Efficacy Of Nitric Oxide In Stroke Research Articles

Effect of continuing versus stopping pre-stroke antihypertensive agents within 12h on outcome after stroke: A subgroup analysis of the efficacy of nitric oxide in stroke (ENOS) trial.

SummaryBackgroundIt is not known whether to continue or temporarily stop existing antihypertensive drugs in patients with acute stroke.MethodsWe performed a prospective subgroup analysis of patients enrolled into the Efficacy of Nitric Oxide in Stroke (ENOS) trial who were randomised to continue vs stop prior antihypertensive therapy within 12 h of stroke onset. The primary outcome was functional outcome, assessed with the modified Rankin Scale at 90 days by observers blinded to treatment assignment, and analysed with ordinal logistic regression.FindingsOf 4011 patients recruited into ENOS from 2001 to 2014, 2097 patients were randomised to continue vs stop prior antihypertensive treatment, and 384 (18.3%, continue 185, stop 199) were enrolled within 12 h of ictus: mean (SD) age 71.8 (11.8) years, female 193 (50.3%), ischaemic stroke 342 (89.1%) and total anterior circulation syndrome 114 (29.7%). As compared with stopping, continuing treatment within 12 h of onset lowered blood pressure by 15.5/9.6 mmHg (p<0.001/<0.001) by 7 days, shifted the modified Rankin Scale to a worse outcome by day 90, adjusted common odds ratio (OR) 1.46 (95% CI 1.01–2.11), and was associated with an increased death rate by day 90 (hazard ratio 2.17, 95% CI 1.24–3.79). Other outcomes (disability - Barthel Index, quality of life - EQ-visual analogue scale, cognition - telephone mini-mental state examination, and mood - Zung depression scale) were also worse with continuing treatment.InterpretationIn this pre-specified subgroup analysis of the large ENOS trial, continuing prior antihypertensive therapy within 12 h of stroke onset in a predominantly ischaemic stroke population was unsafe with worse functional outcome, disability, cognition, mood, quality of life and increased death. Future studies assessing continuing or stopping prior antihypertensives in the context of thrombectomy are awaited.

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

IntroductionNitrate-induced headache is common and may signify responsive cerebral vasculature. We assessed the relationship between nitrate headache and outcome in patients with acute stroke.Materials and methodsPatients were those randomised to...

Imaging markers of small vessel disease and brain frailty, and outcomes in acute stroke

ObjectiveTo assess the association of baseline imaging markers of cerebral small vessel disease (SVD) and brain frailty with clinical outcome after acute stroke in the Efficacy of Nitric Oxide in Stroke (ENOS) trial.MethodsENOS randomized 4,011 patients with acute stroke (<48 hours of onset) to transdermal glyceryl trinitrate (GTN) or no GTN for 7 days. The primary outcome was functional outcome (modified Rankin Scale [mRS] score) at day 90. Cognition was assessed via telephone at day 90. Stroke syndrome was classified with the Oxfordshire Community Stroke Project classification. Brain imaging was adjudicated masked to clinical information and treatment and assessed SVD (leukoaraiosis, old lacunar infarcts/lacunes, atrophy) and brain frailty (leukoaraiosis, atrophy, old vascular lesions/infarcts). Analyses used ordinal logistic regression adjusted for prognostic variables.ResultsIn all participants and those with lacunar syndrome (LACS; 1,397, 34.8%), baseline CT imaging features of SVD and brain frailty were common and independently associated with unfavorable shifts in mRS score at day 90 (all participants: SVD score odds ratio [OR] 1.15, 95% confidence interval [CI] 1.07–1.24; brain frailty score OR 1.25, 95% CI 1.17–1.34; those with LACS: SVD score OR 1.30, 95% CI 1.15–1.47, brain frailty score OR 1.28, 95% CI 1.14–1.44). Brain frailty was associated with worse cognitive scores at 90 days in all participants and in those with LACS.ConclusionsBaseline imaging features of SVD and brain frailty were common in lacunar stroke and all stroke, predicted worse prognosis after all acute stroke with a stronger effect in lacunar stroke, and may aid future clinical decision-making.IdentifierISRCTN99414122.

It is safe to use transdermal glyceryl trinitrate to lower blood pressure in patients with acute ischaemic stroke with carotid stenosis

BackgroundThere is concern that blood pressure (BP) lowering in acute stroke may compromise cerebral perfusion and worsen outcome in the presence of carotid stenosis. We assessed the effect of glyceryl...

Central masked adjudication of stroke diagnosis at trial entry offered no advantage over diagnosis by local clinicians: Secondary analysis and simulation.

BackgroundCentral adjudication of stroke type is commonly implemented in large multicentre clinical trials. We investigated the effect of central adjudication of diagnosis of stroke type at trial entry in the Efficacy of Nitric Oxide in Stroke (ENOS) trial.MethodsENOS recruited patients with acute ischaemic or haemorrhagic stroke, and diagnostic adjudication was carried out using cranial scans. For this study, diagnoses made by local site clinicians were compared with those by central, masked adjudicators using kappa statistics. The trial primary analysis and subgroup analysis by stroke type were re-analysed using stroke diagnosis made by local clinicians, and simulations were used to assess the impact of increased non-differential misclassification and subgroup effects.ResultsAgreement on stroke type (Ischaemic, Intracerebral Haemorrhage, Unknown stroke type, No-stroke) was high (κ = 0.92). Adjudication of stroke type had no impact on the primary outcome or subgroup analysis by stroke type. With misclassification increased to 10 times the level observed in ENOS and a simulated subgroup effect present, adjudication would have affected trial conclusions.ConclusionsStroke type at trial entry was diagnosed accurately by local clinicians in ENOS. Adjudication of stroke type by central adjudicators had no measurable effect on trial conclusions. Diagnostic adjudication may be important if diagnosis is complex and a treatment-diagnosis interaction is expected.

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

AimsAlthough 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.MethodsENOS 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.ResultsThere 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).ConclusionsBlood 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.

Associations of Imaging Markers of Small Vessel Disease and 'Brain Frailty' with Clinical Outcome in Patients with Acute Lacunar Stroke: A Secondary Analysis of the Efficacy of Nitric Oxide in Stroke (ENOS) Trial

Background: Cerebral small vessel disease (SVD) is a common cause of lacunar stroke, cognitive impairment and dementia. We assessed the association of baseline imaging markers of SVD and 'brain frailty' with functional and cognitive outcomes after acute stroke, including lacunar stroke, in the Efficacy of Nitric Oxide in Stroke (ENOS) trial. Methods: ENOS randomised 4011 patients with acute stroke (<48 hours of onset) to transdermal GTN or no GTN for 7 days. The primary outcome was functional outcome (modified Rankin Scale, mRS) at day 90. Stroke syndrome was classified using the Oxfordshire Community Stroke Project classification. Brain imaging was adjudicated masked to clinical information and treatment, and assessed for SVD (leukoaraiosis, old lacunar infarcts/lacunes, atrophy) and 'brain frailty' (leukoaraiosis, atrophy, old vascular lesions). Ordered categorical data were analysed using ordinal logistic regression with adjustment for prognostic variables. Findings: In all participants, and in 1397/4011 (34.8%) participants with lacunar syndromes (LACS), baseline imaging features of SVD and 'brain frailty' on CT were common and independently associated with unfavourable shifts in mRS at day 90 in all participants (SVD score: OR 1.15, 95% CI 1.07-1.24; 'brain frailty' score: OR 1.25, 95% CI 1.17-1.34) and in those with LACS (SVD score: OR 1.30, 95% CI 1.15-1.47; 'brain frailty' score: OR 1.28, 95% CI 1.14-1.44). 'Brain frailty' was associated with worse cognitive scores at 90 days in all and in LACS participants. GTN did not influence three-month outcomes in participants with LACS. Interpretation: Baseline imaging features of SVD and 'brain frailty' were common in lacunar stroke and all stroke, predicted worse prognosis after all acute stroke with a stronger effect in lacunar stroke, and may aid future clinical decision-making. Whether the vascular or neurodegenerative features are more associated with cognitive impairment requires further testing. Trial Registration Number: ISRCTN99414122 Funding Statement: BUPA Foundation and the Medical Research Council. Declaration of Interests: NS reports grants from NIHR HTA (11_129_109) during the conduct of the study. PMB reports grants from British Heart Foundation, grants from NIHR Health Technology Appraisal Prog, during the conduct of the study; other from Platelet Solutions Ltd, personal fees from Diamedica, personal fees from Nestle, personal fees from Phagenesis Ltd, personal fees from ReNeuron, personal fees from Athersys, personal fees from Covidien outside the submitted work. JMW reports grants from Medical Research Council, grants from Fondation Leducq, grants from EU Horizon 2020 during the conduct of the study. JPA, AA, JLB, EB, LAC, AMC, VC, HKC, RAD, JG, PK and SS have nothing to disclose. Ethics Approval Statement: ENOS was approved by ethics committees/competent authorities in all participating countries.

Route of Feeding as a Proxy for Dysphagia After Stroke and the Effect of Transdermal Glyceryl Trinitrate: Data from the Efficacy of Nitric Oxide in Stroke Randomised Controlled Trial

Post-stroke dysphagia is common, associated with poor outcome and often requires non-oral feeding/fluids. The relationship between route of feeding and outcome, as well as treatment with glyceryl trinitrate (GTN), was studied prospectively. The Efficacy of Nitric Oxide in Stroke (ENOS) trial assessed transdermal GTN (5 mg versus none for 7 days) in 4011 patients with acute stroke and high blood pressure. Feeding route (oral = normal or soft diet; non-oral = nasogastric tube, percutaneous endoscopic gastrostomy tube, parenteral fluids, no fluids) was assessed at baseline and day 7. The primary outcome was the modified Rankin Scale (mRS) measured at day 90. At baseline, 1331 (33.2%) patients had non-oral feeding, were older, had more severe stroke and more were female, than 2680 (66.8%) patients with oral feeding. By day 7, 756 patients had improved from non-oral to oral feeding, and 119 had deteriorated. Non-oral feeding at baseline was associated with more impairment at day 7 (Scandinavian Stroke Scale 29.0 versus 43.7; 2p < 0.001), and worse mRS (4.0 versus 2.7; 2p < 0.001) and death (23.6 versus 6.8%; 2p = 0.014) at day 90. Although GTN did not modify route of feeding overall, randomisation ≤6 h of stroke was associated with a move to more oral feeding at day 7 (odds ratio = 0.61, 95% confidence intervals 0.38, 0.98; 2p = 0.040). As a proxy for dysphagia, non-oral feeding is present in 33% of patients with acute stroke and associated with more impairment, dependency and death. GTN moved feeding route towards oral intake if given very early after stroke.Clinical Trial RegistrationClinical Trial Registration-URL: http://www.controlled-trials.com. Unique identifier: ISRCTN99414122.

Abstract TP70: Incidence of Serious Adverse Events Following Acute Stroke: Data From the Efficacy of Nitric Oxide in Stroke (ENOS) Trial

Background: Reporting of serious adverse events (SAEs) is an essential safety procedure in randomised controlled trials. Risk factors for SAEs post-stroke and the relationship of SAEs with outcome were studied in the ENOS trial. Methods: ENOS assessed glyceryl trinitrate (GTN, 5 mg) vs no GTN for 7 days in 4,011 patients with acute stroke and high blood pressure. Information on SAEs was collected up to day 90. SAEs were adjudicated centrally with blinding to treatment assignment. Results: SAEs were reported in 1022 (25.5%) patients, 43.8% of whom died. Patients who suffered SAEs were more likely to be older (mean age 74.2 vs. 69.0 years, p&lt;0.001) and have a history of atrial fibrillation (AF) (relative risk [RR] 1.80, p&lt;0.001). Patients with non-oral feeding at baseline were more vulnerable to SAEs (RR 2.14, p&lt;0.001) and fatal SAEs (RR 3.77, p&lt;0.001) as compared with those with oral feeding. Males were at less risk than females to suffer an SAE (RR 0.83, p&lt;0.001), as were smokers (RR 0.73, p&lt;0.001). Smokers also suffered fewer fatal SAEs (RR 0.55, p&lt;0.001). GTN did not increase the incidence of SAEs. The most common type of SAE was pneumonia (6% incidence) with a high risk of death (RR 9.29, p&lt;0.001). Conclusions: SAEs are associated with a range of risk factors that should be taken into account in clinical practice. AF and non-oral feeding status were associated with increased, and smoking with reduced, risk of of SAEs. Incidence of pneumonia was a common and life threatening issue amongst patients.

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

Background and purposeMore 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.MethodsENOS 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.ResultsBlood 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.ConclusionsAmong 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.

Abstract WP349: Feeding Status After Stroke and Effect of Glyceryl Trinitrate: Data From the Efficacy of Nitric Oxide in Stroke (ENOS) Trial

Background: Post-stroke dysphagia is common, associated with poor outcome, and patients often require non-oral feeding/fluids. The relationship of feeding status on outcome, and treatment with transdermal glyceryl trinitrate (GTN) was studied in the ENOS trial. Methods: ENOS assessed GTN (5 mg vs none for 7 days) in 4,011 patients with acute stroke and high blood pressure. Feeding status (oral = normal diet, soft diet; non-oral = nasogastric tube, percutaneous endoscopic gastrostomy tube, parenteral fluids, none) was assessed at baseline and day 7. The primary outcome was the modified Rankin Scale (mRS) measured at day 90. Analyses of outcomes were adjusted for baseline covariates. †2p&lt;0.001. Results: In comparison with oral feeding, non-oral patients (N=1331, 33.2%) were older (73.9 vs 68.5 years†), more likely to be female (47.3 v 40.4%†) and had more severe stroke (Scandinavian Stroke Scale 24.6 v 38.3†). By day 7, 56.8% patients had improved from non-oral to oral feeding, and 4.4% had deteriorated. Non-oral feeding at baseline was associated with more impairment at day 7 (SSS 29.0 v 43.7†), and higher mRS 4.0 (1.7) v 2.7 (1.6)†) and death (23.6% v 6.8%†) at day 90. Although GTN did not modify feeding status overall, randomisation to GTN &lt;6 hours of stroke was associated with a significant shift to improved feeding status at day 7 (OR=0.61, 95% CI 0.38-0.98). Conclusions: Non-oral feeding status is common in acute stroke and associated with more impairment, dependency and death. Very early administration of GTN improved feeding status, a finding that requires further testing.

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

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. 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. 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. 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. URL: http://www.isrctn.com/ISRCTN99414122. Unique identifier: 99414122.

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.

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. 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. 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). 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. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00989716.

Abstract 156: Glyceryl Trinitrate for Hyperacute Stroke: Results from the Efficacy of Nitric Oxide in Stroke (ENOS) Trial

Background: High blood pressure (BP) is common during the acute phase of stroke and is associated with a poor outcome. Administration of glyceryl trinitrate (GTN), a nitric oxide donor that lowers BP, improved functional outcome in the small ambulance-based paramedic-delivered RIGHT trial. Methods: ENOS was an international prospective randomised single-blind blinded-endpoint trial. Patients with acute (&lt;48 hours) stroke and systolic BP 140-220 mmHg were randomised to GTN (5 mg transdermal) or no GTN. Outcomes included shift in modified Rankin Scale (mRS, primary), Barthel Index (BI) and death at 3 months. Analyses are by regression (binary, ordinal or multiple) with adjustment for baseline covariates; results are odds ratio (OR)/mean difference (MD) with 95% confidence intervals (95% CI). Results: Of 4,011 enrolled patients, 273 were randomised (GTN 144, no GTN 129) within 6 hours of onset of stroke: age 70 (SD 13); BP 167 (18)/91 (13) mmHg; Scandinavian Stroke Scale 32 (12); ischaemic 76%, ICH 22%; stroke-randomisation 4.6 hours. Treatment with GTN was associated with improved mRS (OR 0.51, 95% CI 0.32-0.80), BI (MD 13.5, 95% CI 4.6 to 22.5), and reduced death (OR 0.31, 95% CI 0.11-0.91). Significant improvements in mood, quality of life and cognition were also seen. Summary: In the subgroup of patients randomised within 6 hours of stroke onset, treatment with GTN was associated with less dependency, disability and death. These positive results mirror those seen in the RIGHT pilot trial.

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

BackgroundPoor 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.MethodsClinical and...

Very Low Quality of Life After Acute Stroke

Health-related quality of life, a key outcome after stroke, plays a role in the analysis of treatment cost-effectiveness. Some measures of health-related quality of life allow for a quality of life worse than death; the characteristics of such patients have not been well described. Data from the Efficacy of Nitric Oxide in Stroke (ENOS) trial were used to explore health-related quality of life after stroke. The EuroQol questionnaire (EQ-5D) was performed at day 90, and a health utility score (HUS) was calculated. HUS was defined as follows: poor-good HUS>0, death HUS=0, and very poor HUS<0. The characteristics and outcomes of patients with HUS<0 were then explored. Of the 2569 patients, 303 (11.8%) died, and of the 2238 with quality of life data available, of whom 724 (32.3%) were completed by a proxy, 1959 (87.5%) had an HUS>0 and 279 (12.5%) had an HUS<0. Patients with HUS<0 were more likely to be older, women, have severe stroke, have proxy responders, and be institutionalized. Dominant hemisphere strokes were more likely to have proxy responders but not HUS<0. HUS was strongly correlated with dependency (modified Rankin Scale, r=-0.78) and disability (Barthel index, r=0.84) and moderately correlated with mood (Zung depression score, r=-0.59) and baseline severity (r=0.51). All but 1 patient with modified Rankin Scale of 5 had an HUS<0. Very low health-related quality of life is relatively common after stroke, particularly in patients with mobility problems or who are dependent on help for usual activities, and is related to poor functional outcome measures. http://www.controlled-trials.com/. Unique identifier: ISRCTN99414122.

Abstract TP47: Infarct Growth Does Not Predict Functional Outcome For Small Vessel Stroke

Introduction: Infarct growth has been shown to be a predictor of clinical outcome following ischemic stroke and has been used as a surrogate in reperfusion studies. There are no data whether the association of infarct growth and clinical outcome depends on stroke etiology. Furthermore, there is uncertainty on how to handle small volume infarcts with some studies excluding them from analyses. We studied the relationship between infarct growth and functional outcome in stroke patients with small volume infarcts for subgroups with small and non-small vessel etiologies. Methods: We studied 37 patients in the MRI substudy of the Efficacy of Nitric Oxide in Stroke (ENOS) trial with baseline infarct volumes of ≤5ml. None of the patients were treated with reperfusion strategies. Brain MRI was performed serially at baseline within 48 hours of onset, on days 7 and 90. Infarct growth was measured as the volume difference between final T2 and baseline DWI lesions. Good functional outcome was defined as day 90 modified Rankin score ≤2 and poor as &gt;2. Results: Among the 26 patients with underlying small vessel etiology, there was no difference between those with good and poor outcomes in terms of absolute [median 0.0 (IQR -0.4 to 1.1) vs 0.1 (-0.7 to 0.2) mL, p=0.802] and relative infarct growth [median -3 (-27 to 81) vs 8 (-46 to 10) %, p=0.802]. However, in the 11 patients with etiologies other than small vessel disease, patients with good outcome had less absolute [median -0.9 (-1.6 to 0.7) vs 3.2 (0.2 to 9.1) mL, p=0.033] and relative infarct growth [median -59 (-81 to 9) vs 154 (35 to 292) %, p=0.019] compared to those with poor outcome. Discussion: In small volume strokes, infarct growth was not associated with functional outcome for small vessel stroke although there was a significant association for other stroke etiologies. This novel finding in this small sample should be confirmed in larger studies. Our findings are expected as small vessel stroke involves occlusion of penetrating arterioles which supply small, limited yet strategically important brain regions. Thus, while infarct growth may be a suitable surrogate for clinical outcomes for small volume infarcts due to non-small vessel disease, but it may not be for small vessel strokes.

The efficacy of nitric oxide in stroke (ENOS) trial – where do we stand in Romania?

Introduction. Romania ranks third worldwide for stroke mortality. Although high blood pressure (BP) is a major risk factor for stroke incidence and determinant of outcome, the management of BP in acute stroke remains undefined. The present study assesses patients recruited into the ‘Efficacy of Nitric Oxide in Stroke’ (ENOS) trial from Romania, one of 19 participating countries. Methods. ENOS is an international multicentre prospective randomised controlled trial that is assessing the safety and efficacy of: (i) lowering BP with transdermal glyceryl trinitrate, and (ii) whether pre-stroke antihypertensive therapy should be continued or stopped temporarily, in acute ischaemic stroke or primary intracerebral haemorrhage (PICH). Interventions are given for 7 days and the primary outcome, modified Rankin Scale (mRS), is measured at 90 days. Results. 135 patients were recruited from 3 Romanian sites between March 2009 and August 2011; 56% of these patients were also in the continue-stop arm of the trial. In comparison with the Rest of the World (RoW), Romanian patients were recruited earlier (29 vs. 22 hr), had a higher rate of previous high BP (63 vs. 76%), had less severe stroke at baseline (Scandinavian Stroke Scale, SSS 37 vs. 43/58), were less likely to have a PICH (17 vs. 10%), and had more cases of no visible stroke lesions on baseline CT (27 vs. 49%). Impairment (SSS) at day 7 did not differ. As compared to RoW, the length of stay in hospital was shorter in Romania (14 vs. 9 days); the adjusted death rate at follow-up at 90 days was doubled (odds ratio 1.97, 95% confidence intervals 1.07-3.63) although this was not reflected by a difference in the adjusted rate of death or dependency (mRS&gt;2) at 90 days (OR 1.04, 95% CI 0.66-1.63). Conclusion. ENOS will continue recruiting patients until the summer of 2013. The presented data show that enrolment is feasible in Romania and the trial has been found to be easy to manage and recruit into.

Is lowering blood pressure hazardous in patients with significant ipsilateral carotid stenosis and acute ischaemic stroke? Interim assessment in the ‘Efficacy of Nitric Oxide in Stroke’ Trial

High blood pressure (BP) in acute stroke patients is both common and associated with a poor outcome, although best management remains unclear. Particular uncertainty exists in patients with carotid stenosis in whom lowering BP might reduce cerebral perfusion and worsen outcome. Efficacy of Nitric Oxide in Stroke (ENOS) is an international, randomized controlled trial investigating the effect of lowering BP with glyceryl trinitrate in 5000 patients with acute stroke. This analysis is based on patients with ischaemic stroke for whom information on the carotid status was available. Neurological impairment (Scandinavian Stroke Scale) and rate of recurrent stroke were assessed on day 7, and the functional outcome (modified Rankin score) was determined on day 90. ENOS is ongoing, therefore analyses are blinded to treatment. At the time of analysis, 565 patients with ischaemic stroke had been randomized into ENOS and data on carotid status were available in 394 (70%) of these patients. Ipsilateral stenosis > or =50% was present in 50 patients (13%). Six of 344 (2%, 95% confidence interval: 0.7, 4%) patients with ipsilateral stenosis <50% had a recurrent stroke by 7 days as compared with none of 50 patients (0%, 95% confidence interval: 0, 9%) (P=0.73) with stenosis > or =50%. No significant difference in impairment was present on day 7; mean Scandinavian Stroke Scale with stenosis 38.3 versus no stenosis 43.2 (P=0.48). Adjusted functional outcome after 90 days was worse in those with a baseline carotid stenosis > or =50%; median modified Rankin score 3.0 versus 2.0 (P=0.03). Interim data provide reassurance that it is reasonable to continue including patients with carotid stenosis into trials of acute BP lowering (such as ENOS).

Major Ongoing Stroke Trials

Major Ongoing Stroke Trials