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Functional outcomes of pre-hospital thrombolysis in a mobile stroke treatment unit compared with conventional care: an observational registry study

BACKGROUND Specialised CT-equipped mobile stroke treatment units shorten time to intravenous thrombolysis in acute ischaemic stroke by starting treatment before hospital admission; however, direct effects of pre-hospital thrombolysis on clinical outcomes have not been shown. We aimed to compare 3-month functional outcomes after intravenous thrombolysis in patients with acute ischaemic who had received emergency mobile care or and conventional care. METHODS In this observational registry study, patients with ischaemic stroke received intravenous thrombolysis (alteplase) either within a stroke emergency mobile (STEMO) vehicle (pre-hospital care covering 1·3 million inhabitants of Berlin) or within conventional care (normal ambulances and in-hospital care at the Charité Campus Benjamin Franklin in Berlin). Patient data on treatment, outcome, and demographics were documented in STEMO (pre-hospital) or conventional care (in-hospital) registries. The primary outcome was the proportion of patients who had lived at home without assistance before stroke and had a 3-month modified Rankin Scale (mRS) score of 1 or lower. Our multivariable logistic regression was adjusted for demographics, comorbidities, and stroke severity. This study is registered with ClinicalTrials.gov, number NCT02358772. FINDINGS Between Feb 5, 2011, and March 5, 2015, 427 patients were treated within the STEMO vehicle and their data were entered into a pre-hospital registry. 505 patients received conventional care and their data were entered into an in-hospital thrombolysis registry. Of these, 305 patients in the STEMO group and 353 in the conventional care group met inclusion criteria and were included in the analysis. 161 (53%) patients in the STEMO group versus 166 (47%) in the conventional care group had an mRS score of 1 or lower (p=0·14). Compared with conventional care, adjusted odds ratios (ORs) for STEMO care for the primary outcome (OR 1·40, 95% CI 1·00-1·97; p=0·052) were not significant. Intracranial haemorrhage (p=0·27) and 7-day mortality (p=0·23) did not differ significantly between treatment groups. INTERPRETATION We found no significant difference between the proportion of patients with a mRS score of 1 or lower receiving STEMO care compared with conventional care. However, our results suggest that pre-hospital start of intravenous thrombolysis might lead to improved functional outcome in patients. This evidence requires substantiation in future large-scale trials. FUNDING Zukunftsfonds Berlin, the Technology Foundation Berlin with EU co-financing by the European Regional Development Fund via Investitionsbank Berlin, and the German Federal Ministry for Education and Research via the Center for Stroke Research Berlin.

Dose-Related Effects of Statins on Symptomatic Intracerebral Hemorrhage and Outcome After Thrombolysis for Ischemic Stroke

Background and Purpose— The aim of our study was to assess whether statins have dose-dependent effects on risk of symptomatic intracerebral hemorrhage (sICH) and outcome after intravenous thrombolysis for ischemic stroke. Methods— We pooled data from 2 European intravenous thrombolysis registries. Statin doses were stratified in 3 groups according to the attainable lowering of cholesterol levels (low dose: simvastatin 20 mg or equivalent; medium dose: simvastatin 40 mg or equivalent; and high dose: simvastatin 80 mg or equivalent). sICH was defined according to the European Cooperative Acute Stroke Study. Modified Rankin Scale score 0 to 2 at 3 months was considered a favorable outcome. Results— Among 1446 patients analyzed (median age, 75 years; median initial National Institutes of Health Stroke Scale score, 11; 54% men), 317 (22%) used statins before intravenous thrombolysis. Of them, 120 patients had low-dose, 134 medium-dose, and 63 high-dose statin therapy. sICH occurred in 4% of patients (n=53). Frequency of sICH was 2%, 6%, and 13% in patients with low-, medium-, and high-dose statin treatment, respectively (P<0.01). Adjusted odds ratio (OR) for sICH was 2.4 (95% confidence interval [CI], 1.1–5.3) and 5.3 (95% CI, 2.3–12.3) for patients with medium- and high-dose statins compared with non–statin users. Statin users more often achieved favorable outcome compared with non–statin users (58% versus 51%; P=0.03). An independent association of statin use with favorable outcome was detected (adjusted OR, 1.8; 95% CI, 1.3–2.5). The association was maintained when stratifying for statin dose, although it was not significant in the high-dose group anymore (OR, 1.7; 95% CI, 0.9–3.2). Conclusions— We observed an association between increasing dose of statin use and risk of sICH after intravenous thrombolysis. Nevertheless, there was an overall beneficial effect of previous statin use on favorable 3-month outcome.

Prognostic relevance of cardiac troponin T levels and their dynamic changes measured with a high-sensitivity assay in acute ischaemic stroke: analyses from the TRELAS cohort.

BACKGROUND/OBJECTIVES To assess the prognostic relevance of cardiac troponin T (cTnT) values and their serial changes as measured with a high-sensitivity assay in acute ischaemic stroke. METHODS AND RESULTS In total, 1016 consecutive acute ischaemic stroke patients were registered prospectively within a two-year period. High-sensitivity cTnT was quantitated on admission and the following day. Patients were stratified into three groups: below the 99 th percentile of a healthy reference population (< 14 ng/l; n = 409), moderately elevated cTnT (below the median of remaining patients, 14-30 ng/l; n=299) and high cTnT (> 30 ng/l; n = 308). Outcome measures were unfavourable outcome (modified Rankin Scale ≥ 2 at hospital discharge, n=604) and in-hospital mortality (n = 36). Peak cTnT levels were significantly associated with unfavourable outcome (adjusted odds ratios versus reference for moderately elevated cTnT 1.7, 95% confidence interval [CI] 1.1-2.7 and for high cTnT 3.1, 95% CI 1.8-5.6). The optimal cut-off for determining unfavourable outcome proved to be 16 ng/l. Adding this cut-off to clinical variables led to a significant improvement of c-statistics (0.851 versus 0.838, p=0.02). Dynamic changes (δ ≥ 50%) of cTnT were detected in 137 patients (13%). Multiple Cox regression analysis showed an independent association of dynamic changes in cTnT with in-hospital mortality (hazard ratio 2.3, 95% CI 1.1-4.7). The model-fitting (p<0.001) and c-statistics (0.889 versus 0.863, p = 0.08) improved most after dynamic change in cTnT had been added to a regression model which included clinical variables alone. CONCLUSIONS Our study adds novel findings relevant for interpretation of highly sensitive cTnT assays in acute ischaemic stroke: a) Myocardial injury is detectable in more than half of patients; b) even moderately elevated cTnT is associated with unfavourable outcome (optimal cut-off 16 ng/l); and c) dynamic changes in cTnT indicate an increased risk of in-hospital death.

Severe Renal Impairment Is Associated With Symptomatic Intracerebral Hemorrhage After Thrombolysis for Ischemic Stroke

Background and Purpose— Patients with renal impairment (RI) have an increased risk of both thrombotic and hemorrhagic events. We aimed to clarify whether RI increases the risk of intracerebral hemorrhage (ICH) after intravenous thrombolysis with recombinant tissue plasminogen activator. Methods— Patients who received intravenous thrombolysis with recombinant tissue plasminogen activator within 4.5 hours of symptom onset were retrospectively analyzed. Creatinine levels on admission served to calculate glomerular filtration rate (GFR) to estimate RI according to International Classification of Diseases criteria. Effect of RI on symptomatic ICH (sICH) was assessed using dichotomized (GFR <90 and <30 mL/min) and continuous GFR (centered data to test for linear and centered and squared data to test for curvilinear association). Results— Of the 740 patients included, 83% had any RI (GFR <90 mL/min) and 5% had severe RI (GFR <30 mL/mL); 4.6% experienced sICH. Univariate comparisons revealed higher prevalence of sICH in patients with severe RI (P<0.01) but not with any RI. GFR as a continuous variable (centered and squared) was also associated with sICH (P=0.02), but GFR on its own was not. Severe RI and GFR (centered and squared) remained independently associated with sICH in multiple regression analyses. Conclusions— Severe RI (GFR <30 mL/min) is associated with sICH after intravenous thrombolysis with recombinant tissue plasminogen activator. The association is curvilinear. Severe RI must be taken into account when balancing the risk–benefit ratio of intravenous thrombolysis with recombinant tissue plasminogen activator.

Safety of Thrombolysis in Patients With Acute Ischemic Stroke and Cerebral Cavernous Malformations

Background and Purpose— Data on safety of intravenous thrombolysis with recombinant tissue-type plasminogen activator for acute ischemic stroke in patients with coexisting cerebral cavernous malformations (CCMs) are scarce. We assessed the risk of thrombolysis-associated hemorrhage in these patients. Methods— We searched our tertiary care hospital thrombolysis register for patients with CCM confirmed by MRI (3 T, Siemens, TimTrio) before thrombolysis for acute ischemic stroke. CCMs were graded into subtypes according to the Zabramski classification on the basis of their MRI appearance. The primary end point was symptomatic intracerebral hemorrhage according to European Cooperative Acute Stroke Study III (ECASS III) criteria. The secondary end point was any parenchymal hemorrhage. Results— In a total of 350 patients (median age, 76 years; interquartile range, 68–84; median National Institutes of Health Stroke Scale score, 8; interquartile range, 5–14; 51.4% women), CCMs were found in 9 patients (2.6%). Seven patients had a single CCM, and 2 patients had multiple CCMs with a total number of 12 CCMs in all patients. The subtype of CCMs was type III in 9 cases and type I in 3 cases. Symptomatic intracerebral hemorrhage occurred in 1 of 9 patients with CCM versus 11 of 341 patients without CCM (P=0.27). Parenchymal hemorrhage occurred in 2 of 9 patients with CCM versus 27 of 341 patients (P=0.17) without CCM. Conclusions— Given the limitations of our study (mainly low number of patients with CCM), the risk of thrombolysis-associated hemorrhage in patients with CCM remains uncertain. Although our data do not suggest an increased hazard from thrombolysis in patients with CCM, larger studies are necessary to determine definitively the influence of CCMs on parenchymal hemorrhage and symptomatic intracerebral hemorrhage.

Endovascular procedures versus intravenous thrombolysis in stroke with tandem occlusion of the anterior circulation.

PURPOSE Stroke with tandem occlusion within the anterior circulation presents a lower probability of recanalization and good clinical outcome after intravenous (IV) thrombolysis than stroke with single occlusion. The present study describes the impact of endovascular procedures (EPs) compared with IV thrombolysis alone on recanalization and clinical outcome. MATERIALS AND METHODS Thirty patients with symptom onset less than 4.5 hours and tandem occlusion within the anterior circulation were analyzed retrospectively. Recanalization was assessed per Thrombolysis In Cerebral Infarction (TICI) classification on computed tomography, magnetic resonance imaging, or digital subtraction angiography within 24 hours. Infarct size was detected on follow-up imaging as a dichotomized variable, ie, more than one third of the territory of the middle cerebral artery. Clinical outcomes were major neurologic improvement, independent outcome (90-d modified Rankin Scale [mRS] score), symptomatic intracerebral hemorrhage (sICH; per European Cooperative Acute Stroke Study criteria), and death within 7 days. RESULTS Patients treated with EPs (n = 14) were significantly younger and had a history of arterial hypertension more frequently than patients treated with IV thrombolysis alone (n = 16). Recanalization (ie, TICI score 2b/3; EP, 64%; IV, 19%; P = .01), major neurologic improvement (EP, 64%; IV, 19%; P = .01), and independent outcome (mRS score ≤ 2; EP, 54% IV, 13%; P = .02) occurred more often in the EP group, whereas infarct sizes greater than one third of the MCA territory (EP, 43%; IV, 81%; P = .03) were observed less often. Rates of sICH (P = .12) and death within 7 days (P = .74) did not differ significantly. CONCLUSIONS Higher recanalization rate, smaller infarct volume, and better clinical outcome in the EP group should encourage researchers to include this subgroup of patients in prospective randomized trials comparing IV thrombolysis versus EP in stroke.

National Institutes of Health Stroke Scale for Prediction of Proximal Vessel Occlusion in Anterior Circulation Stroke

Given the growing evidence regarding endovascular treatment (EVT) of anterior circulation (AC) stroke due to proximal vessel occlusion (VO) (1–3), it will now be increasingly important to identify eligible patients for EVT. Since diagnostic resources are limited and multimodal CT-imaging may also entail a potential risk, it will be necessary to focus prehospital triage on patients with the highest likelihood of VO. We read with interest the article by Cooray et al. published recently in the IJS (4). A major finding was that an NIHSS > 10 was the optimal cut point for prediction of VO. Despite the impressive sample size and quality of data, the authors acknowledge that the major shortcoming is the lack of localization of VO. Thus, patients with distal VO not eligible for EVT were probably included in a relevant proportion which resulted in a relatively low positive predictive value (PPV 63·6%) for VO at the optimal NIHSS cut point (4). This encouraged us to retrospectively analyze our single-center thrombolysis registry (5,6). The aim was to identify the optimal NIHSS cutoff for prediction of proximal VO (terminal ICA, carotid-T, MCA-M1) in patients with AC stroke presenting within the 4·5-hour time window. Patients eligible for thrombolysis preferably undergo MRI (3T TimTrio) at our institution and receive TOF-MRA regardless of stroke severity (7). Since March 2008, data on 229 patients with MRI and TOF-MRA before treatment were available [median age 75years, 46·3% male, median NIHSS10 (IQR5-16)]. Proximal VO was detected in 97 (42·4%; 93 MCAM1, 2 Carotid-T and 2 terminal ICA), a distal VO in 48 (47 MCA-M2 or–M3, 1 ACA), and no VO in 84 patients. A NIHSS score > 10 was found to be the optimal cutoff for prediction of proximal VO (c-statistics 0·77, sensitivity 76·3%, specificity 76·5%, PPV 70·5%, NPV 81·5%). Given a predefined sensitivity of at least 90%, the optimal threshold was NIHSS > 4 (sensitivity 95·8%, specificity 30·3%, PPV 50·3%, NPV 90·9%). In conclusion, similar to Cooray et al., an NIHSS score > 10 was highly predictive for proximal VO in patients presenting with AC stroke. Lower scores (e.g. NIHSS > 4) may be chosen to increase sensitivity.

A Score for Risk of Thrombolysis-Associated Hemorrhage Including Pretreatment with Statins

Background Symptomatic intracranial hemorrhage (sICH) after intravenous thrombolysis with recombinant tissue-plasminogen activator (rt-PA) for acute ischemic stroke is associated with a poor functional outcome. We aimed to develop a score assessing risk of sICH including novel putative predictors—namely, pretreatment with statins and severe renal impairment. Methods We analyzed our local cohort (Berlin) of patients receiving rt-PA for acute ischemic stroke between 2006 and 2016. Outcome was sICH according to ECASS-III criteria. A multiple regression model identified variables associated with sICH and receiver operating characteristics were calculated for the best discriminatory model for sICH. The model was validated in an independent thrombolysis cohort (Basel). Results sICH occurred in 53 (4.0%) of 1,336 patients in the derivation cohort. Age, baseline National Institutes of Health Stroke Scale, systolic blood pressure on admission, blood glucose on admission, and prior medication with medium- or high-dose statins were associated with sICH and included into the risk of intracranial hemorrhage score. The validation cohort included 983 patients of whom 33 (3.4%) had a sICH. c-Statistics for sICH was 0.72 (95% CI 0.66–0.79) in the derivation cohort and 0.69 (95% CI 0.60–0.77) in the independent validation cohort. Inclusion of severe renal impairment did not improve the score. Conclusion We developed a simple score with fair discriminating capability to predict rt-PA-related sICH by adding prior statin use to known prognostic factors of sICH. This score may help clinicians to identify patients with higher risk of sICH requiring intensive monitoring.

Response to Letter Regarding Article, “Severe Renal Impairment Is Associated With Symptomatic Intracerebral Hemorrhage After Thrombolysis for Ischemic Stroke”

We thank Dr Power for his interest in our article. Indeed, a research interface between nephrology and neurology is essential to understand mechanism of stroke and its therapeutics in patients with kidney disease. We totally agree with Dr Power that using a single calculated estimated glomerular filtration rate (eGFR) value resembles a snapshot of renal function only. Several preadmission measurements and complementary tests would have allowed for a more detailed picture of renal function.1 Having said that, it would have been difficult to obtain these measurements before stroke in our research …

Ontology-Based Semantic Annotation of Documents in the Context of Patient Identification for Clinical Trials

In this paper, we describe the use of ontologies in the context of a system for identifying patients that are eligible for clinical trials. The main purpose of this clinical research data warehouse (CRDW) is to support patient recruitment based on routine data from the hospital’s clinical information system (CIS). In contrast to most other systems for similar purposes, the CRDW also makes use of information present in clinical documents like admission reports, radiological findings and discharge letters. The linguistic analysis recognizes negated and coordinated phrases. It is supported by clinical domain ontologies that enable the identification of main terms and their properties, as well as semantic search with synonyms, hypernyms, and syntactic variants. The CRDW system is currently being tested at hospitals of the Charite - Universitatsmedizin Berlin and the Vivantes - Netzwerk fur Gesundheit GmbH. In the paper, we provide an evaluation of the system based on real world data obtained from the daily routine work of the study assistants.