Michael V. Mazya

Predicting the Risk of Symptomatic Intracerebral Hemorrhage in Ischemic Stroke Treated With Intravenous Alteplase Safe Implementation of Treatments in Stroke (SITS) Symptomatic Intracerebral Hemorrhage Risk Score

Background and Purpose— Symptomatic intracerebral hemorrhage (SICH) is a serious complication in patients with acute ischemic stroke treated with intravenous thrombolysis. We aimed to develop a clinical score that can easily be applied to predict the risk of SICH. Methods— We analyzed data from 31 627 patients treated with intravenous alteplase enrolled in the Safe Implementation of Treatments in Stroke (SITS) International Stroke Thrombolysis Register. The outcome measure was SICH per the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) definition: a Type 2 parenchymal hemorrhage with deterioration in National Institutes of Health Stroke Scale score of ≥4 points or death. Univariate risk factors associated with the outcome were entered into a logistic regression model after stratification of continuous variables. Adjusted ORs for the independent risk factors were converted into points, which were summated to produce a risk score. Results— We identified 9 independent risk factors for SICH: baseline National Institutes of Health Stroke Scale, serum glucose, systolic blood pressure, age, body weight, stroke onset to treatment time, aspirin or combined aspirin and clopidogrel, and history of hypertension. The overall rate of SICH was 1.8%. The risk score ranged from 0 to 12 points and showed a >70-fold graded increase in the rate of SICH for patients with a score ≥10 points (14.3%) compared with a score of 0 point (0.2%). The prognostic discriminating capability by C statistic was 0.70. Conclusions— The SITS SICH risk score predicts large cerebral parenchymal hemorrhages associated with severe clinical deterioration. The score could aid clinicians to identify patients at high as well as low risk of SICH after intravenous alteplase.

The Heidelberg Bleeding Classification Classification of Bleeding Events After Ischemic Stroke and Reperfusion Therapy

Intracranial hemorrhage is an important safety end point in clinical trials.1–6 Yet, not each intracranial hemorrhage detected by computed tomography (CT) or magnetic resonance imaging (MRI) worsens neurological symptoms and impairs outcomes. Consequently, intracranial hemorrhages after ischemic stroke and reperfusion therapy are classified by both imaging characteristics and the association with clinical worsening. Pure radiological classification uses the location, form, and extent of hemorrhage and its relation to ischemic injury to distinguish among hemorrhage subtypes that may differ in impairment of neurological function and prognosis. Mixed radiological–clinical classification adds clinical symptoms to the presence of radiological hemorrhage to classify intracranial hemorrhages as symptomatic or asymptomatic. Historically, modern approaches to classifying hemorrhage after reperfusion therapy began with the emphasis of Pessin et al1 on the radiographic distinction between hemorrhagic infarction (HI) and parenchymatous hematoma (PH) after embolic stroke. They stated that HI refers to the pathological condition in which petechial or more confluent hemorrhages occupy a portion of an area of ischemic infarction. PH in an area of infarction; in contrast, is a solid clot of blood with mass effect, which displaces and destroys brain tissue.1 They later proposed that HI (in contrast to PH) could be more of a CT curiosity than a dreaded complication.2 Wolpert et al5 defined HI as areas of barely visible increased density with indistinct margins within an infarct or areas of increased density with indistinct margins and a speckled or mottled appearance or multiple areas of coalescent hemorrhage. A mass effect could be present because of the either edema or hemorrhagic component and PH (later named parenchymal hematoma3) and as very dense, homogenous region(s) of circumscribed increased density usually with mass effect. Both HI and PH are presumably caused by the same postischemic pathophysiology, bleeding from damaged …

Summary of Evidence on Early Carotid Intervention for Recently Symptomatic Stenosis Based on Meta-Analysis of Current Risks

Background and Purpose— This study aimed to assess the evidence on the periprocedural (<30 days) risks of carotid intervention in relation to timing of procedure in patients with recently symptomatic carotid stenosis. Methods— A systematic literature review of studies published in the past 8 years reporting periprocedural stroke/death after carotid endarterectomy (CEA) and carotid stenting (CAS) related to the time between qualifying neurological symptoms and intervention was performed. Pooled estimates of periprocedural risk for patients treated within 0 to 48 hours, 0 to 7 days, and 0 to 15 days were derived with proportional meta-analyses and reported separately for patients with stroke and transient ischemic attack as index events. Results— Of 47 studies included, 35 were on CEA, 7 on CAS, and 5 included both procedures. The pooled risk of periprocedural stroke was 3.4% (95% confidence interval [CI], 2.6–4.3) after CEA and 4.8% (95% CI, 2.5–7.8) after CAS performed <15 days; stroke/death rates were 3.8% and 6.9% after CEA and CAS, respectively. Pooled periprocedural stroke risk was 3.3% (95% CI, 2.1–4.6) after CEA and 4.8% (95% CI, 2.5–7.8) after CAS when performed within 0 to 7 days. In hyperacute surgery (<48 hours), periprocedural stroke risk after CEA was 5.3% (95% CI, 2.8–8.4) but with relevant risk differences among patients treated after transient ischemic attack (2.7%; 95% CI, 0.5–6.9) or stroke (8.0%; 95% CI, 4.6–12.2) as index. Conclusions— CEA within 15 days from stroke/transient ischemic attack can be performed with periprocedural stroke risk <3.5%. CAS within the same period may carry a stroke risk of 4.8%. Similar periprocedural risks occur after CEA and CAS performed earlier, within 0 to 7 days. Carotid revascularization can be safely performed within the first week (0–7 days) after symptom onset.

IV thrombolysis in very severe and severe ischemic stroke Results from the SITS-ISTR Registry

Objective: To study the safety of off-label IV thrombolysis in patients with very severe stroke (NIH Stroke Scale [NIHSS] scores >25) compared with severe stroke (NIHSS scores 15–25), where treatment is within European regulations. Methods: Data were analyzed from 57,247 patients with acute ischemic stroke receiving IV tissue plasminogen activator in 793 hospitals participating in the Safe Implementation of Thrombolysis in Stroke (SITS) International Stroke Thrombolysis Registry (2002–2013). Eight hundred sixty-eight patients (1.5%) had NIHSS scores >25 and 19,995 (34.9%) had NIHSS scores 15–25. Outcome measures were parenchymal hemorrhage, symptomatic intracerebral hemorrhage, mortality, and functional outcome. Results: Parenchymal hemorrhage occurred in 10.7% vs 11.0% (p = 0.79), symptomatic intracerebral hemorrhage per SITS-MOST (SITS–Monitoring Study) in 1.4% vs 2.5% (p = 0.052), death at 3 months in 50.4% vs 26.9% (p < 0.001), and functional independence at 3 months in 14.0% vs 29.0% (p < 0.001) of patients with NIHSS scores >25 and NIHSS scores 15–25, respectively. Multivariate adjustment did not change findings from univariate comparisons. Posterior circulation stroke was more common in patients with NIHSS scores >25 (36.2% vs 7.4%, p < 0.001), who were also more often obtunded or comatose on presentation (58.4% vs 7.1%, p < 0.001). Of patients with NIHSS scores >25, 26.2% were treated >3 hours from symptom onset vs 14.5% with NIHSS scores of 15–25. Conclusions: Our data show no excess risk of cerebral hemorrhage in patients with NIHSS score >25 compared to score 15–25, suggesting that the European contraindication to IV tissue plasminogen activator treatment at NIHSS levels >25 may be unwarranted. Increased mortality and lower rates of functional independence in patients with NIHSS score >25 are explained by higher stroke severity, impaired consciousness on presentation due to posterior circulation ischemia, and longer treatment delays.

External Validation of the SEDAN Score for Prediction of Intracerebral Hemorrhage in Stroke Thrombolysis

Background and Purpose— The SEDAN score is a prediction rule for assessment of the risk of symptomatic intracerebral hemorrhage (SICH) per the European Cooperative Acute Stroke Study (ECASS) II definition in patients with acute ischemic stroke treated with intravenous thrombolysis. We assessed the performance of the score in predicting SICH per the ECASS II and Safe Implementation of Treatments in Stroke Monitoring Study (SITS-MOST) definitions in the SITS–International Stroke Thrombolysis Register (SITS-ISTR). Methods— We calculated the SEDAN score in 34 251 patients with complete data, enrolled into the SITS-ISTR. The risk for SICH by both definitions was calculated per score category. Odds ratios for SICH per point increase of the score were obtained using logistic regression. The predictive performance was assessed using area under the curve of the receiver operating characteristic (AUC-ROC). Results— The predictive capability for SICH per ECASS II was moderate at AUC-ROC=0.66. With rising scores, there was a moderate increase in risk for SICH per ECASS II (odds ratio, 1.65 per point; 95% confidence interval, 1.59–1.72; P<0.001), with SICH rates between 1.6% for 0 points and 16.9% for ≥5 points, average 5.1%. The predictive capability for SICH per SITS–MOST was weaker, AUC-ROC=0.60, with lower increase per score point (odds ratio, 1.36 per point; 95% confidence interval, 1.28–1.46; P<0.001), and SICH rates between 0.8% for 0 points and 5.4% for ≥5 points, average 1.8%. Conclusions— In this very large data set, the predictive and discriminatory performances of the SEDAN score were only moderate for SICH per ECASS II and low for SICH per SITS–Monitoring Study.

External Validation of the ASTRAL and DRAGON Scores for Prediction of Functional Outcome in Stroke

Background and Purpose— ASTRAL (Acute Stroke Registry and Analysis of Lausanne) and DRAGON (includes dense middle cerebral artery sign, prestroke modified Rankin Scale score, age, glucose, onset to treatment, National Institutes of Health Stroke Scale score) are 2 recently developed scores for predicting functional outcome after acute stroke in unselected acute ischemic stroke patients and in patients treated with intravenous thrombolysis, respectively. We aimed to perform external validation of these scores to assess their predictive performance in the large multicentre Safe Implementation of Thrombolysis in Stroke-International Stroke Thrombolysis Register. Methods— We calculated the ASTRAL and DRAGON scores in 36 131 and 33 716 patients, respectively, registered in Safe Implementation of Thrombolysis in Stroke-International Stroke Thrombolysis Register between 2003 and 2013. The proportion of patients with 3-month modified Rankin Scale scores of 3 to 6 was observed for each score point and compared with the predicted proportion according to the risk scores. Calibration was assessed using calibration plots, and predictive performance was assessed using area under the curve of the receiver operating characteristic. Multivariate logistic regression coefficients for the variables in the 2 scores were compared with the original derivation cohorts. Results— The ASTRAL showed an area under the curve of 0.790 (95% confidence interval, 0.786–0.795) and the DRAGON an area under the curve of 0.774 (95% confidence interval, 0.769–0.779). All ASTRAL parameters except range of visual fields and all DRAGON parameters were significantly associated with functional outcome in multivariate analysis. Conclusions— The ASTRAL and DRAGON scores show an acceptable predictive performance. ASTRAL does not require imaging-data and therefore may have an advantage for the use in prehospital patient assessment. Prospective studies of both scores evaluating the impact of their use on patient outcomes after intravenous thrombolysis and endovascular therapy are needed.

Changes in European Label and Guideline Adherence After Updated Recommendations for Stroke Thrombolysis Results From the Safe Implementation of Treatments in Stroke Registry

Background—Intravenous thrombolysis (IVT) for acute ischemic stroke is subject to label and guideline contraindications. Updated European guidelines in 2008/2009 recommended IVT in selected patients aged >80 years and stroke onset-to-treatment time 3 to 4.5 hours, which the label still prohibited. Our aim was to compare contraindication nonadherence before and after the guideline update. Methods and Results—Data on IVT-treated patients with stroke at 232 European hospitals participating in the Safe Implementation of Treatments in Stroke registry during both periods 2006 to 2007 (n=6354) and 2010 to 2011 (n=12 046). After the 2008/2009 guideline update, the proportion of patients nonadherent to label increased from 23.6% to 51.1% (P<0.001). Specifically, nonadherence to onset-to-treatment time >3 hours increased from 8.2% to 27.9% and IVT in patients aged >80 years from 8.9% to 17.2% (both P<0.001). Nonadherence also increased to the contraindications severe stroke (National Institutes of Health Stroke Scale score >25), onset-to-treatment time >4.5 hours, blood pressure >185/110 mm Hg, and ongoing oral anticoagulation (all P⩽0.001). Higher hospital IVT patient volumes were associated with higher nonadherence rates. Conclusions—After the European guideline update, new recommendations were promptly adopted and nonadherence to the unchanged label increased. Label contraindications should be updated.

Minor stroke due to large artery occlusion. When is intravenous thrombolysis not enough? Results from the SITS International Stroke Thrombolysis Register:

Purpose Beyond intravenous thrombolysis, evidence is lacking on acute treatment of minor stroke caused by large artery occlusion. To identify candidates for additional endovascular therapy, we aimed to determine the frequency of non-haemorrhagic early neurological deterioration in patients with intravenous thrombolysis-treated minor stroke caused by occlusion of large proximal and distal cerebral arteries. Secondary aims were to establish risk factors for non-haemorrhagic early neurological deterioration and report three-month outcomes in patients with and without non-haemorrhagic early neurological deterioration. Method We analysed data from the SITS International Stroke Thrombolysis Register on 2553 patients with intravenous thrombolysis-treated minor stroke (NIH Stroke Scale scores 0–5) and available arterial occlusion data. Non-haemorrhagic early neurological deterioration was defined as an increase in NIH Stroke Scale score ≥4 at 24 h, without parenchymal hematoma on follow-up imaging within 22–36 h. Findings The highest frequency of non-haemorrhagic early neurological deterioration was seen in 30% of patients with terminal internal carotid artery or tandem occlusions (internal carotid artery + middle cerebral artery) (adjusted odds ratio: 10.3 (95% CI 4.3–24.9), p < 0.001) and 17% in extracranial carotid occlusions (adjusted odds ratio 4.3 (2.5–7.7), p < 0.001) versus 3.1% in those with no occlusion. Proximal middle cerebral artery-M1 occlusions had non-haemorrhagic early neurological deterioration in 9% (adjusted odds ratio 2.1 (0.97–4.4), p = 0.06). Among patients with any occlusion and non-haemorrhagic early neurological deterioration, 77% were dead or dependent at three months. Conclusions Patients with minor stroke caused by internal carotid artery occlusion, with or without tandem middle cerebral artery involvement, are at high risk of disabling deterioration, despite intravenous thrombolysis treatment. Acute vessel imaging contributes usefully even in minor stroke to identify and consider endovascular treatment, or intensive monitoring at a comprehensive stroke centre, for patients at high risk of neurological deterioration.

Professional guideline versus product label selection for treatment with IV thrombolysis: An analysis from SITS registry:

Introduction Thrombolysis usage in ischaemic stroke varies across sites. Divergent advice from professional guidelines and product labels may contribute. Patients and methods We analysed SITS-International registry patients enrolled January 2010 through June 2016. We grouped sites into organisational tertiles by number of patients arriving ≤2.5 h and treated ≤3 h, percentage arriving ≤2.5 h and treated ≤3 h, and numbers treated ≤3 h. We assigned scores of 1–3 (lower/middle/upper) per variable and 2 for onsite thrombectomy. We classified sites as lower efficiency (summed scores 3–5), medium efficiency (6–8) or higher efficiency (9–11). Sites were also grouped by adherence with European product label and ESO guideline: ‘label adherent’ (>95% on-label), ‘guideline adherent’ (≥5% off-label, ≥95% on-guideline) or ‘guideline non-adherent’ (>5% off-guideline). We cross-tabulated site-efficiency and adherence. We estimated the potential benefit of universally selecting by ESO guidance, using onset-to-treatment time-specific numbers needed to treat for day 90 mRS 0–1. Results A total of 56,689 patients at 597 sites were included: 163 sites were higher efficiency, 204 medium efficiency and 230 lower efficiency. Fifty-six sites were ‘label adherent’, 204 ‘guideline adherent’ and 337 ‘guideline non-adherent’. There were strong associations between site-efficiency and adherence (P < 0.001). Almost all ‘label adherent’ sites (55, 98%) were lower efficiency. If all patients were treated by ESO guidelines, an additional 17,031 would receive alteplase, which translates into 1922 more patients with favourable three-month outcomes. Discussion Adherence with product labels is highest in lower efficiency sites. Closer alignment with professional guidelines would increase patients treated and favourable outcomes. Conclusion Product labels should be revised to allow treatment of patients ≤4.5 h from onset and aged ≥80 years.

Are you suffering from a large arterial occlusion? Please raise your arm!

Background and purpose Triage tools to identify candidates for thrombectomy are of utmost importance in acute stroke. No prognostic tool has yet gained any widespread use. We compared the predictive value of various models based on National Institutes of Health Stroke Scale (NIHSS) subitems, ranging from simple to more complex models, for predicting large artery occlusion (LAO) in anterior circulation stroke. Methods Patients registered in the SITS international Stroke Register with available NIHSS and radiological arterial occlusion data were analysed. We compared 2042 patients harbouring an LAO with 2881 patients having no/distal occlusions. Using binary logistic regression, we developed models ranging from simple 1 NIHSS-subitem to full NIHSS-subitems models. Sensitivities and specificities of the models for predicting LAO were examined. Results The model with highest predictive value included all NIHSS subitems for predicting LAO (area under the curve (AUC) 0.77), yielding a sensitivity and specificity of 69% and 76%, respectively. The second most predictive model (AUC 0.76) included 4-NIHSS-subitems (level of consciousness commands, gaze, facial and arm motor function) yielding a sensitivity and specificity of 67% and 75%, respectively. The simplest model included only deficits in arm motor-function (AUC 0.72) for predicting LAO, yielding a sensitivity and specificity of 67% and 72%, respectively. Conclusions Although increasingly more complex models yield a higher discriminative performance for predicting LAO, differences between models are not large. Assessing grade of arm dysfunction along with an established stroke-diagnosis model may serve as a surrogate measure of arterial occlusion-status, thereby assisting in triage decisions.