Intracerebral hemorrhage in patients treated with intravenous thrombolysis for acute ischemic stroke

Background. Nearly 30000 people suffer a stroke in Sweden every year. Stroke is the third most common cause of death after heart disease and cancer carrying a 17% mortality rate at three months. It is the most common cause of neurological disability in adults. Intravenous thrombolysis with alteplase is the only approved pharmacological therapy for acute ischemic stroke, improving neurological and functional outcome in one third of all treated patients. Meanwhile, thrombolytic treatment can in itself cause intracerebral hemorrhage. The aim of this thesis was to study risk factors associated with this complication, in a large cohort of ischemic stroke patients treated with intravenous alteplase. Methods. All studies were based on patient data contained within the Safe Implementation of Treatments of Stroke - International Stroke Thrombolysis Register (SITS-ISTR). The main outcomes of interest were symptomatic intracerebral hemorrhage (SICH) by SITS-MOST, ECASS II and NINDS definitions, functional status at 3 months (modified Rankin Scale), and death at 7 days and 3 months. Study 1. We aimed to develop a clinical scoring algorithm predicting the risk of SICH, using data from 31627 patients. Baseline and demographic factors associated with SICH were entered into a logistic regression model. Adjusted odds ratios (OR) were converted into points, summated to produce a risk score. We identified 9 predictors of SICH: stroke severity, plasma glucose, 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 score ranged from 0 to 12 points, showing a >70-fold increase in the rate of SICH for patients with a score ≥10 points (14,3%) compared to 0 points (0,2%), with an acceptable predictive performance, AUC-ROC = 0,70. We concluded that the SITS SICH Score is able to predict large thrombolysis-related SICH associated with severe clinical deterioration. Study 2. The SEDAN score is another prediction algorithm for SICH. We assessed its predictive performance for two definitions of SICH. Odds ratios for SICH per one-point increase of the score were obtained using logistic regression. 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 ECASS II (OR 1,7 per point, p<0,001), SICH rates between 1,6% for 0 points and 16,9% for ≥5 points. Prediction of SICH per SITS-MOST was weaker, AUC-ROC = 0,60, rates between 0,8% for 0 points and 5,4% for ≥5 points. We concluded that the predictive performance of the SEDAN was moderate for SICH per ECASS II and low for SICH per SITS-MOST. Study 3. The European license for alteplase contraindicates its use in stroke patients treated with warfarin. Conversely, American guidelines accept it in patients with an international normalized ratio (INR) ≤1,7. We studied the influence of warfarin on SICH, arterial recanalization, functional outcome and mortality in 768 patients with baseline warfarin treatment and INR≤1,7. They were older, had more comorbidities, and more severe strokes compared to patients without warfarin. There were no differences in SICH rates, mortality or functional outcome between warfarin and non-warfarin patients after adjustment for differences in age, stroke severity and co-morbidities. Arterial recanalization defined as the disappearance of a baseline hyperdense cerebral artery sign at 22-36 hour imaging was increased in warfarin patients at 63% vs 55%, p=0,022. Study 4. Hemorrhage following stroke thrombolysis can occur in brain parenchyma remote from acutely ischemic tissue (PHr), as well as in local relation to the infarct (PH). We investigated the risk factors, mortality and functional outcome in patients with the poorly understood complication of PHr, as well as PH, and concomitant occurrence of both. We compared baseline data in 970 patients (2,2%) with PHr, 2325 patients (5,3%) with local PH, and 39761 patients (91,4%) without PH or PHr. Independent risk factors were obtained by multivariate logistic regression. Increasing age and blood pressure were the only strong risk factors for PHr. High stroke severity, atrial fibrillation, CT hyperdense cerebral artery sign, i e factors indicating large artery occlusion, were associated with local PH. Functional independence at 3 months was more common in PHr than PH (34% vs 24%, p<0,001), 3 month mortality was lower (34% vs 39%, p<0,001). PH and PHr were equally often symptomatic. The better outcome in PHr is explained by PHr occurring in patients with milder strokes. We concluded that the differences in risk factors likely indicate an influence of underlying small vessel disease in PHr, and large vessel occlusion in PH

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’ (&gt;95% on-label), ‘guideline adherent’ (≥5% off-label, ≥95% on-guideline) or ‘guideline non-adherent’ (&gt;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 &lt; 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

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 &#60; 0.001) and 17% in extracranial carotid occlusions (adjusted odds ratio 4.3 (2.5–7.7), p &#60; 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

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

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

Safety and outcomes of routine endovascular thrombectomy in large artery occlusion recorded in the SITS Register: An observational study

[Background and objective] We aimed to evaluate the safety and outcomes of thrombectomy in anterior circulation acute ischaemic stroke recorded in the SITS–International Stroke Thrombectomy Register (SITS-ISTR) and compare them with pooled randomized controlled trials (RCTs) and two national registry studies.[Methods] We identified centres recording ≥10 consecutive patients in the SITS-ISTR with at least 70% of available modified Rankin Scale (mRS) at 3 months during 2014–2019. We defined large artery occlusion as intracranial internal carotid artery, first and second segment of middle cerebral artery and first segment of anterior cerebral artery. Outcome measures were functional independence (mRS score 0-2) and death at 3 months and symptomatic intracranial haemorrhage (SICH) per modified SITS-MOST.[Results] Results are presented in the following order: SITS-ISTR, RCTs, MR CLEAN Registry and German Stroke Registry (GSR). Median age was 73, 68, 71 and 75 years; baseline NIHSS score was 16, 17, 16 and 15; prior intravenous thrombolysis was 62%, 83%, 78% and 56%; onset to reperfusion time was 289, 285, 267 and 249 min; successful recanalization (mTICI score 2b or 3) was 86%, 71%, 59% and 83%; functional independence at 3 months was 45.5% (95% CI: 44–47), 46.0% (42–50), 38% (35–41) and 37% (35–41), respectively; death was 19.2% (19–21), 15.3% (12.7–18.4), 29.2% (27–32) and 28.6% (27–31); and SICH was 3.6% (3–4), 4.4% (3.0–6.4), 5.8% (4.7–7.1) and not available.[Conclusion] Thrombectomy in routine clinical use registered in the SITS-ISTR showed safety and outcomes comparable to RCTs, and better functional outcomes and lower mortality than previous national registry studies.SITS (Safe Implementation of Treatment in Stroke) is financed directly and indirectly by grants from Karolinska Institutet, Stockholm County Council, the Swedish Heart-Lung Foundation, the Swedish Order of St. John, Friends of Karolinska Institutet and private donors, as well as from an unrestricted sponsorship from Boehringer Ingelheim. SITS has previously received grants from the European Union Framework 7, the European Union Public Health Authority, Ferrer International and EVER Pharma. SITS is currently conducting studies supported by Boehringer Ingelheim and Biogen, as well as in collaboration with Karolinska Institutet, supported by Stryker, Covidien and Phenox. N Ahmed is supported by grants provided by the Stockholm County Council and the Swedish Heart-Lung Foundation. S Holmin is supported by grants provided by the Söderberg Foundations, the Stockholm County Council, the Erling Persson Foundation, VINNOVA and HMT. Irene Escudero-Martínez has received a grant from ‘Fundación Progreso y Salud, Junta de Andalucía’ (grant EF-0437-2018). RM has been supported by the project no. LQ1605 from the National Program of Sustainability II (MEYS CR). RH has been supported by the grants no. DRO–UHHK 00179906 from the Ministry of Health of the Czech Republic and no. PROGRES Q40 from Charles University, Czech Republic.Peer reviewe

Consensus statements and recommendations from the ESO-Karolinska Stroke Update Conference, Stockholm 11–13 November 2018

The purpose of the European Stroke Organisation–Karolinska Stroke Update Conference is to provide updates on recent stroke therapy research and to give an opportunity for the participants to discuss how these results may be implemented into clinical routine. The meeting started 22 years ago as Karolinska Stroke Update, but since 2014 it is a joint conference with European Stroke Organisation. Importantly, it provides a platform for discussion on the European Stroke Organisation guidelines process and on recommendations to the European Stroke Organisation guidelines committee on specific topics. By this, it adds a direct influence from stroke professionals otherwise not involved in committees and work groups on the guideline procedure. The discussions at the conference may also inspire new guidelines when motivated. The topics raised at the meeting are selected by the scientific programme committee mainly based on recent important scientific publications. This year’s European Stroke Organisation–Karolinska Stroke Update Meeting was held in Stockholm on 11–13 November 2018. There were 11 scientific sessions discussed in the meeting including two short sessions. Each session except the short sessions produced a consensus statement (Full version with background, issues, conclusions and references are published as web-material and at www.eso-karolinska.org and http://eso-stroke.org) and recommendations which were prepared by a writing committee consisting of session chair(s), scientific secretary and speakers. These statements were presented to the 250 participants of the meeting. In the open meeting, general participants commented on the consensus statement and recommendations and the final document were adjusted based on the discussion from the general participants Recommendations (grade of evidence) were graded according to the 1998 Karolinska Stroke Update meeting with regard to the strength of evidence. Grade A Evidence: Strong support from randomised controlled trials and statistical reviews (at least one randomised controlled trial plus one statistical review). Grade B Evidence: Support from randomised controlled trials and statistical reviews (one randomised controlled trial or one statistical review). Grade C Evidence: No reasonable support from randomised controlled trials, recommendations based on small randomised and/or non-randomised controlled trials evidence

Consensus statements and recommendations from the ESO-Karolinska Stroke Update Conference, Stockholm 11-13 November 2018

The purpose of the European Stroke Organisation-Karolinska Stroke Update Conference is to provide updates on recent stroke therapy research and to give an opportunity for the participants to discuss how these results may be implemented into clinical routine. The meeting started 22 years ago as Karolinska Stroke Update, but since 2014 it is a joint conference with European Stroke Organisation. Importantly, it provides a platform for discussion on the European Stroke Organisation guidelines process and on recommendations to the European Stroke Organisation guidelines committee on specific topics. By this, it adds a direct influence from stroke professionals otherwise not involved in committees and work groups on the guideline procedure. The discussions at the conference may also inspire new guidelines when motivated. The topics raised at the meeting are selected by the scientific programme committee mainly based on recent important scientific publications. This year's European Stroke Organisation-Karolinska Stroke Update Meeting was held in Stockholm on 11-13 November 2018. There were 11 scientific sessions discussed in the meeting including two short sessions. Each session except the short sessions produced a consensus statement (Full version with background, issues, conclusions and references are published as web-material and at and ) and recommendations which were prepared by a writing committee consisting of session chair(s), scientific secretary and speakers. These statements were presented to the 250 participants of the meeting. In the open meeting, general participants commented on the consensus statement and recommendations and the final document were adjusted based on the discussion from the general participants Recommendations (grade of evidence) were graded according to the 1998 Karolinska Stroke Update meeting with regard to the strength of evidence. Grade A Evidence: Strong support from randomised controlled trials and statistical reviews (at least one randomised controlled trial plus one statistical review). Grade B Evidence: Support from randomised controlled trials and statistical reviews (one randomised controlled trial or one statistical review). Grade C Evidence: No reasonable support from randomised controlled trials, recommendations based on small randomised and/or non-randomised controlled trials evidence.Peer reviewe

Radiological evaluation in patients with clinical suspicion of cerebral venous sinus thrombosis presenting with nontraumatic headache-a retrospective observational study with a validation cohort

Background Clinical suspicion of cerebral venous sinus thrombosis (CVST) is imprecise due to non-specific symptoms such as headache. The aim was to retrospectively assess the diagnostic value of nonenhanced CT (neCT) in patients with nontraumatic headache and clinically suspected CVST. Methods A retrospective consecutive series of patients referred 2013-2015 for radiology were evaluated. Eligible patients had nontraumatic headache and suspicion of CVST stated in the referral, investigated with CT venography (CTV) and nonenhanced CT (neCT). neCT scans were re-evaluated for the presence of CVST or other pathology. All CTVs were checked for the presence of CVST. The validation cohort consisted of 10 patients with nontraumatic CVT (2017-2019). Results Less than 1% (1/104) had a suspected thrombus on neCT, confirmed by subsequent CTV. The remaining 99% had a CTV excluding CVST. Eleven percent had other imaging findings explaining their symptoms. In the patient with CVST, the thrombosed dural sinus was high attenuating (maximum HU 89) leading to the suspicion of CVST confirmed by CTV. The validation cohort (n = 10) confirmed the presence of a high attenuating (HU &gt; 65) venous structure in the presence of a confirmed thrombus in all patients presenting within 10 days (suspicion written in referral, 10%). Conclusions Despite clinical suspicion, imaging findings of CVST in nontraumatic headache are uncommon. Evaluating neCT for high attenuation in dural sinuses, followed by CTV for confirmation in selected cases seems reasonable. CVST should be recognized by all radiologists and requires a high level of awareness when reading neCT for other indications

Modeling the Decay in Probability of Receiving Endovascular Thrombectomy on the Basis of Time From Stroke Onset

Background American Heart Association guidelines specify infarct core volume as 1 determinant of eligibility for endovascular thrombectomy. Therefore, it is important to understand how time‐dependent infarct core growth translates to a patient's declining probability of thrombectomy eligibility. Modeling the probability that a patient with suspected large‐vessel occlusion would qualify for thrombectomy on the basis of their expected time from stroke onset to treatment can help inform the optimal prehospital emergency transport protocols, maximizing the likelihood of an excellent patient outcome. Methods We extended a published physiological model of infarct core growth to derive a decay curve of thrombectomy eligibility (based on a given infarct core volume threshold) as a function of time from stroke onset. We then adapted an existing model of the time‐dependent probability of an excellent outcome to incorporate this decay curve. Using the adapted model, we determined the optimal prehospital emergency transport protocols in Alberta, Canada, and compared these with the protocols that assumed all patients were thrombectomy eligible. Results The probability of qualifying for thrombectomy decays exponentially as time elapses from stroke onset. We found that the area where mothership is the optimal transport protocol increased by 18.6% after incorporating our decay curve of thrombectomy eligibility into the underlying optimization model. The benefit of mothership versus drip‐and‐ship also increased in the areas where mothership was favored, and in areas where drip‐and‐ship was favored, the benefit of drip‐and‐ship weakened. We also performed a number of sensitivity analyses to observe how these results change on the basis of our assumptions for model parameters. Conclusion This methodology provides a novel, physiology‐based approach to derive a thrombectomy eligibility curve. These models are necessary to better optimize prehospital transport decisions and consequently improve outcomes of patients with suspected large‐vessel occlusion