 1484 patients with acute ischemic stroke. QoL was measured at 180 days postrandomization using the Short Form-36 health survey, which assesses QoL across 8 domains. The relationship between sex and each domain was assessed using ordinal regression, both unadjusted and adjusted for key prognostic factors. Results— Of the 1484 patients randomized into TAIST, 216 had died at 180 days postrandomization. A total of 1268 survivors were included in this analysis, 694 males (55%) and 574 females (45%). Females tended to score lower than males across all QoL domains (apart from general health); statistically significant lower scores were seen for physical functioning (OR: 0.58, 95% CI: 0.47 to 0.72), vitality (OR: 0.79, 95% CI: 0.64 to 0.98), and mental health (OR: 0.75, 95% CI: 0.61 to 0.93). The results for physical functioning and mental health remained significant after adjustment for prognostic variables (OR: 0.73, 95% CI: 0.58 to 0.92; OR: 0.76, 95% CI: 0.60 to 0.95, respectively). Conclusions— QoL, in particular physical function and mental health domains, is lower in female patients after stroke. This difference persists even after correction for known prognostic factors such as age and stroke severity.

Granulocyte-colony - Stimulating factor mobilizes bone marrow stem cells in patients with subacute ischemic stroke: The Stem cell Trial of recovery EnhanceMent after Stroke (STEMS) pilot randomized, controlled trial (ISRCTN 16784092)

Background and Purpose— Loss of motor function is common after stroke and leads to significant chronic disability. Stem cells are capable of self-renewal and of differentiating into multiple cell types, including neurones, glia, and vascular cells. We assessed the safety of granulocyte-colony–stimulating factor (G-CSF) after stroke and its effect on circulating CD34+ stem cells. Methods— We performed a 2-center, dose-escalation, double-blind, randomized, placebo-controlled pilot trial (ISRCTN 16784092) of G-CSF (6 blocks of 1 to 10 &mgr;g/kg SC, 1 or 5 daily doses) in 36 patients with recent ischemic stroke. Circulating CD34+ stem cells were measured by flow cytometry; blood counts and measures of safety and functional outcome were also monitored. All measures were made blinded to treatment. Results— Thirty-six patients, whose mean±SD age was 76±8 years and of whom 50% were male, were recruited. G-CSF (5 days of 10 &mgr;g/kg) increased CD34+ count in a dose-dependent manner, from 2.5 to 37.7 at day 5 (area under curve, P=0.005). A dose-dependent rise in white cell count (P<0.001) was also seen. There was no difference between treatment groups in the number of patients with serious adverse events: G-CSF, 7/24 (29%) versus placebo 3/12 (25%), or in their dependence (modified Rankin Scale, median 4, interquartile range, 3 to 5) at 90 days. Conclusions— G-CSF is effective at mobilizing bone marrow CD34+ stem cells in patients with recent ischemic stroke. Administration is feasible and appears to be safe and well tolerated. The fate of mobilized cells and their effect on functional outcome remain to be determined.

Feasibility of an Ambulance-Based Stroke Trial, and Safety of Glyceryl Trinitrate in Ultra-Acute Stroke The Rapid Intervention With Glyceryl Trinitrate in Hypertensive Stroke Trial (RIGHT, ISRCTN66434824)

Background and Purpose— The practicalities of doing ambulance-based trials where paramedics perform all aspects of a clinical trial involving patients with ultra-acute stroke have not been assessed. Methods— We performed a randomized controlled trial with screening, consent, randomization, and treatment performed by paramedics prior to hospitalization. Patients with probable ultra-acute stroke (<4 hours) and systolic blood pressure (SBP) >140 mm Hg were randomized to transdermal glyceryl trinitrate (GTN; 5 mg/24 hours) or none (blinding under gauze dressing) for 7 days with the first dose given by paramedics. The primary outcome was SBP at 2 hours. Results— Of a planned 80 patients, 41 (25 GTN, 16 no GTN) were enrolled >22 months with median age [interquartile range] 79 [16] years; men 22 (54%); SBP 168 [46]; final diagnosis: stroke 33 (80%) and transient ischemic attack 3 (7%). Time to randomization was 55 [75] minutes. After treatment with GTN versus no GTN, SBP at 2 hours was 153 [31] versus 174 [27] mm Hg, respectively, with difference −18 [30] mm Hg (P=0.030). GTN improved functional outcome with a shift in the modified Rankin Scale by 1 [3] point (P=0.040). The rates of death, 4 (16%) versus 6 (38%; P=0.15), and serious adverse events, 14 (56%) versus 10 (63%; P=0.75), did not differ between GTN and no GTN. Conclusions— Paramedics can successfully enroll patients with ultra-acute stroke into an ambulance-based trial. GTN reduces SBP at 2 hours and seems to be safe in ultra-acute stroke. A larger trial is needed to assess whether GTN improves functional outcome. Clinical Trial Registration— URL: http://www.controlled-trials.com/ISRCTN66434824/66434824. Unique identifier: 66434824.

Relationship between outcome and baseline blood pressure and other haemodynamic measures in acute ischaemic stroke: data from the TAIST trial

Background A poor outcome after stroke is associated independently with high blood pressure during the acute phase; however, relationships with other haemodynamic measures [heart rate (HR), pulse pressure (PP), rate–pressure product (RPP)] remain less clear. Methods The Tinzaparin in Acute Ischaemic Stroke Trial is a randomised, controlled trial assessing the safety and efficacy of tinzaparin versus aspirin in 1484 patients with acute ischaemic stroke. Systolic blood pressure (SBP), diastolic blood pressure (DBP) and HR measurements taken immediately prior to randomization were averaged, and the mid-blood pressure (MBP), PP, mean arterial pressure (MAP), pulse pressure index, and RPP were calculated. The relationship between these haemodynamic measures and functional outcome (death or dependency, modified Rankin Scale > 2) and early recurrent stroke, were studied with adjustment for baseline prognostic factors and treatment group. Odds ratios (OR) and 95% confidence intervals (CI) refer to a change in haemodynamic measure by 10 points. Results A poor functional outcome was associated with SBP (adjusted OR; 1.11; 95% CI, 1.03–1.21), HR (adjusted OR; 1.15; 95% CI, 1.00–1.31), MBP (adjusted OR; 1.15, 95% CI, 1.03–1.29), PP (adjusted OR; 1.14; 95% CI, 1.02–1.26), MAP (adjusted OR; 1.15; 95% CI, 1.02–1.31) and RPP (adjusted OR; 1.01; 95% CI, 1.00–1.02). Early recurrent stroke was associated with SBP, DBP, MBP and MAP. Conclusions A poor outcome is independently associated with elevations in blood pressure, HR and their derived haemodynamic variables, including PP and the RPP. Agents that modify these measures may improve functional outcome after stroke.

Inhibition of Rho-kinase protects cerebral barrier from ischaemia-evoked injury through modulations of endothelial cell oxidative stress and tight junctions

Ischaemic strokes evoke blood–brain barrier (BBB) disruption and oedema formation through a series of mechanisms involving Rho‐kinase activation. Using an animal model of human focal cerebral ischaemia, this study assessed and confirmed the therapeutic potential of Rho‐kinase inhibition during the acute phase of stroke by displaying significantly improved functional outcome and reduced cerebral lesion and oedema volumes in fasudil‐ versus vehicle‐treated animals. Analyses of ipsilateral and contralateral brain samples obtained from mice treated with vehicle or fasudil at the onset of reperfusion plus 4 h post‐ischaemia or 4 h post‐ischaemia alone revealed these benefits to be independent of changes in the activity and expressions of oxidative stress‐ and tight junction‐related parameters. However, closer scrutiny of the same parameters in brain microvascular endothelial cells subjected to oxygen–glucose deprivation ± reperfusion revealed marked increases in prooxidant NADPH oxidase enzyme activity, superoxide anion release and in expressions of antioxidant enzyme catalase and tight junction protein claudin‐5. Cotreatment of cells with Y‐27632 prevented all of these changes and protected in vitro barrier integrity and function. These findings suggest that inhibition of Rho‐kinase after acute ischaemic attacks improves cerebral integrity and function through regulation of endothelial cell oxidative stress and reorganization of intercellular junctions.

Post-stroke dysphagia: A review and design considerations for future trials

Post-stroke dysphagia (a difficulty in swallowing after a stroke) is a common and expensive complication of acute stroke and is associated with increased mortality, morbidity, and institutionalization due in part to aspiration, pneumonia, and malnutrition. Although most patients recover swallowing spontaneously, a significant minority still have dysphagia at six months. Although multiple advances have been made in the hyperacute treatment of stroke and secondary prevention, the management of dysphagia post-stroke remains a neglected area of research, and its optimal management, including diagnosis, investigation and treatment, have still to be defined.

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.

A Randomised Controlled Trial of Triple Antiplatelet Therapy (Aspirin, Clopidogrel and Dipyridamole) in the Secondary Prevention of Stroke: Safety, Tolerability and Feasibility

Background Aspirin, dipyridamole and clopidogrel are effective in secondary vascular prevention. Combination therapy with three antiplatelet agents might maximise the benefit of antiplatelet treatment in the secondary prevention of ischaemic stroke. Methodology/Principal Findings A randomised, parallel group, observer-blinded phase II trial compared the combination of aspirin, clopidogrel and dipyridamole with aspirin alone. Adult patients with ischaemic stroke or transient ischaemic attack (TIA) within 5 years were included. The primary outcome was tolerability to treatment assessed as the number of patients completing randomised treatment. Recruitment was halted prematurely after publication of the ESPRIT trial (which confirmed that combined aspirin and dipyridamole is more effective than aspirin alone). 17 patients were enrolled: male 12 (71%), mean age 62 (SD 13) years, lacunar stroke syndrome 12 (71%), median stroke/TIA onset to randomisation 8 months. Treatment was discontinued in 4 of 9 (44%) patients receiving triple therapy vs. none of 8 taking aspirin (p = 0.08). One recurrent stroke occurred in a patient in the triple group who was noncompliant of all antiplatelet medications. The number of patients with adverse events and bleeding complications, and their severity, were significantly greater in the triple therapy group (p<0.01). Conclusions/Significance Long term triple antiplatelet therapy was asociated with a significant increase in adverse events and bleeding rates, and their severity, and a trend to increased discontinuations. However, the patients had a low risk of recurrence and future trials should focus on short term therapy in high risk patients characterised by a very recent event or failure of dual antiplatelet therapy. Trial Registration Controlled-Trials.com ISRCTN83673558