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  • 1
    Online Resource
    Online Resource
    Etiology of Large Vessel Occlusion Posterior Circulation Stroke: Results of the MR CLEAN Registry
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Stroke Vol. 53, No. 8 ( 2022-08), p. 2468-2477
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 53, No. 8 ( 2022-08), p. 2468-2477
    Abstract: In patients with large vessel occlusion stroke of the anterior circulation, underlying cause is a determinant of outcome. Whether this is the case for posterior circulation large vessel occlusion stroke has yet to be determined. We aimed to report on cause in patients with posterior circulation stroke treated with endovascular thrombectomy and to analyze the association with functional outcome. Methods: We used data of patients with posterior circulation stroke included in the MR CLEAN (Multicenter Randomized Controlled Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) registry, a prospective multicenter observational study, between 2014 and 2018. Stroke cause was categorized into large artery atherosclerosis (LAA), cardioembolism, arterial dissection, embolic stroke of undetermined source (ESUS), other determined cause, or undetermined cause. For primary analysis on the association between cause and outcome, we used multivariable ordinal logistic regression analysis to estimate the adjusted common odds ratio for a shift towards a better functional outcome on the modified Rankin Scale at 90 days with LAA as a reference group. Secondary outcomes included favorable functional outcome (modified Rankin Scale score 0–3), National Institutes of Health Stroke Scale score at 24 to 48 hours, reperfusion on digital subtraction angiography, and stroke progression. Results: Of 264 patients with posterior circulation stroke, 84 (32%) had LAA, 48 (18%) cardioembolism, 31 (12%) dissection, and 14 (5%) ESUS. Patients with a dissection were younger (48 [interquartile range, 43–60] years) and had a lower National Institutes of Health Stroke Scale at baseline (12 [interquartile range, 6–31] ) than patients with other cause. Functional outcome was better for patients with cardioembolism and ESUS compared to LAA (modified Rankin Scale adjusted common odds ratio, 2.4 [95% CI, 1.1–5.2], respectively adjusted common odds ratio, 3.1 [95% CI, 1.0–9.3] ). Patients with a dissection had a lower chance of successful reperfusion compared with LAA (adjusted odds ratio, 0.20 [95% CI, 0.06–0.70]). Conclusions: Unlike the anterior circulation, most frequent cause in our posterior large vessel occlusion stroke cohort is LAA followed by cardioembolism, dissection, and ESUS. Patients with cardioembolism and ESUS have a better prognosis for functional outcome after endovascular thrombectomy than patients with LAA.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/STROKEAHA.121.038054
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
    detail.hit.zdb_id: 1467823-8
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  • 2
    Online Resource
    Online Resource
    Deep learning-based white matter lesion volume on CT is associated with outcome after acute ischemic stroke
    Springer Science and Business Media LLC ; 2024
    In:  European Radiology
    Details
    In: European Radiology, Springer Science and Business Media LLC
    Type of Medium: Online Resource
    ISSN: 1432-1084
    URL: Article
    DOI: 10.1007/s00330-024-10584-z
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2024
    detail.hit.zdb_id: 1472718-3
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  • 3
    Online Resource
    Online Resource
    Validity of Early Outcomes as Indicators for Comparing Hospitals on Quality of Stroke Care
    Ovid Technologies (Wolters Kluwer Health) ; 2023
    In:  Journal of the American Heart Association Vol. 12, No. 8 ( 2023-04-18)
    Details
    In: Journal of the American Heart Association, Ovid Technologies (Wolters Kluwer Health), Vol. 12, No. 8 ( 2023-04-18)
    Abstract: Insight into outcome variation between hospitals could help to improve quality of care. We aimed to assess the validity of early outcomes as quality indicators for acute ischemic stroke care for patients treated with endovascular therapy (EVT). Methods and Results We used data from the MR CLEAN (Multicenter Randomized Controlled Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) Registry, a large multicenter prospective cohort study including 3279 patients with acute ischemic stroke undergoing EVT. Random effect linear and proportional odds regression were used to analyze the effect of case mix on between‐hospital differences in 2 early outcomes: the National Institutes of Health Stroke Scale (NIHSS) score at 24 to 48 hours and the expanded thrombolysis in cerebral infarction score. Between‐hospital variation in outcomes was assessed using the variance of random hospital effects (tau 2 ). In addition, we estimated the correlation between hospitals' EVT‐patient volume and (case‐mix–adjusted) outcomes. Both early outcomes and case‐mix characteristics varied significantly across hospitals. Between‐hospital variation in the expanded thrombolysis in cerebral infarction score was not influenced by case‐mix adjustment (tau 2 =0.17 in both models). In contrast, for the NIHSS score at 24 to 48 hours, case‐mix adjustment led to a decrease in variation between hospitals (tau 2 decreases from 0.19 to 0.17). Hospitals' EVT‐patient volume was strongly correlated with higher expanded thrombolysis in cerebral infarction scores ( r =0.48) and weakly with lower NIHSS score at 24 to 48 hours ( r =0.15). Conclusions Between‐hospital variation in NIHSS score at 24 to 48 hours is significantly influenced by case‐mix but not by patient volume. In contrast, between‐hospital variation in expanded thrombolysis in cerebral infarction score is strongly influenced by EVT‐patient volume but not by case‐mix. Both outcomes may be suitable for comparing hospitals on quality of care, provided that adequate adjustment for case‐mix is applied for NIHSS score.
    Type of Medium: Online Resource
    ISSN: 2047-9980
    URL: Article
    DOI: 10.1161/JAHA.122.027647
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2023
    detail.hit.zdb_id: 2653953-6
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  • 4
    Online Resource
    Online Resource
    Estimation of treatment effects in observational stroke care data: comparison of statistical approaches
    Springer Science and Business Media LLC ; 2022
    In:  BMC Medical Research Methodology Vol. 22, No. 1 ( 2022-04-10)
    Details
    In: BMC Medical Research Methodology, Springer Science and Business Media LLC, Vol. 22, No. 1 ( 2022-04-10)
    Abstract: Various statistical approaches can be used to deal with unmeasured confounding when estimating treatment effects in observational studies, each with its own pros and cons. This study aimed to compare treatment effects as estimated by different statistical approaches for two interventions in observational stroke care data. Patients and methods We used prospectively collected data from the MR CLEAN registry including all patients ( n  = 3279) with ischemic stroke who underwent endovascular treatment (EVT) from 2014 to 2017 in 17 Dutch hospitals. Treatment effects of two interventions – i.e., receiving an intravenous thrombolytic (IVT) and undergoing general anesthesia (GA) before EVT – on good functional outcome (modified Rankin Scale ≤2) were estimated. We used three statistical regression-based approaches that vary in assumptions regarding the source of unmeasured confounding: individual-level (two subtypes), ecological, and instrumental variable analyses. In the latter, the preference for using the interventions in each hospital was used as an instrument. Results Use of IVT (range 66–87%) and GA (range 0–93%) varied substantially between hospitals. For IVT, the individual-level (OR ~ 1.33) resulted in significant positive effect estimates whereas in instrumental variable analysis no significant treatment effect was found (OR 1.11; 95% CI 0.58–1.56). The ecological analysis indicated no statistically significant different likelihood (β = − 0.002%; P  = 0.99) of good functional outcome at hospitals using IVT 1% more frequently. For GA, we found non-significant opposite directions of points estimates the treatment effect in the individual-level (ORs ~ 0.60) versus the instrumental variable approach (OR = 1.04). The ecological analysis also resulted in a non-significant negative association (0.03% lower probability). Discussion and conclusion Both magnitude and direction of the estimated treatment effects for both interventions depend strongly on the statistical approach and thus on the source of (unmeasured) confounding. These issues should be understood concerning the specific characteristics of data, before applying an approach and interpreting the results. Instrumental variable analysis might be considered when unobserved confounding and practice variation is expected in observational multicenter studies.
    Type of Medium: Online Resource
    ISSN: 1471-2288
    URL: Article
    DOI: 10.1186/s12874-022-01590-0
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2041362-2
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  • 5
    Online Resource
    Online Resource
    Importance of Occlusion Site for Thrombectomy Technique in Stroke : Comparison Between Aspiration and Stent Retriever
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  Stroke Vol. 52, No. 1 ( 2021-01), p. 80-90
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 52, No. 1 ( 2021-01), p. 80-90
    Abstract: Thrombectomy with stent retriever and direct aspiration are equally effective in the endovascular treatment of anterior circulation acute ischemic stroke. We report efficacy and safety of initial treatment technique per occlusion segment. Methods: For this study, we analyzed data from the MR CLEAN Registry, a prospective, observational study in all centers that perform endovascular therapy in the Netherlands. We used ordinal logistic regression analysis to compare clinical and technical results of first line direct aspiration treatment with that of stent retriever thrombectomy stratified for occlusion segment. Primary outcome measure was functional outcome at 3 months. Secondary outcome measures included reperfusion grade expressed as the extended Thrombolysis in Cerebral Infarction score, periprocedural complication risk, time to reperfusion, and mortality. Results: Of the 2282 included patients, 1658 (73%) were initially treated with stent retriever and 624 (27%) with aspiration. Four hundred sixty-two patients had an occlusion of the intracranial part of the carotid artery, 1349 of the proximal middle cerebral artery, and 471 of the distal parts of the middle cerebral artery. There was no difference in functional outcome between aspiration and stent retriever thrombectomy (odds ratio, 1.0 [95% CI, 0.9–1.2]) in any of the occlusion segments ( P value for interaction=0.2). Reperfusion rate was higher in the aspiration group (odds ratio, 1.4 [95% CI, 1.1–1.6]) and did not differ between occlusion segments ( P value for interaction=0.6). Procedure times were shorter in the aspiration group (minutes 50 versus 65 minutes; P 〈 0.0001). There was no difference in periprocedural complications or mortality. Conclusions: In unselected patients with anterior circulation infarcts, we observed equal functional outcome of aspiration and stent retriever thrombectomy in all occlusion segments. When aspiration was the first line treatment modality, reperfusion rates were higher and procedure times shorter in all occlusion segments.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/STROKEAHA.120.030031
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
    detail.hit.zdb_id: 1467823-8
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  • 6
    Online Resource
    Online Resource
    Endovascular Treatment for Acute Ischemic Stroke in Patients on Oral Anticoagulants : Results From the MR CLEAN Registry
    Ovid Technologies (Wolters Kluwer Health) ; 2020
    In:  Stroke Vol. 51, No. 6 ( 2020-06), p. 1781-1789
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 51, No. 6 ( 2020-06), p. 1781-1789
    Abstract: The use of oral anticoagulants (OAC) is considered a contra-indication for intravenous thrombolytics as acute treatment of ischemic stroke. However, little is known about the risks and benefits of endovascular treatment in patients on prior OAC. We aim to compare outcomes after endovascular treatment between patients with and without prior use of OAC. Methods— Data of patients with acute ischemic stroke caused by an intracranial anterior circulation occlusion, included in the nationwide, prospective, MR CLEAN Registry between March 2014 and November 2017, were analyzed. Outcomes of interest included symptomatic intracranial hemorrhage and functional outcome at 90 days (modified Rankin Scale score). Outcomes between groups were compared with (ordinal) logistic regression analyses, adjusted for prognostic factors. Results— Three thousand one hundred sixty-two patients were included in this study, of whom 502 (16%) used OAC. There was no significant difference in the occurrence of symptomatic intracranial hemorrhage between patients with and without prior OACs (5% versus 6%; adjusted odds ratio, 0.63 [95% CI, 0.38–1.06]). Patients on OACs had worse functional outcomes than patients without OACs (common odds ratio, 0.57 [95% CI, 0.47–0.66] ). However, this observed difference in functional outcome disappeared after adjustment for prognostic factors (adjusted common odds ratio, 0.91 [95% CI, 0.74–1.13]). Conclusions— Prior OAC use in patients treated with endovascular treatment for ischemic stroke is not associated with an increased risk of symptomatic intracranial hemorrhage or worse functional outcome compared with no prior OAC use. Therefore, prior OAC use should not be a contra-indication for endovascular treatment.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/STROKEAHA.119.028675
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2020
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  • 7
    Online Resource
    Online Resource
    Admission Blood Pressure in Relation to Clinical Outcomes and Successful Reperfusion After Endovascular Stroke Treatment
    Ovid Technologies (Wolters Kluwer Health) ; 2020
    In:  Stroke Vol. 51, No. 11 ( 2020-11), p. 3205-3214
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 51, No. 11 ( 2020-11), p. 3205-3214
    Abstract: Optimal blood pressure (BP) targets before endovascular treatment (EVT) for acute ischemic stroke are unknown. We aimed to assess the relation between admission BP and clinical outcomes and successful reperfusion after EVT. Methods: We used data from the MR CLEAN (Multicenter Randomized Controlled Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) Registry, an observational, prospective, nationwide cohort study of patients with ischemic stroke treated with EVT in routine clinical practice in the Netherlands. Baseline systolic BP (SBP) and diastolic BP (DBP) were recorded on admission. The primary outcome was the score on the modified Rankin Scale at 90 days. Secondary outcomes included successful reperfusion (extended Thrombolysis in Cerebral Infarction score 2B-3), symptomatic intracranial hemorrhage, and 90-day mortality. Multivariable logistic and linear regression were used to assess the associations of SBP and DBP with outcomes. The relations between BPs and outcomes were tested for nonlinearity. Parameter estimates were calculated per 10 mm Hg increase or decrease in BP. Results: We included 3180 patients treated with EVT between March 2014 and November 2017. The relations between admission SBP and DBP with 90-day modified Rankin Scale scores and mortality were J-shaped, with inflection points around 150 and 81 mm Hg, respectively. An increase in SBP above 150 mm Hg was associated with poor functional outcome (adjusted common odds ratio, 1.09 [95% CI, 1.04–1.15]) and mortality at 90 days (adjusted odds ratio, 1.09 [95% CI, 1.03–1.16] ). Following linear relationships, higher SBP was associated with a lower probability of successful reperfusion (adjusted odds ratio, 0.97 [95% CI, 0.94–0.99]) and with the occurrence of symptomatic intracranial hemorrhage (adjusted odds ratio, 1.06 [95% CI, 0.99–1.13] ). Results for DBP were largely similar. Conclusions: In patients with acute ischemic stroke treated with EVT, higher admission BP is associated with lower probability of successful reperfusion and with poor clinical outcomes. Further research is needed to investigate whether these patients benefit from BP reduction before EVT.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/STROKEAHA.120.029907
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2020
    detail.hit.zdb_id: 1467823-8
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  • 8
    Online Resource
    Online Resource
    Collateral Circulation and Outcome in Atherosclerotic Versus Cardioembolic Cerebral Large Vessel Occlusion
    Ovid Technologies (Wolters Kluwer Health) ; 2019
    In:  Stroke Vol. 50, No. 12 ( 2019-12), p. 3360-3368
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 50, No. 12 ( 2019-12), p. 3360-3368
    Abstract: Due to chronic hypoperfusion, cervical atherosclerosis may promote cerebral collateral circulation. We hypothesized that patients with ischemic stroke due to cervical carotid atherosclerosis have a more extensive collateral circulation and better outcomes than patients with cardioembolism. We tested this hypothesis in a population of patients who underwent endovascular treatment for large vessel occlusion. Methods— From the MR-CLEAN Registry (Multicenter Randomized Controlled Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands), we selected consecutive adult endovascular treatment patients (March 2014 to June 2016) with acute ischemic stroke due to anterior circulation large vessel occlusion and compared patients with cervical carotid artery stenosis 〉 50% to those with cardioembolic etiology. The primary outcome was collateral score, graded on a 4-point scale. Secondary outcomes included the modified Rankin Scale (mRS) score and mortality at 90 days. We performed multivariable regression analyses and adjusted for potential confounders. Results— Of 1627 patients in the Registry, 190 patients with cervical carotid atherosclerosis and 476 with cardioembolism were included. Patients with cervical carotid atherosclerosis were younger (median 69 versus 76 years, P 〈 0.001), more often male (67% versus 47%, P 〈 0.001), more often had an internal carotid artery terminus occlusion (33% versus 18%, P 〈 0.001), and a lower prestroke mRS (mRS score, 0–2; 96% versus 85%, P 〈 0.001), than patients with cardioembolism. Stroke due to cervical carotid atherosclerosis was associated with higher collateral score (adjusted common odds ratio, 1.67 [95% CI, 1.17–2.39]) and lower median mRS at 90 days (adjusted common odds ratio, 1.45 [95% CI, 1.03–2.05] ) compared with cardioembolic stroke. There was no statistically significant difference in proportion of mRS 0–2 (aOR, 1.36 [95% CI, 0.90–2.07]) or mortality at 90 days (aOR, 0.80 [95% CI, 0.48–1.34] ). Conclusions— Patients with stroke due to cervical carotid atherosclerosis had a more extensive cerebral collateral circulation and a slightly better median mRS at 90 days than patients with cardioembolic stroke.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/STROKEAHA.119.026299
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2019
    detail.hit.zdb_id: 1467823-8
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  • 9
    Online Resource
    Online Resource
    Workflow Intervals of Endovascular Acute Stroke Therapy During On- Versus Off-Hours : The MR CLEAN Registry
    Ovid Technologies (Wolters Kluwer Health) ; 2019
    In:  Stroke Vol. 50, No. 10 ( 2019-10), p. 2842-2850
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 50, No. 10 ( 2019-10), p. 2842-2850
    Abstract: Endovascular treatment (EVT) of patients with acute ischemic stroke because of large vessel occlusion involves complicated logistics, which may cause a delay in treatment initiation during off-hours. This might lead to a worse functional outcome. We compared workflow intervals between endovascular treatment–treated patients presenting during off- and on-hours. Methods— We retrospectively analyzed data from the MR CLEAN Registry, a prospective, multicenter, observational study in the Netherlands and included patients with an anterior circulation large vessel occlusion who presented between March 2014 and June 2016. Off-hours were defined as presentation on Monday to Friday between 17:00 and 08:00 hours, weekends (Friday 17:00 to Monday 8:00) and national holidays. Primary end point was first door to groin time. Secondary end points were functional outcome at 90 days (modified Rankin Scale) and workflow time intervals. We stratified for transfer status, adjusted for prognostic factors, and used linear and ordinal regression models. Results— We included 1488 patients of which 936 (62.9%) presented during off-hours. Median first door to groin time was 140 minutes (95% CI, 110–182) during off-hours and 121 minutes (95% CI, 85–157) during on-hours. Adjusted first door to groin time was 14.6 minutes (95% CI, 9.3–20.0) longer during off-hours. Door to needle times for intravenous therapy were slightly longer (3.5 minutes, 95% CI, 0.7–6.3) during off-hours. Groin puncture to reperfusion times did not differ between groups. For transferred patients, the delay within the intervention center was 5.0 minutes (95% CI, 0.5–9.6) longer. There was no significant difference in functional outcome between patients presenting during off- and on-hours (adjusted odds ratio, 0.92; 95% CI, 0.74–1.14). Reperfusion rates and complication rates were similar. Conclusions— Presentation during off-hours is associated with a slight delay in start of endovascular treatment in patients with acute ischemic stroke. This treatment delay did not translate into worse functional outcome or increased complication rates.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/STROKEAHA.119.025381
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2019
    detail.hit.zdb_id: 1467823-8
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  • 10
    Online Resource
    Online Resource
    Dual thrombolytic therapy with mutant pro-urokinase and small bolus alteplase for ischemic stroke (DUMAS): study protocol for a multicenter randomized controlled phase II trial
    Springer Science and Business Media LLC ; 2022
    In:  Trials Vol. 23, No. 1 ( 2022-08-09)
    Details
    In: Trials, Springer Science and Business Media LLC, Vol. 23, No. 1 ( 2022-08-09)
    Abstract: The effectiveness of alteplase for ischemic stroke treatment is limited, partly due to the occurrence of intracranial and extracranial hemorrhage. Mutant pro-urokinase (m-proUK) does not deplete fibrinogen and lyses fibrin only after induction with alteplase. Therefore, this treatment has the potential to be safer and more efficacious than treatment with alteplase alone. The aim of this study is to assess the safety and efficacy of thrombolytic treatment consisting of a small bolus alteplase followed by m-proUK compared with standard thrombolytic treatment with alteplase in patients presenting with ischemic stroke. Methods DUMAS is a multicenter, phase II trial with a prospective randomized open-label blinded end-point (PROBE) design, and an adaptive design for dose optimization. Patients with ischemic stroke, who meet the criteria for treatment with intravenous (IV) alteplase can be included. Patients eligible for endovascular thrombectomy are excluded. Patients are randomly assigned (1:1) to receive a bolus of IV alteplase (5mg) followed by a continuous IV infusion of m-proUK (40 mg/h during 60 min) or usual care with alteplase (0.9 mg/kg). Depending on the results of interim analyses, the dose of m-proUK may be revised to a lower dose (30 mg/h during 60 min) or a higher dose (50 mg/h during 60 min). We aim to include 200 patients with a final diagnosis of ischemic stroke. The primary outcome is any post-intervention intracranial hemorrhage (ICH) on neuroimaging at 24 h according to the Heidelberg Bleeding Classification, analyzed with binary logistic regression. Efficacy outcomes include stroke severity measured with the National Institutes of Health Stroke Scale (NIHSS) at 24 h and 5–7 days, score on the modified Rankin scale (mRS) assessed at 30 days, change (pre-treatment vs. post-treatment) in abnormal perfusion volume, and blood biomarkers of thrombolysis at 24 h. Secondary safety endpoints include symptomatic intracranial hemorrhage, death, and major extracranial hemorrhage. This trial will use a deferred consent procedure. Discussion When dual thrombolytic therapy with a small bolus alteplase and m-proUK shows the anticipated effect on the outcome, this will lead to a 13% absolute reduction in the occurrence of ICH in patients with ischemic stroke. Trial registration NL7409 (November 26, 2018)/NCT04256473 (February 5, 2020)
    Type of Medium: Online Resource
    ISSN: 1745-6215
    URL: Article
    DOI: 10.1186/s13063-022-06596-z
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2040523-6
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