Adam Kobayashi

Prediction of haematoma growth and outcome in patients with intracerebral haemorrhage using the CT-angiography spot sign (PREDICT): a prospective observational study

BACKGROUND In patients with intracerebral haemorrhage (ICH), early haemorrhage expansion affects clinical outcome. Haemostatic treatment reduces haematoma expansion, but fails to improve clinical outcomes in many patients. Proper selection of patients at high risk for haematoma expansion seems crucial to improve outcomes. In this study, we aimed to prospectively validate the CT-angiography (CTA) spot sign for prediction of haematoma expansion. METHODS PREDICT (predicting haematoma growth and outcome in intracerebral haemorrhage using contrast bolus CT) was a multicentre prospective observational cohort study. We recruited patients aged 18 years or older, with ICH smaller than 100 mL, and presenting at less than 6 h from symptom onset. Using two independent core laboratories, one neuroradiologist determined CTA spot-sign status, whereas another neurologist masked for clinical outcomes and imaging measured haematoma volumes by computerised planimetry. The primary outcome was haematoma expansion defined as absolute growth greater than 6 mL or a relative growth of more than 33% from initial CT to follow-up CT. We reported data using standard descriptive statistics stratified by the CTA spot sign. Mortality was assessed with Kaplan-Meier survival analysis. FINDINGS We enrolled 268 patients. Median time from symptom onset to baseline CT was 135 min (range 22-470), and time from onset to CTA was 159 min (32-475). 81 (30%) patients were spot-sign positive. The primary analysis included 228 patients, who had a follow-up CT before surgery or death. Median baseline ICH volume was 19·9 mL (1·5-80·9) in spot-sign-positive patients versus 10·0 mL (0·1-102·7) in spot-sign negative patients (p<0·001). Median ICH expansion was 8·6 mL (-9·3 to 121·7) for spot-sign positive patients and 0·4 mL (-11·7 to 98·3) for spot-negative patients (p<0·001). In those with haematoma expansion, the positive predictive value for the spot sign was61% (95% CI 47–73) for the positive predictive value and 78% (71–84) for the negative predictive value, with 51% (39–63) sensitivity and 85% (78–90) specificity[corrected]. Median 3-month modified Rankin Scale (mRS) was 5 in CTA spot-sign-positive patients, and 3 in spot-sign-negative patients (p<0·001). Mortality at 3 months was 43·4% (23 of 53) in CTA spot-sign positive versus 19·6% (31 of 158) in CTA spot-sign-negative patients (HR 2·4, 95% CI 1·4-4·0, p=0·002). INTERPRETATION These findings confirm previous single-centre studies showing that the CTA spot sign is a predictor of haematoma expansion. The spot sign is recommended as an entry criterion for future trials of haemostatic therapy in patients with acute ICH. FUNDING Canadian Stroke Consortium and NovoNordisk Canada.

Influence of Gender on Baseline Features and Clinical Outcomes among 17,370 Patients with Confirmed Ischaemic Stroke in the International Stroke Trial

Aim: We sought to determine whether there were differences between men and women with acute stroke in their baseline characteristics and outcome in a large cohort of patients randomized in the International Stroke Trial (IST). Methods: Of the 19,435 patients randomized in the IST, 17,370 had an ischemic stroke confirmed by CT scan or autopsy (8,003 female and 9,367 male). In males and females, we compared baseline characteristics (age, frequency of atrial fibrillation, pre-stroke administration of aspirin and systolic blood pressure, conscious level, stroke syndrome) and outcome at 14 days and 6 months (death, complications, dependency, recovery, place of residence). We developed a specific logistic regression model to adjust for case-mix in order to evaluate the separate influence of gender on outcome. Results: Female patients were older, suffered more frequently from atrial fibrillation, had higher systolic blood pressure at randomization and generally had more severe strokes (a higher proportion were unconscious or drowsy or had a total anterior circulation syndrome). Females had higher 14-day and 6-month case fatality and were more likely to be dead or dependent at six months (and consequently more likely to require institutional or residential care). Gender was an independent predictor of death or dependency at 6 months. Conclusions: The adverse effect of female gender on outcome indicates that further research to explore the underlying biological mechanism is justified, and that more intensive acute and long-term treatment may be needed to improve outcome among female patients with stroke.

Factors Influencing In-Hospital Delay in Treatment With Intravenous Thrombolysis

Background and Purpose— Shortening door-to-needle time (DNT) for the thrombolytic treatment of stroke can improve treatment efficacy by reducing onset-to-treatment time. The goal of our study was to explore the association between DNT and outcome and to identify factors influencing DNT to better understand why some patients are treated late. Methods— Prospectively collected data from the Safe Implementation of Treatments in Stroke-East registry (SITS-EAST: 9 central and eastern European countries) on all patients treated with thrombolysis between February 2003 and February 2010 were analyzed. Multiple logistic regression analysis was used to identify predictors of DNT ⩽60 minutes. Results— Altogether, 5563 patients were treated with thrombolysis within 4.5 hours of symptom onset. Of these, 2097 (38%) had DNT ⩽60 minutes. In different centers, the proportion of patients treated with DNT ⩽60 minutes ranged from 18% to 84% (P<0.0001). Patients with longer DNT (in 60-minute increments) had less chance of achieving a modified Rankin Scale score of 0 to 1 at 3 months (adjusted OR, 0.86; 95% CI, 0.77–0.97). DNT ⩽60 minutes was independently predicted by younger age (in 10-year increments; OR, 0.92; 95% CI, 0.87–0.97), National Institutes of Health Stroke Scale score 7 to 24 (OR, 1.44; 95% CI, 1.2–1.7), onset-to-door time (in 10-minute increments; OR, 1.19; 95% CI, 1.17–1.22), treatment center (P<0.001), and country (P<0.001). Conclusions— Thrombolysis of patients with older age and mild or severe neurological deficit is delayed. The perception that there is sufficient time before the end of the thrombolytic window also delays treatment. It is necessary to improve adherence to guidelines and to treat patients sooner after arrival to hospital.

European recommendations on organisation of Interventional care in acute stroke (EROICAS)

Five recently published randomized controlled trials (RCTs) and respective meta-analyses provide strong evidence that endovascular thrombectomy (EVT) combined with best medical treatment, including intravenous (IV) tissue plasminogen activator (tPA) (IV thrombolysis, IVT) for eligible patients, improves the outcomes of appropriately selected patients with acute ischemic stroke in the setting of proximal occlusions in the carotid circulation (large vessel occlusion, LVO). Four out of the five studies were stopped early after a first RCT showed the superiority of EVT combined with medical management over medical management alone. Such premature trial termination will on average lead to overestimation of the treatment effect. Nonetheless, since all fiveRCTs showed consistent benefit of EVT over optimal medical management alone, and a dose–effect relation (reperfusion rates vs. clinical outcome), the benefit of EVT is considered established. After the publication of the ‘‘Consensus statement by ESO-Karolinska Stroke Update’’ as timely response to the new evidence, the purpose of EROICAS is to provide recommendations based on a structured collaborative process conducted by six relevant European professional societies.

Update on the third international stroke trial (IST-3) of thrombolysis for acute ischaemic stroke and baseline features of the 3035 patients recruited

BackgroundIntravenous recombinant tissue plasminogen activator (rtPA) is approved in Europe for use in patients with acute ischaemic stroke who meet strictly defined criteria. IST-3 sought to improve the external validity and precision of the estimates of the overall treatment effects (efficacy and safety) of rtPA in acute ischaemic stroke, and to determine whether a wider range of patients might benefit.DesignInternational, multi-centre, prospective, randomized, open, blinded endpoint (PROBE) trial of intravenous rtPA in acute ischaemic stroke. Suitable patients had to be assessed and able to start treatment within 6 hours of developing symptoms, and brain imaging must have excluded intracranial haemorrhage and stroke mimics.ResultsThe initial pilot phase was double blind and then, on 01/08/2003, changed to an open design. Recruitment began on 05/05/2000 and closed on 31/07/2011, by which time 3035 patients had been included, only 61 (2%) of whom met the criteria for the 2003 European approval for thrombolysis. 1617 patients were aged over 80 years at trial entry. The analysis plan will be finalised, without reference to the unblinded data, and published before the trial data are unblinded in early 2012. The main trial results will be presented at the European Stroke Conference in Lisbon in May 2012 with the aim to publish simultaneously in a peer-reviewed journal. The trial result will be presented in the context of an updated Cochrane systematic review. We also intend to include the trial data in an individual patient data meta-analysis of all the relevant randomised trials.ConclusionThe data from the trial will: improve the external validity and precision of the estimates of the overall treatment effects (efficacy and safety) of iv rtPA in acute ischaemic stroke; provide: new evidence on the balance of risk and benefit of intravenous rtPA among types of patients who do not clearly meet the terms of the current EU approval; and, provide the first large-scale randomised evidence on effects in patients over 80, an age group which had largely been excluded from previous acute stroke trials.Trial registrationISRCTN25765518

Intravenous alteplase in ischemic stroke patients not fully adhering to the current drug license in Central and Eastern Europe

Background The current European license for alteplase in acute ischemic stroke excludes from treatment large groups of patients. Nevertheless, in everyday practice, many patients receive off-label thrombolysis at the physicians discretion. Aim Our aim was to evaluate safety and effectiveness of intravenous alteplase in patients not fully adhering to the drug license compared with those treated strictly according to the license in Central and Eastern Europe. Methods We analyzed the data contributed to Safe Implementation of Thrombolysis in Stroke registry from nine countries between February 2003 and February 2010. Statistical analysis included multivariate logistic regression. Results Of 5594 consecutive patients, 1919 patients (34·3%) not fully adhered to the license. The most frequent deviations were: time-to-treatment >3 h (13·1%), use of intravenous antihypertensives (8·3%), age >80 years (7·3%), oral anticoagulation (4·2%), a previous stroke with concomitant diabetes (3·9%), and previous stroke <three-months (2·7%). The off-label group showed a significantly higher rate of symptomatic intracranial haemorrhage, which was not confirmed in the multivariate analysis. License nonadherence significantly increased the risk of death or dependency (odds ratio 1·26; 95% confidence interval: 1·08–1·48), with a trend for increased mortality (odds ratio 1·17; 95% confidence interval: 0·97–1·42). Isolated time-to-treatment >3 h was an independent predictor of unfavorable outcome (odds ratio 1·32; 95% confidence interval: 1·01–1·71). Conclusion Our findings show that patients not fully adhering to the European license are not at increased risk of symptomatic intracranial haemorrhage but achieve less favorable outcome. Some contraindications appear more redundant than others. However, the final conclusions about safety and effectiveness should be based on the results of ongoing randomized trials.

Oxfordshire Community Stroke Project Clinical Stroke Syndrome and Appearances of Tissue and Vascular Lesions on Pretreatment CT in Hyperacute Ischemic Stroke Among the First 510 Patients in the Third International Stroke Trial (IST-3)

Background and Purpose— The Oxfordshire Community Stroke Project (OCSP) clinical stroke syndrome classification correlates well with the stroke lesion in established ischemic stroke, but there are few data in patients with hyperacute stroke. We wished to assess whether the OCSP correlated with the site and size of the ischemic lesion and location of cerebral vessel lesion on computed tomography (CT) in hyperacute stroke. Methods— Prospective study of ischemic stroke patients presenting within 6 hours of onset in the Third International Stroke Trial (IST-3), a randomized, controlled trial of rt-PA. OCSP syndrome was assigned by a computer-based algorithm. The CT assessment was made by a neuroradiologist blinded to clinical details. Results— We assessed baseline data and CT findings for the first 510 patients; early tissue ischemic changes were present in 329/510 (65%) total anterior circulation syndrome (TACS) - 79%; partial anterior circulation syndrome (PACS) - 57%, lacunar syndrome (LACS) - 40%; posterior circulation syndrome (POCS) - 33%. The site and size of ischemic change on CT was compatible with the clinical syndrome in 79%, 37%, 2%, and 14%, respectively. Assuming that all patients with a normal CT scan will develop an incompatible lesion these numbers reflected the “worst possible scenario.” For the “best possible scenario” we presumed that those with a normal CT will develop concordant ischemic change and the proportions were 100%, 80%, 62% and 81%, respectively. The hyperattenuated artery sign was seen in 206/510 (40%); (TACS 54%; PACS 35%, LACS 5%, and POCS 19%). Conclusions— Within 6 hours of stroke, in patients with a nonlacunar syndrome, the OCSP syndrome correlated well with the pattern of ischemic change on CT. For clinicians who wish to restrict the use of thrombolytic therapy to large-artery ischemic stroke, concordance of clinical and CT appearances may give greater confidence in making therapeutic decisions in hyperacute stroke. In centers where immediate access to MR is limited, use of the classification may help focus use of MR on patients with suspected LACS and POCS. The utility of the classification may further increase if IST-3 establishes that the OCSP syndrome significantly modifies response to thrombolytic therapy.

Hyperperfusion Syndrome after Carotid Endarterectomy and Carotid Stenting

Background: Hyperperfusion syndrome (HS) is a relatively rare but possibly serious complication of carotid revascularization procedures. Impaired cerebral autoregulation and postrevascularization changes in cerebral blood flow are the main mechanisms involved in the development of HS. Most up-to-date studies addressing this issue are retrospective and tend to concentrate on carotid endarterectomy (CEA), neglecting carotid stenting (CAS). Our aim was to compare the frequency of clinical signs of HS and hyperperfusion detected by transcranial Doppler (TCD) in patients undergoing CAS or CEA due to carotid stenosis. Methods: In this prospective observational study, we evaluated 61 patients scheduled for routine CAS or CEA. Each patient was examined by a neurologist before and after the revascularization procedure to assess the clinical status. Severe headache, ocular or facial pain, confusion, visual disturbances, epileptic seizures or any focal deficits not caused by cerebral ischemia were considered clinical signs of HS. Peak systolic velocity (PSV), end-diastolic velocity, mean velocity (MV), and pulsatility index were measured by TCD once before and twice after the intervention (within 6 h after and 2-5 days after the procedure). Hyperperfusion was defined as a >100% increase in the middle cerebral artery (MCA) blood velocity, evaluated separately for PSV and MV after the procedure compared with the baseline value. Cerebrovascular reactivity (CVR) was evaluated with a TCD acetazolamide test before the intervention. Results: CAS (n = 33) and CEA (n = 28) patients were included in the study. There was no difference between the groups in the frequency of clinical signs of HS (21.2 vs. 21.4%) and ratio of TCD hyperperfusion (12.1 vs. 14.3%). In the CAS group, ipsilateral MCA velocity significantly increased directly after the intervention and 2-5 days later, while it increased in the CEA group only 2-5 days after the intervention. The sensitivity and specificity of hyperperfusion, defined by MV, for HS signs were 38.5 and 93.8%, respectively, whereas those defined by PSV were 30.8 and 89.6%, respectively. The sensitivity and specificity of impaired CVR (<25%) for HS signs were 63.6 and 73.5%, respectively. Conclusions: There is no difference in the frequency of HS clinical signs and hyperperfusion detected by TCD between patients after CAE and CAS. Clinical signs suggested HS does not always correspond with TCD hyperperfusion. However, both the CVR test and TCD measurements of MCA velocity can help identify patients at high risk for HS.

Eligibility of stroke units in Poland for administration of intravenous thrombolysis

Systemic thrombolysis treatment was approved in Poland in 2003 and should be performed in specialist stroke units (SU). We performed a survey to determine stroke service preparedness for thrombolysis treatment in Poland. We sent a questionnaire evaluating the neurological departments in Poland, where stroke patients are treated. We divided them into four categories: (i) class A SU (fulfilling criteria of the National Program for Stroke Prevention and Therapy and European Stroke Initiative guidelines), (ii) class B (conditionally fulfilling criteria), (iii) class C (not fulfilling criteria), and (iv) departments without SU. Only class A units are eligible for implementing thrombolysis. We obtained response from 194 of 222 (87.4%) departments; 90 (46.4%) declared having an SU. According to criteria, 20 class A, 56 class B, 14 class C. During one year, 71 208 patients were admitted to hospitals; 69 982 (98.2%) to neurological departments. A total of 10 959 (15.4%) were treated in class A SU, 23 650 (33.2%) in class B, 5153 (7.2%) in class C, whereas 30 220 (42.4%) in neurological departments without SU. Our survey showed that only 15.4% stroke patients in Poland are admitted to high‐quality SU, where thrombolysis may potentially be administered. Improvement of SU quality in Poland is necessary for wide implementation of new methods of stroke therapy.

Lack of experience of intravenous thrombolysis for acute ischaemic stroke does not influence the proportion of patients treated

Objectives: To determine the eligibility of patients with ischaemic stroke admitted to the 2nd Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland, for intravenous thrombolysis; to identify the major exclusions and assess whether organisational changes in the in-hospital stroke pathway and informative campaign in the local community and medical services can increase the number of patients treated; and to establish whether lack of previous experience with thrombolytic treatment or trials is predictive of the low proportion of patients treated. Methods: A survey of the database of patients with stroke admitted during the first 30 months after the introduction of intravenous thrombolysis for acute ischaemic stroke was conducted to search for all eligible patients. This included patients admitted within 2 h of symptom onset (assuming a 1 h door-to-needle time), age <80 years, National Institute of Health Stroke Scale (NIHSS) Score of 5–22, seizures at onset, platelet count >100 000/ml, glycaemia 50–400 mg/dl and international normalised ratio (INR) <1.6. The number of eligible patients was compared with the number actually treated. Results: 745 patients with acute ischaemic stroke were admitted during the study period. 18.4% were admitted within 2 h of symptom onset, 71% were aged <80 years, 55.4% had an NIHSS score between 5 and 22, 96.1% had INR <1.6, 98.9% had a platelet count >100 000/ml, 99.4% had blood glucose concentrations of 50–400 mg/dl and 97.4% had no seizures at onset. After adjusting for all inclusion criteria, 7.1% of the patients were found to be potentially eligible and 8.7% were actually treated (p = 0.25). Of the 65 treated patients, 63.1% were independent after 3 months, 16.9% died and none had a symptomatic intracranial haemorrhage. Conclusions: The proportion of patients with ischaemic stroke treated with intravenous thrombolysis in a previously inexperienced centre was not lower than in other centres and in countries where this treatment has been provided for a longer period of time. The number of patients treated was higher than that estimated mainly owing to organisational changes introduced in our centre, allowing treatment of those admitted between 2 and 3 h after symptom onset.