Clinical benefit of improved Prehospital stroke scales to detect stroke patients with large vessel occlusions: results from a conditional probabilistic model

Background Clinical scales to detect large vessel occlusion (LVO) may help to determine the optimal transport destination for patients with suspected acute ischemic stroke (AIS). The clinical benefit associated with improved diagnostic accuracy of these scales has not been quantified. Methods We used a previously reported conditional model to estimate the probability of good outcome (modified Rankin scale sore ≤2) for patients with AIS and unknown vessel status occurring in regions with greater proximity to a primary than to a comprehensive stroke center. Optimal rapid arterial occlusion evaluation (RACE) scale cutoff scores were calculated based on time-dependent effect-size estimates from recent randomized controlled trials. Probabilities of good outcome were compared between a triage strategy based on these cutoffs and a strategy based on a hypothetical perfect LVO detection tool with 100% diagnostic accuracy. Results In our model, the additional benefit of a perfect LVO detection tool as compared to optimal transport-time dependent RACE cutoff scores ranges from 0 to 5%. It is largest for patients with medium stroke symptom severity (RACE score 5) and in geographic environments with longer transfer time between the primary and comprehensive stroke center. Conclusion Based on a probabilistic conditional model, the results of our simulation indicate that more accurate prehospital clinical LVO detections scales may be associated with only modest improvements in the expected probability of good outcome for patients with suspected acute ischemic stroke and unknown vessel status

Disability Adjusted Life Years due to Ischaemic Stroke Preventable by Real-Time Stroke Detection—A Cost-Utility Analysis of Hypothetical Stroke Detection Devices

Background: Ischaemic stroke remains a significant contributor to permanent disability world-wide. Therapeutic interventions for acute ischaemic stroke (AIS) are available, but need to be administered early after symptom onset in order to be effective. Currently, one of the main factors responsible for poor clinical outcome is an unnecessary long time between symptom onset and arrival at a hospital (pre-hospital delay). In the future, technological devices with the capability of real-time detection of AIS may become available. The health economic implications of such devices have not been explored.Methods: We developed a novel probabilistic model to estimate the maximally allowable annual costs of different hypothetical real-time AIS detection devices in different populations given currently accepted willingness-to-pay thresholds. Distributions of model parameters were extracted from the literature. Effectiveness of the intervention was quantified as reduction in disability-adjusted life-years associated with faster access to thrombolysis and mechanical thrombectomy. Incremental costs were calculated from a societal perspective including acute treatment costs and long-term costs for nursing care, home help, and loss of production. The impact of individual model parameters was explored in one-way and multi-way sensitivity analyses.Results: The model yields significantly shorter prehospital delays and a higher proportion of acute ischaemic patients that fulfill the time-based eligibility criteria for thrombolysis or mechanical thrombectomy in the scenario with a real-time stroke detection device as compared to the control scenario. Depending on the sociodemographic and geographic characteristics of the study population and operating characteristics of the device, the maximally allowable annual cost for the device to operate in a cost-effective manner assuming a willingness-to-pay threshold of GBP 30.000 ranges from GBP 22.00 to GBP 9,952.00. Considering the results of multiway sensitivity analyses, the upper bound increases to GBP 29,449.10 in the subgroup of young patients with a very high annual risk of ischaemic stroke (50 years/20% annual risk).Conclusion: Data from probabilistic modeling suggest that real-time AIS detection devices can be expected to be cost-effective only for a small group of highly selected individuals

Pre-hospital Triage of Acute Ischemic Stroke Patients—Importance of Considering More Than Two Transport Options

Background: Patients with acute ischemic stroke (AIS) and large vessel occlusion benefit from rapid access to mechanical thrombectomy in addition to intravenous thrombolysis. Prehospital triage algorithms to determine the optimal transport destination for AIS patients with unknown vessel status have so far only considered two alternatives: the nearest comprehensive (CSC) and the nearest primary stroke center (PSC). Objective: This study explores the importance of considering a larger number of PSCs during pre-hospital triage of AIS patients. Methods: Analysis was performed in random two-dimensional abstract geographic stroke care infrastructure environments and two models based on real-world geographic scenarios. Transport times to CSCs and PSCs were calculated to define sub-regions with specific triage properties. Possible transport destinations included the nearest CSC, the nearest PSC, and any of the remaining PSCs that are not closest to the scene, but transport to which would imply a shorter total time-to-CSC-via-PSC. Results: In abstract geographic environments, themedian relative size of the sub-region where a triage decision is required ranged from 34 to 92%. The median relative size of the sub-region where more than two triage options need to be considered ranged from 0 to 56%. The achievable reduction in time-to-thrombectomy (“benefit”) exceeded the increase in time-to-thrombolysis (“harm”) by a factor of 2 in 30.5–37.0%of the sub-region where more than two triage options need to be considered. Results were confirmed in geographic environments based on real-world urban and rural stroke care infrastructures. Conclusion: Pre-hospital triage algorithms for AIS patients that only take into account the nearest CSC and the nearest PSC as transport destinations may be unable to identify the optimal transport destination for a significant proportion of patients

Disability adjusted life years due to ischaemic stroke preventable by real-time stroke detection—a cost-utility analysis of hypothetical stroke detection devices

Background: Ischaemic stroke remains a significant contributor to permanent disability world-wide. Therapeutic interventions for acute ischaemic stroke (AIS) are available, but need to be administered early after symptom onset in order to be effective. Currently, one of the main factors responsible for poor clinical outcome is an unnecessary long time between symptom onset and arrival at a hospital (pre-hospital delay). In the future, technological devices with the capability of real-time detection of AIS may become available. The health economic implications of such devices have not been explored. Methods: We developed a novel probabilistic model to estimate the maximally allowable annual costs of different hypothetical real-time AIS detection devices in different populations given currently accepted willingness-to-pay thresholds. Distributions of model parameters were extracted from the literature. Effectiveness of the intervention was quantified as reduction in disability-adjusted life-years associated with faster access to thrombolysis and mechanical thrombectomy. Incremental costs were calculated from a societal perspective including acute treatment costs and long-term costs for nursing care, home help, and loss of production. The impact of individual model parameters was explored in one-way and multi-way sensitivity analyses. Results: The model yields significantly shorter prehospital delays and a higher proportion of acute ischaemic patients that fulfill the time-based eligibility criteria for thrombolysis or mechanical thrombectomy in the scenario with a real-time stroke detection device as compared to the control scenario. Depending on the sociodemographic and geographic characteristics of the study population and operating characteristics of the device, the maximally allowable annual cost for the device to operate in a cost-effective manner assuming a willingness-to-pay threshold of GBP 30.000 ranges from GBP 22.00 to GBP 9,952.00. Considering the results of multiway sensitivity analyses, the upper bound increases to GBP 29,449.10 in the subgroup of young patients with a very high annual risk of ischaemic stroke (50 years/20% annual risk). Conclusion: Data from probabilistic modeling suggest that real-time AIS detection devices can be expected to be cost-effective only for a small group of highly selected individuals

Über Möglichkeiten zur Verbesserung des Zugangs zu rekanalisierenden Maßnahmen bei akutem ischämischem Schlaganfall

In den fünf in diese Habilitationsschrift eingebunden Arbeiten haben wir Ergebnisse vorgestellt, die dazu verwendet werden können, den Zugang zu rekanalisierenden Maßnahmen für Patienten mit akutem ischämischem Schlaganfall, d.h. zur intravenösen Thrombolyse und zur mechanischen Thrombektomie, zu verbessern. Wir haben die klinischen Auswirkungen von prähospitaler Triage auf Basis klinischer Schlaganfallschwereskalen abgeschätzt und mit dem Vorschlag, individualisierte variable Trennwerte anstatt eines festen Trennwertes zu verwenden, eine konzeptionelle Weiterbildung bestehender Algorithmen entwickelt. Zusätzlich wurden die Auswirkungen prähospitaler Triage unter Gesichtspunkten der Ressourcenallokation systembezogen untersucht und die kosteneffektive Einsetzbarkeit zukünftig zuerwartender technischer Neuerungen im Bereich der prähospitalen Triage einerseits sowie für die Reduktion der prähospitalen Behandlungsverzögerung durch Echtzeit-Detektion von ischämischen Schlaganfällen andererseits quantitativ abgeschätzt. Abgerundet wurde die Arbeiten in dieser Schrift mit einer Untersuchung zu Unterschieden der prähospitalen Behandlungsverzögerung in einer großen prospektiven Kohorte von prähospital behandelten Schlaganfallpatienten.In the five papers included in this habilitation thesis, we presented results that can be used to improve access to recanalization therapies for patients with acute ischemic stroke, namely intravenous thrombolysis and mechanical thrombectomy. We assessed the clinical implications of prehospital triage based on clinical stroke symptom severity scales and developed a conceptual improvement of existing algorithms by suggesting that individualized variable cutoff values ​​should be used instead of a fixed cutoff value. In addition, we assessed the effects of prehospital triage on resource allocation and quantified the cost-effectiveness of future technological advances in prehospital triage and the reduction of prehospital treatment delay by real-time detection of acute ischemic stroke. The work in this paper concludes with a study on differences in prehospital treatment delay in a large prospective cohort of prehospital-treated stroke patients

Access to thrombolysis for non-resident and resident stroke patients-a registry-based comparative study from Berlin

Objectives Stroke can happen to people away from home. It is unknown whether non-resident and resident stroke patients have equal access to thrombolysis. Materials and methods Consecutive patients cared for by the Stroke Emergency Mobile between 2011 and 2016 after prompting suspicion of acute stroke during the emergency call were included in our registry. Patients were categorized as residents or non-residents based on their main address. Clinical characteristics, thrombolysis rates, and time intervals from symptom onset/last seen well to alarm and to thrombolysis were compared between groups adjusting for age, pre-stroke modified Rankin Scale (mRS) score, and National Institutes of Health Stroke Scale (NIHSS) score. Results Of 4,254 patients for whom a stroke dispatch was activated, 2,451 had ischemic or hemorrhagic strokes, including 73 non-residents. Non-resident stroke patients were younger (median 69.4 vs. 76.6 years, p < 0.001), had less pre-stroke disability (mRS ≥ 2:17.8 vs. 47.5%, p < 0.001) and less severe strokes (median NIHSS 4 vs. 5, p = 0.02). Thrombolysis rates were higher in non-residents (30.9 vs. 22.0% of ischemic stroke patients, p = 0.04) and emergency calls were made faster (symptom onset/last-seen-well-to-alarm time 35 vs. 144 min, p = 0.04). A lower proportion of non-residents had unknown time of symptom onset (21.9 vs. 46.4%, p < 0.001). For patients with known time of symptom onset, thrombolysis rates, and prehospital delays were similar among non-residents and residents. Conclusion In this study, non-resident stroke patients had higher rates of thrombolysis than residents. This may be explained by a lower proportion of patients with unknown time of symptom onset

Pre-hospital Triage of Acute Ischemic Stroke Patients—Importance of Considering More Than Two Transport Options

Background: Patients with acute ischemic stroke (AIS) and large vessel occlusion benefit from rapid access to mechanical thrombectomy in addition to intravenous thrombolysis. Prehospital triage algorithms to determine the optimal transport destination for AIS patients with unknown vessel status have so far only considered two alternatives: the nearest comprehensive (CSC) and the nearest primary stroke center (PSC).Objective: This study explores the importance of considering a larger number of PSCs during pre-hospital triage of AIS patients.Methods: Analysis was performed in random two-dimensional abstract geographic stroke care infrastructure environments and two models based on real-world geographic scenarios. Transport times to CSCs and PSCs were calculated to define sub-regions with specific triage properties. Possible transport destinations included the nearest CSC, the nearest PSC, and any of the remaining PSCs that are not closest to the scene, but transport to which would imply a shorter total time-to-CSC-via-PSC.Results: In abstract geographic environments, the median relative size of the sub-region where a triage decision is required ranged from 34 to 92%. The median relative size of the sub-region where more than two triage options need to be considered ranged from 0 to 56%. The achievable reduction in time-to-thrombectomy (“benefit”) exceeded the increase in time-to-thrombolysis (“harm”) by a factor of 2 in 30.5–37.0% of the sub-region where more than two triage options need to be considered. Results were confirmed in geographic environments based on real-world urban and rural stroke care infrastructures.Conclusion: Pre-hospital triage algorithms for AIS patients that only take into account the nearest CSC and the nearest PSC as transport destinations may be unable to identify the optimal transport destination for a significant proportion of patients

Current smoking does not modify the treatment effect of intravenous thrombolysis in acute ischemic stroke patients—a post-hoc analysis of the WAKE-UP trial

Background: The “smoking paradox” indicates that patients with acute ischemic stroke (AIS) who smoke at the time of their stroke may have a better prognosis after intravenous thrombolysis than non-smokers. However, findings are inconsistent and data analyzing the effect of smoking on treatment efficacy of intravenous thrombolysis are scarce. Methods: We performed a pre-specified post-hoc subgroup analysis of the Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke (WAKE-UP) trial that randomized AIS patients with unknown time of symptom onset who had diffusion-weighted imaging-fluid attenuation inversion recovery (DWI-FLAIR) mismatch to either alteplase or placebo. Patients were categorized as current smokers or non-smokers (including former smokers and never-smokers). Baseline demographic and clinical characteristics, as well as clinical and imaging follow-up data were analyzed according to smoking status. Results: Four hundred and eighty six patients were included in the analysis. Current smokers (133, 27.4%) were younger (60.1 ± 13.0 vs. 67.2 ± 10.3 years; p &lt; 0.001) and less often had arterial hypertension (45.0% vs. 56.8%; p = 0.02) or atrial fibrillation (3.8% vs. 15.3%; p &lt; 0.001). The acute stroke presentation was more often due to large vessel occlusion among current smokers (27.1 vs. 16.2%; p = 0.01), and smokers had a trend towards more severe strokes (National Institutes of Health Stroke Scale score&gt;10 in 27.1% vs. 19.5%; p = 0.08). The treatment effect of alteplase, quantified as odds ratio for a favorable outcome (modified Rankin Scale [mRS] score at 90 days of 0 or 1), did not differ between current smokers and non-smokers (p-value for interaction: 0.59). After adjustment for age and stroke severity, neither the proportion of patients with favorable outcome, nor the median mRS score at 90 days differed between current smokers and non-smokers. When additional potential confounders were included in the model, the median mRS score was higher in current smokers than in non-smokers (cOR of better outcome for current smokers vs. non-smokers: 0.664 [0.451–0.978], p = 0.04). Conclusions: In patients with mild to moderate MRI-proven AIS and unknown time of symptom onset with DWI-FLAIR mismatch, current smokers had worse functional outcome as compared to non-smokers. Current smoking did not modify the treatment effect of alteplase. Clinical Trial registration: Main trial (WAKE-UP): ClinicalTrials.gov, NCT01525290; and EudraCT, 2011-005906-32. Registered 02 February 2012

Cerebral microbleeds and treatment effect of intravenous thrombolysis in acute stroke: an analysis of the WAKE-UP randomized clinical trial

Background and Objectives: Cerebral microbleeds (CMBs) are common in acute ischemic stroke patients and are associated with increased risk of intracerebral hemorrhage (ICH) after intravenous thrombolysis. Whether CMBs modify the treatment effect of thrombolysis is unknown. Methods: We performed a pre-specified analysis of the prospective randomized controlled multicenter WAKE-UP trial including patients with acute ischemic stroke with unknown time of symptom onset and DWI-FLAIR mismatch on MRI receiving alteplase or placebo. Patients were screened and enrolled between September 2012 and June 2017 (with final follow-up in September 2017). Patients were randomized to treatment with intravenous thrombolysis with alteplase at 0.9 mg / kg body weight or placebo. CMB status (presence, number, and distribution) was assessed after study completion by three raters blinded to clinical information following a standardized protocol. Outcome measures were excellent functional outcome at 90 days, defined by modified Rankin Scale score (mRS)≤1, and symptomatic intracerebral hemorrhage (ICH) according to NINDS trial criteria 22 to 36 hours after treatment. Results: Of 503 patients enrolled in the WAKE-UP trial, 459 (91.3%; 288 [63%] men) were available for analysis; 98 (21.4%) had at least 1 CMB on baseline imaging; 45 (9.8%) had exactly 1 CMB, 37 (8.1%) had 2-4 CMBs, and 16 (3.5%) had ≥5 CMBs. Presence of CMBs was associated with a non-significant increased risk of symptomatic ICH (11.2% versus 4.2%; adjusted odds ratio 2.32 [95% CI 0.99-5.43]; P=.052), but had no effect on functional outcome at 90 days (mRS≤1: 45.8% versus 50.7%; adj. OR 0.99 [0.59-1.64]; P=.955). Patients receiving alteplase had better functional outcome (mRS≤1: 54.6% versus 44.6%, adj. OR 1.61 [1.07-2.43], P=.022) without evidence of heterogeneity in relation to CMB presence (P value of the interactive term .546). Results were similar for subpopulations with strictly lobar (presumed cerebral amyloid angiopathy-related) or non-strictly-lobar CMB distribution. Discussion: In the randomized-controlled WAKE-UP trial, we saw no evidence of reduced treatment effect of alteplase in acute ischemic stroke patients with one or more CMBs. Additional studies are needed to determine the treatment effect of alteplase and its benefit-harm-ratio in patients with a larger number of CMBs. Trial registration: ClinicalTrials.gov number, NCT01525290 (https://clinicaltrials.gov/ct2/show/NCT01525290); EudraCT number, 2011-005906-32 (https://www.clinicaltrialsregister.eu/ctr-search/trial/2011-005906-32/GB). Classification of Evidence: This study provides Class II evidence that for patients with acute ischemic stroke with unknown time of onset and DWI-FLAIR mismatch who received IV alteplase, CMBs are not significantly associated with functional outcome at 90 days

New remote cerebral microbleeds in acute ischemic stroke: an analysis of the randomized, placebo-controlled WAKE-UP trial

No abstract available