Influence of Time to Achieve Target Systolic Blood Pressure on Outcome After Intracerebral Hemorrhage: The Blood Pressure in Acute Stroke Collaboration.

OBJECTIVE: To investigate whether an earlier time to achieving and maintaining systolic blood pressure (SBP) at 120 to 140 mm Hg is associated with favorable outcomes in a cohort of patients with acute intracerebral hemorrhage. METHODS: We pooled individual patient data from randomized controlled trials registered in the Blood Pressure in Acute Stroke Collaboration. Time was defined as time form symptom onset plus the time (hour) to first achieve and subsequently maintain SBP at 120 to 140 mm Hg over 24 hours. The primary outcome was functional status measured by the modified Rankin Scale at 90 to 180 days. A generalized linear mixed models was used, with adjustment for covariables and trial as a random effect. RESULTS: A total of 5761 patients (mean age, 64.0 [SD, 13.0], 2120 [36.8%] females) were included in analyses. Earlier SBP control was associated with better functional outcomes (modified Rankin Scale score, 3-6; odds ratio, 0.98 [95% CI, 0.97-0.99]) and a significant lower risk of hematoma expansion (0.98, 0.96-1.00). This association was stronger in patients with bigger baseline hematoma volume (>10 mL) compared with those with baseline hematoma volume ≤10 mL (0.006 for interaction). Earlier SBP control was not associated with cardiac or renal adverse events. CONCLUSIONS: Our study confirms a clear time relation between early versus later SBP control (120-140 mm Hg) and outcomes in the one-third of patients with intracerebral hemorrhage who attained sustained SBP levels within this range. These data provide further support for the value of early recognition, rapid transport, and prompt initiation of treatment of patients with intracerebral hemorrhage.

Effects of a Province-wide Triaging System for TIA: The ASPIRE Intervention.

BACKGROUND AND OBJECTIVES: Urgent transient ischemic attack (TIA) management to reduce stroke recurrence is challenging, particularly in rural and remote areas. In Alberta, Canada, despite an organized stroke system, data from 1999 to 2000 suggested that stroke recurrence after TIA was as high as 9.5% at 90 days. Our objective was to determine whether a multifaceted population-based intervention resulted in a reduction in recurrent stroke after TIA. METHODS: In this quasi-experimental health services research intervention study, we implemented a TIA management algorithm across the entire province, centered around a 24-hour physician's TIA hotline and public and health provider education on TIA. From administrative databases, we linked emergency department discharge abstracts to hospital discharge abstracts to identify incident TIAs and recurrent strokes at 90 days across a single payer system with validation of recurrent stroke events. The primary outcome was recurrent stroke; with a secondary composite outcome of recurrent stroke, acute coronary syndrome, and all-cause death. We used an interrupted time series regression analysis of age-adjusted and sex-adjusted stroke recurrence rates after TIA, incorporating a 2-year preimplementation period (2007-2009), a 15-month implementation period, and a 2-year postimplementation period (2010-2012). Logistic regression was used to examine outcomes that did not fit the time series model. RESULTS: We assessed 6,715 patients preimplementation and 6,956 patients postimplementation. The 90-day stroke recurrence rate in the pre-Alberta Stroke Prevention in TIA and mild Strokes (ASPIRE) period was 4.5% compared with 5.3% during the post-ASPIRE period. There was neither a step change (estimate 0.38; p = 0.65) nor slope change (parameter estimate 0.30; p = 0.12) in recurrent stroke rates associated with the ASPIRE intervention implementation period. Adjusted all-cause mortality (odds ratio 0.71, 95% CI 0.56-0.89) was significantly lower after the ASPIRE intervention. DISCUSSION: The ASPIRE TIA triaging and management interventions did not further reduce stroke recurrence in the context of an organized stroke system. The apparent lower mortality postintervention may be related to improved surveillance after events identified as TIAs, but secular trends cannot be excluded. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that a standardized population-wide algorithmic triage system for patients with TIA did not reduce recurrent stroke rate.

Prior anticoagulation and bridging thrombolysis improve outcomes in patients with atrial fibrillation undergoing endovascular thrombectomy for anterior circulation stroke.

BACKGROUND: Where stroke occurs with pre-existing atrial fibrillation (AF)studies validating the safety and efficacy of bridging thrombolysis, and the use of endovascular thrombectomy (EVT) in the setting of prior anticoagulation, are limited to single-center reports. METHODS: In a retrospective analysis, AF patients undergoing EVT for anterior circulation large vessel occlusion stroke enrolled in a prospectively-maintained, international multicenter database (International Stroke Perfusion Imaging Registry (INSPIRE)) between 2016 and 2019 were studied. Patients were categorized by anticoagulation status: anticoagulated (warfarin/non-vitamin K oral anticoagulants) versus not anticoagulated. Patients not anticoagulated were further divided into intravenous thrombolysis versus no thrombolysis. Outcomes compared between groups included 90-day modified Rankin Scale, 90-day mortality, rates of symptomatic intracerebral hemorrhage (sICH), and good reperfusion (modified Thrombolysis In Cerebral Infarction (mTICI) 2b-3). RESULTS: Of 563 AF patients, 118 (21%) were on anticoagulation. AF patients on anticoagulation showed improved 90-day functional outcomes (adjusted odds ratio (aOR) 1.68, 95% confidence interval (95% CI) 1.00 to 2.82). Mortality (26.3% vs 23.8%), sICH (4.5% vs 3.9%), and rates of good reperfusion (91.3% vs 88.0%) were similar between those anticoagulated and those not anticoagulated. Thrombolysis before EVT in AF patients was independently associated with improved 90-day functional outcomes (aOR 1.81, 95% CI 1.18 to 2.79) and reduced mortality (aOR 0.51, 95% CI 0.31 to 0.84), with similar sICH rates (3.4% vs 4.5%). CONCLUSIONS: Anticoagulated patients with AF who underwent EVT had improved 90-day functional outcomes and similar sICH rates. Thrombolysis before EVT in AF patients was associated with improved 90-day functional outcomes and reduced mortality.

Optimal CT perfusion thresholds for core and penumbra in acute posterior circulation infarction.

Background: At least 20% of strokes involve the posterior circulation (PC). Compared to the anterior circulation, posterior circulation infarction (POCI) are frequently misdiagnosed. CT perfusion (CTP) has advanced stroke care by improving diagnostic accuracy and expanding eligibility for acute therapies. Clinical decisions are predicated upon precise estimates of the ischaemic penumbra and infarct core. Current thresholds for defining core and penumbra are based upon studies of anterior circulation stroke. We aimed to define the optimal CTP thresholds for core and penumbra in POCI. Methods: Data were analyzed from 331-patients diagnosed with acute POCI enrolled in the International-stroke-perfusion-registry (INSPIRE). Thirty-nine patients with baseline multimodal-CT with occlusion of a large PC-artery and follow up diffusion weighted MRI at 24-48 h were included. Patients were divided into two-groups based on artery-recanalization on follow-up imaging. Patients with no or complete recanalisation were used for penumbral and infarct-core analysis, respectively. A Receiver operating curve (ROC) analysis was used for voxel-based analysis. Optimality was defined as the CTP parameter and threshold which maximized the area-under-the-curve. Linear regression was used for volume based analysis determining the CTP threshold which resulted in the smallest mean volume difference between the acute perfusion lesion and follow up MRI. Subanalysis of PC-regions was performed. Results: Mean transit time (MTT) and delay time (DT) were the best CTP parameters to characterize ischaemic penumbra (AUC = 0.73). Optimal thresholds for penumbra were a DT >1 s and MTT>145%. Delay time (DT) best estimated the infarct core (AUC = 0.74). The optimal core threshold was a DT >1.5 s. The voxel-based analyses indicated CTP was most accurate in the calcarine (Penumbra-AUC = 0.75, Core-AUC = 0.79) and cerebellar regions (Penumbra-AUC = 0.65, Core-AUC = 0.79). For the volume-based analyses, MTT >160% demonstrated best correlation and smallest mean-volume difference between the penumbral estimate and follow-up MRI (R 2 = 0.71). MTT >170% resulted in the smallest mean-volume difference between the core estimate and follow-up MRI, but with poor correlation (R 2 = 0.11). Conclusion: CTP has promising diagnostic utility in POCI. Accuracy of CTP varies by brain region. Optimal thresholds to define penumbra were DT >1 s and MTT >145%. The optimal threshold for core was a DT >1.5 s. However, CTP core volume estimates should be interpreted with caution.

Time Course of Early Hematoma Expansion in Acute Spot-Sign Positive Intracerebral Hemorrhage: Prespecified Analysis of the SPOTLIGHT Randomized Clinical Trial.

BACKGROUND: In the SPOTLIGHT trial (Spot Sign Selection of Intracerebral Hemorrhage to Guide Hemostatic Therapy), patients with a computed tomography (CT) angiography spot-sign positive acute intracerebral hemorrhage were randomized to rFVIIa (recombinant activated factor VIIa; 80 µg/kg) or placebo within 6 hours of onset, aiming to limit hematoma expansion. Administration of rFVIIa did not significantly reduce hematoma expansion. In this prespecified analysis, we aimed to investigate the impact of delays from baseline imaging to study drug administration on hematoma expansion. METHODS: Hematoma volumes were measured on the baseline CT, early post-dose CT, and 24 hours CT scans. Total hematoma volume (intracerebral hemorrhage+intraventricular hemorrhage) change between the 3 scans was calculated as an estimate of how much hematoma expansion occurred before and after studying drug administration. RESULTS: Of the 50 patients included in the trial, 44 had an early post-dose CT scan. Median time (interquartile range) from onset to baseline CT was 1.4 hours (1.2-2.6). Median time from baseline CT to study drug was 62.5 (55-80) minutes, and from study drug to early post-dose CT was 19 (14.5-30) minutes. Median (interquartile range) total hematoma volume increased from baseline CT to early post-dose CT by 10.0 mL (-0.7 to 18.5) in the rFVIIa arm and 5.4 mL (1.8-8.3) in the placebo arm (P=0.96). Median volume change between the early post-dose CT and follow-up scan was 0.6 mL (-2.6 to 8.3) in the rFVIIa arm and 0.7 mL (-1.6 to 2.1) in the placebo arm (P=0.98). Total hematoma volume decreased between the early post-dose CT and 24-hour scan in 44.2% of cases (rFVIIa 38.9% and placebo 48%). The adjusted hematoma growth in volume immediately post dose for FVIIa was 0.998 times that of placebo ([95% CI, 0.71-1.43]; P=0.99). The hourly growth in FFVIIa was 0.998 times that for placebo ([95% CI, 0.994-1.003]; P=0.50; Table 3). CONCLUSIONS: In the SPOTLIGHT trial, the adjusted hematoma volume growth was not associated with Factor VIIa treatment. Most hematoma expansion occurred between the baseline CT and the early post-dose CT, limiting any potential treatment effect of hemostatic therapy. Future hemostatic trials must treat intracerebral hemorrhage patients earlier from onset, with minimal delay between baseline CT and drug administration. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01359202.

Tenecteplase versus alteplase for stroke thrombolysis evaluation (TASTE): A multicentre, prospective, randomized, open-label, blinded-endpoint, controlled phase III non-inferiority trial protocol.

RATIONALE: Alteplase is the only approved thrombolytic agent for acute stroke. An alternative plasminogen activator, tenecteplase, has been previously shown to increase early biological effectiveness (reperfusion) resulting in early clinical recovery in acute stroke patients with target mismatch on perfusion imaging; however, phase III data are lacking. AIM AND HYPOTHESIS: In this study, we assess the efficacy and safety of tenecteplase compared to alteplase in acute stroke patients with target mismatch on perfusion imaging. METHODS AND DESIGN: Tenecteplase (0.25 mg/kg) versus alteplase (0.9 mg/kg) for Stroke Thrombolysis Evaluation (TASTE) is a multicentre, prospective, randomized, open-label, blinded-endpoint (PROBE), controlled phase III non-inferiority trial (2 arms with 1:1 randomization) with an adaptive sample size re-estimation in patients with acute ischemic stroke meeting target mismatch criteria on perfusion imaging. SAMPLE SIZE ESTIMATES: Recruiting 728 patients (1:1 tenecteplase vs alteplase) would yield 90% power (two-sided alpha 0.05) to detect a treatment effect of 8% (26% modified Rankin scale (mRS) 0-1 in alteplase arm and 34% mRS 0-1 in tenecteplase arm), with an absolute non-inferiority margin of 3%. Following the pre-planned "promising zone" adaptive sample size re-estimation, the final sample size was set at 832 patients. STUDY OUTCOMES: The primary outcome measure is the proportion of patients with an mRS score of 0-1 at 3 months. Secondary outcomes include the categorical shift in mRS at 3 months; the proportion of patients with: mRS 0-2, 5-6, and 6; reduction of the National Institutes of Health Stroke Scale (NIHSS) by 8 or more points or reaching 0-1 at 24 h; symptomatic intracerebral hemorrhage within 36 h; and death. DISCUSSION: This pivotal trial will provide important data on the role of tenecteplase in acute ischemic stroke, and the use of imaging-based treatment decision-making for stroke thrombolysis. CLINICAL TRIAL PROTOCOL: Trial Registration: ACTRN12613000243718, EudraCT 2015-002657-36.

Ultra-Long Transfers for Endovascular Thrombectomy-Mission Impossible?: The Australia-New Zealand Experience.

BACKGROUND: Endovascular thrombectomy (EVT) access in remote areas is limited. Preliminary data suggest that long distance transfers for EVT may be beneficial; however, the magnitude and best imaging strategy at the referring center remains uncertain. We hypothesized that patients transferred >300 miles would benefit from EVT, achieving rates of functional independence (modified Rankin Scale [mRS] score of 0-2) at 3 months similar to those patients treated at the comprehensive stroke center in the randomized EVT extended window trials and that the selection of patients with computed tomography perfusion (CTP) at the referring site would be associated with ordinal shift toward better outcomes on the mRS. METHODS: This is a retrospective analysis of patients transferred from 31 referring hospitals >300 miles (measured by the most direct road distance) to 9 comprehensive stroke centers in Australia and New Zealand for EVT consideration (April 2016 through May 2021). RESULTS: There were 131 patients; the median age was 64 [53-74] years and the median baseline National Institutes of Health Stroke Scale score was 16 [12-22]. At baseline, 79 patients (60.3%) had noncontrast CT+CT angiography, 52 (39.7%) also had CTP. At the comprehensive stroke center, 114 (87%) patients underwent cerebral angiography, and 96 (73.3%) proceeded to EVT. At 3 months, 62 patients (48.4%) had an mRS score of 0 to 2 and 81 (63.3%) mRS score of 0 to 3. CTP selection at the referring site was not associated with better ordinal scores on the mRS at 3 months (mRS median of 2 [1-3] versus 3 [1-6] in the patients selected with noncontrast CT+CT angiography, P=0.1). Nevertheless, patients selected with CTP were less likely to have an mRS score of 5 to 6 (odds ratio 0.03 [0.01-0.19]; P<0.01). CONCLUSIONS: In selected patients transferred >300 miles, there was a benefit for EVT, with outcomes similar to those treated in the comprehensive stroke center in the EVT extended window trials. Remote hospital CTP selection was not associated with ordinal mRS improvement, but was associated with fewer very poor 3-month outcomes.

Association of Endovascular Thrombectomy With Functional Outcome in Patients With Acute Stroke With a Large Ischemic Core.

BACKGROUND AND OBJECTIVES: Endovascular thrombectomy (EVT) is effective for patients with large vessel occlusion (LVO) stroke with smaller volumes of CT perfusion (CTP)-defined ischemic core. However, the benefit of EVT is unclear in those with a core volume >70 mL. We aimed to compare outcomes of EVT and non-EVT patients with an ischemic core volume ≥70 mL, hypothesizing that there would be a benefit from EVT for fair outcome (3-month modified Rankin scale [mRS] 0-3) after stroke. METHODS: A retrospective analysis of patients enrolled into a multicenter (Australia, China, and Canada) registry (2012-2020) who underwent CTP within 24 hours of stroke onset and had a baseline ischemic core volume ≥70 mL was performed. The primary outcome was the estimation of the association of EVT in patients with core volume ≥70 mL and within 70-100 and ≥100 mL subgroups with fair outcome. RESULTS: Of the 3,283 patients in the registry, 299 had CTP core volume ≥70 mL and 269 complete data (135 had core volume between 70 and 100 mL and 134 had core volume ≥100 mL). EVT was performed in 121 (45%) patients. EVT-treated patients were younger (median 69 vs 75 years; p = 0.011), had lower prestroke mRS, and smaller median core volumes (92 [79-116.5] mL vs 105.5 [85.75-138] mL, p = 0.004). EVT-treated patients had higher odds of achieving fair outcome in adjusted analysis (30% vs 13.9% in the non-EVT group; adjusted odds ratio [aOR] 2.1, 95% CI 1-4.2, p = 0.038). The benefit was seen predominantly in those with 70-100 mL core volume (71/135 [52.6%] EVT-treated), with 54.3% in the EVT-treated vs 21% in the non-EVT group achieving a fair outcome (aOR 2.5, 95% CI 1-6.2, p = 0.005). Of those with a core volume ≥100 mL, 50 of the 134 (37.3%) underwent EVT. Proportions of fair outcome were very low in both groups (8.1% vs 8.7%; p = 0.908). DISCUSSION: We found a positive association of EVT with the 3-month outcome after stroke in patients with a baseline CTP ischemic core volume 70-100 mL but not in those with core volume ≥100 mL. Randomized data to confirm these findings are required. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that EVT is associated with better motor outcomes 3 months after CTP-defined ischemic stroke with a core volume of 70-100 mL.

Quantitative susceptibility-weighted imaging in presence of strong susceptibility sources: Application to hemorrhage.

PURPOSE: To optimize quantitative susceptibility-weighted imaging also known as true susceptibility-weighted imaging (tSWI) for strong susceptibility sources like hemorrhage and compare to standard susceptibility-weighted imaging (SWI) and quantitative susceptibility mapping (QSM). METHODS: Ten patients with known intracerebral hemorrhage (ICH) were scanned using a 3D SWI sequence. The magnitude and phase images were utilized to compute QSM, tSWI and SWI images. tSWI parameters including the upper threshold for creating susceptibility-weighted masks and the multiplication factor were optimized for hemorrhage depiction. Combined tSWI was also computed with independent optimized parameters for both veins and hemorrhagic regions. tSWI results were compared to SWI and QSM utilizing region-of-interest measurements, Pearson's correlation and Kruskal-Wallis test. RESULTS: Fifteen hemorrhages were found, with mean susceptibility 0.81 ± 0.37 ppm. Unlike SWI which utilizes a phase mask, tSWI uses a mask computed from QSM. In tSWI, the weighted mask required an extended upper threshold far beyond the standard level for more effective visualization of hemorrhage texture. The upper threshold was set to the mean maximum susceptibility in the hemorrhagic region (3.24 ppm) with a multiplication factor of 2. The blooming effect, seen in SWI, was observed to be larger in hemorrhages with higher susceptibility values (r = 0.78, p < 0.001) with reduced blooming on tSWI. On SWI, 4 out of 15 hemorrhages showed phase wrap artifacts in the hemorrhagic region and all patients showed some phase wraps in the air-tissue interface near the auditory and frontal sinuses. These phase wrap artifacts were absent on tSWI. In hemorrhagic regions, a higher correlation was observed between the actual susceptibility values and mean gray value for tSWI (r = -0.93, p < 0.001) than SWI (r = -0.87, p < 0.001). CONCLUSION: In hemorrhage, tSWI minimizes both blooming effects and phase wrap artifacts observed in SWI. However, unlike SWI, tSWI requires an altered upper threshold for best hemorrhage depiction that greatly differs from the standard value. tSWI can be used as a complementary technique for visualizing hemorrhage along with SWI.

Intensive Blood Pressure Lowering and DWI Lesions in Intracerebral Hemorrhage: Exploratory Analysis of the ATACH-2 Randomized Trial.

BACKGROUND: With the increasing use of magnetic resonance imaging in the assessment of acute intracerebral hemorrhage, diffusion-weighted imaging hyperintense lesions have been recognized to occur at sites remote to the hematoma in up to 40% of patients. We investigated whether blood pressure reduction was associated with diffusion-weighted imaging hyperintense lesions in acute intracerebral hemorrhage and whether such lesions are associated with worse clinical outcomes by analyzing imaging data from a randomized trial. METHODS: We performed exploratory subgroup analyses in an open-label randomized trial that investigated acute blood pressure lowering in 1000 patients with intracerebral hemorrhage between May 2011 and September 2015. Eligible participants were assigned to an intensive systolic blood pressure target of 110-139 mm Hg versus 140-179 mm Hg with the use of intravenous nicardipine. Of these, 171 patients had requisite magnetic resonance imaging sequences for inclusion in these subgroup analyses. The primary outcome was the presence of diffusion-weighted imaging hyperintense lesions. Secondary outcomes included death or disability and serious adverse event at 90 days. RESULTS: Diffusion-weighted imaging hyperintense lesions were present in 25% of patients (mean age 62 years). Hematoma volume > 30 cm3 was an adjusted predictor (adjusted relative risk 2.41, 95% confidence interval 1.00-5.80) of lesion presence. Lesions occurred in 25% of intensively treated patients and 24% of standard treatment patients (relative risk 1.01, 95% confidence interval 0.71-1.43, p = 0.97). Patients with diffusion-weighted imaging hyperintense lesions had similar frequencies of death or disability at 90 days, compared with patients without lesions. CONCLUSIONS: Randomized assignment to intensive acute blood pressure lowering did not result in a greater frequency of diffusion-weighted imaging hyperintense lesion. Alternative mechanisms of diffusion-weighted imaging hyperintense lesion formation other than hemodynamic fluctuations need to be explored. Clinical trial registration ClinicalTrials.gov (Ref. NCT01176565; https://clinicaltrials.gov/ct2/show/NCT01176565 ).

Early lowering of blood pressure after acute intracerebral haemorrhage: a systematic review and meta-analysis of individual patient data.

OBJECTIVE: To summarise evidence of the effects of blood pressure (BP)-lowering interventions after acute spontaneous intracerebral haemorrhage (ICH). METHODS: A prespecified systematic review of the Cochrane Central Register of Controlled Trials, EMBASE and MEDLINE databases from inception to 23 June 2020 to identify randomised controlled trials that compared active BP-lowering agents versus placebo or intensive versus guideline BP-lowering targets for adults <7 days after ICH onset. The primary outcome was function (distribution of scores on the modified Rankin scale) 90 days after randomisation. Radiological outcomes were absolute (>6 mL) and proportional (>33%) haematoma growth at 24 hours. Meta-analysis used a one-stage approach, adjusted using generalised linear mixed models with prespecified covariables and trial as a random effect. RESULTS: Of 7094 studies identified, 50 trials involving 11 494 patients were eligible and 16 (32.0%) shared patient-level data from 6221 (54.1%) patients (mean age 64.2 [SD 12.9], 2266 [36.4%] females) with a median time from symptom onset to randomisation of 3.8 hours (IQR 2.6-5.3). Active/intensive BP-lowering interventions had no effect on the primary outcome compared with placebo/guideline treatment (adjusted OR for unfavourable shift in modified Rankin scale scores: 0.97, 95% CI 0.88 to 1.06; p=0.50), but there was significant heterogeneity by strategy (pinteraction=0.031) and agent (pinteraction<0.0001). Active/intensive BP-lowering interventions clearly reduced absolute (>6 ml, adjusted OR 0.75, 95%CI 0.60 to 0.92; p=0.0077) and relative (≥33%, adjusted OR 0.82, 95%CI 0.68 to 0.99; p=0.034) haematoma growth. INTERPRETATION: Overall, a broad range of interventions to lower BP within 7 days of ICH onset had no overall benefit on functional recovery, despite reducing bleeding. The treatment effect appeared to vary according to strategy and agent. PROSPERO REGISTRATION NUMBER: CRD42019141136.

Real-World Cost-Effectiveness of Late Time Window Thrombectomy for Patients With Ischemic Stroke.

Background: To compare the cost-effectiveness of providing endovascular thrombectomy (EVT) for patients with ischemic stroke in the >4.5 h time window between patient groups who met and did not meet the perfusion imaging trial criteria. Methods: A discrete event simulation (DES) model was developed to simulate the long-term outcome post EVT in patients meeting or not meeting the extended time window clinical trial perfusion imaging criteria at presentation, vs. medical treatment alone (including intravenous thrombolysis). The effectiveness of thrombectomy in patients meeting the landmark trial criteria (DEFUSE 3 and DAWN) was derived from a prospective cohort study of Australian patients who received EVT for ischemic stroke, between 2015 and 2019, in the extended time window (>4.5 h). Results: Endovascular thrombectomy was shown to be a cost-effective treatment for patients satisfying the clinical trial criteria in our prospective cohort [incremental cost-effectiveness ratio (ICER) of $11,608/quality-adjusted life year (QALY) for DEFUSE 3-postive or $34,416/QALY for DAWN-positive]. However, offering EVT to patients outside of clinical trial criteria was associated with reduced benefit (-1.02 QALY for DEFUSE 3; -1.43 QALY for DAWN) and higher long-term patient costs ($8,955 for DEFUSE 3; $9,271 for DAWN), thereby making it unlikely to be cost-effective in Australia. Conclusions: Treating patients not meeting the DAWN or DEFUSE 3 clinical trial criteria in the extended time window for EVT was associated with less gain in QALYs and higher cost. Caution should be exercised when considering this procedure for patients not satisfying the trial perfusion imaging criteria for EVT.

Stroke Patients With Faster Core Growth Have Greater Benefit From Endovascular Therapy.

BACKGROUND AND PURPOSE: This study aimed to explore whether the therapeutic benefit of endovascular thrombectomy (EVT) was mediated by core growth rate. METHODS: This retrospective cohort study identified acute ischemic stroke patients with large vessel occlusion and receiving reperfusion treatment, either EVT or intravenous thrombolysis (IVT), within 4.5 hours of stroke onset. Patients were divided into 2 groups: EVT versus IVT only patients (who had no access to EVT). Core growth rate was estimated by the acute core volume on perfusion computed tomography divided by the time from stroke onset to perfusion computed tomography. The primary clinical outcome was good outcome defined by 3-month modified Rankin Scale score of 0-2. Tissue outcome was the final infarction volume. RESULTS: A total of 806 patients were included, 429 in the EVT group (recanalization rate of 61.6%) and 377 in the IVT only group (recanalization rate of 44.7%). The treatment effect of EVT versus IVT only was mediated by core growth rate, showing a significant interaction between EVT treatment and core growth rate in predicting good clinical outcome (interaction odds ratio=1.03 [1.01-1.05], P=0.007) and final infarct volume (interaction odds ratio=-0.44 [-0.87 to -0.01], P=0.047). For patients with fast core growth of >25 mL/h, EVT treatment (compared with IVT only) increased the odds of good clinical outcome (adjusted odds ratio=3.62 [1.21-10.76], P=0.021) and resulted in smaller final infarction volume (37.5 versus 73.9 mL, P=0.012). For patients with slow core growth of <15 mL/h, there were no significant differences between the EVT and the IVT only group in either good clinical outcome (adjusted odds ratio=1.44 [0.97-2.14], P=0.070) or final infarction volume (22.6 versus 21.9 mL, P=0.551). CONCLUSIONS: Fast core growth was associated with greater benefit from EVT compared with IVT in the early <4.5-hour time window.

Assessing the Relative Value of CT Perfusion Compared to Non-contrast CT and CT Angiography in Prognosticating Reperfusion-Eligible Acute Ischemic Stroke Patients.

In the present study we sought to measure the relative statistical value of various multimodal CT protocols at identifying treatment responsiveness in patients being considered for thrombolysis. We used a prospectively collected cohort of acute ischemic stroke patients being assessed for IV-alteplase, who had CT-perfusion (CTP) and CT-angiography (CTA) before a treatment decision. Linear regression and receiver operator characteristic curve analysis were performed to measure the prognostic value of models incorporating each imaging modality. One thousand five hundred and sixty-two sub-4.5 h ischemic stroke patients were included in this study. A model including clinical variables, alteplase treatment, and NCCT ASPECTS was weak (R 2 0.067, P < 0.001, AUC 0.605) at predicting 90 day mRS. A second model, including dynamic CTA variables (collateral grade, occlusion severity) showed better predictive accuracy for patient outcome (R 2 0.381, P < 0.001, AUC 0.781). A third model incorporating CTP variables showed very high predictive accuracy (R 2 0.488, P < 0.001, AUC 0.899). Combining all three imaging modalities variables also showed good predictive accuracy for outcome but did not improve on the CTP model (R 2 0.439, P < 0.001, AUC 0.825). CT perfusion predicts patient outcomes from alteplase therapy more accurately than models incorporating NCCT and/or CT angiography. This data has implications for artificial intelligence or machine learning models.

Pre-hospital triage of suspected acute stroke patients in a mobile stroke unit in the rural Alberta.

Mobile Stroke Unit (MSU) expedites the delivery of intravenous thrombolysis in acute stroke patients. We further evaluated the functional outcome of patients shipped to a tertiary care centre or repatriated to local hospitals after triage by MSU in acute stroke syndrome in rural northern Alberta. Consecutive patients with suspected acute stroke syndrome were included. On the basis of neurology consultation and, Computed Tomography findings, patients, who were thrombolysed or needed advanced care were transported to the Comprehensive stroke center (CSC) (Triage to CSC group). Other patients were repatriated to local hospital care (Triage to LHC group). A total of 156 patients were assessed in MSU, 73 (46.8%) were female and the mean age was 66.6 ± 15 years. One hundred and eight (69.2%) patients, including 41 (26.3%) treated with thrombolysis were transported to the CSC (Triage to CSC group) and 48 (30.8%) were repatriated to local hospital care. The diagnosis made in MSU and final diagnosis were matching in 88% (95) and 91.7% (44, p = 0.39) in Triage to CSC and Triage to LHC groups respectively. Prehospital triage by MSU of acute stroke syndrome can reliably repatriate patients to the home hospital. The proposed model has the potential to triage patients according to their medical needs by enabling treatment in home hospitals whenever reasonable.

A Prospective Economic Evaluation of Rapid Endovascular Therapy for Acute Ischemic Stroke.

BACKGROUND: During the Randomized Assessment of Rapid Endovascular Treatment (EVT) of Ischemic Stroke (ESCAPE) trial, patient-level micro-costing data were collected. We report a cost-effectiveness analysis of EVT, using ESCAPE trial data and Markov simulation, from a universal, single-payer system using a societal perspective over a patient's lifetime. METHODS: Primary data collection alongside the ESCAPE trial provided a 3-month trial-specific, non-model, based cost per quality-adjusted life year (QALY). A Markov model utilizing ongoing lifetime costs and life expectancy from the literature was built to simulate the cost per QALY adopting a lifetime horizon. Health states were defined using the modified Rankin Scale (mRS) scores. Uncertainty was explored using scenario analysis and probabilistic sensitivity analysis. RESULTS: The 3-month trial-based analysis resulted in a cost per QALY of $201,243 of EVT compared to the best standard of care. In the model-based analysis, using a societal perspective and a lifetime horizon, EVT dominated the standard of care; EVT was both more effective and less costly than the standard of care (-$91). When the time horizon was shortened to 1 year, EVT remains cost savings compared to standard of care (∼$15,376 per QALY gained with EVT). However, if the estimate of clinical effectiveness is 4% less than that demonstrated in ESCAPE, EVT is no longer cost savings compared to standard of care. CONCLUSIONS: Results support the adoption of EVT as a treatment option for acute ischemic stroke, as the increase in costs associated with caring for EVT patients was recouped within the first year of stroke, and continued to provide cost savings over a patient's lifetime.Clinical Trial Registration: NCT01778335.

Association of Reperfusion After Thrombolysis With Clinical Outcome Across the 4.5- to 9-Hours and Wake-up Stroke Time Window: A Meta-Analysis of the EXTEND and EPITHET Randomized Clinical Trials.

Importance: Intravenous alteplase reduces disability after ischemic stroke in patients 4.5 to 9 hours after onset and with wake-up onset stroke selected using perfusion imaging mismatch. However, whether the benefit is consistent across the 4.5- to 6-hours, 6- to 9-hours, and wake-up stroke epochs is uncertain. Objective: To examine the association of reperfusion with reduced disability, including by onset-to-randomization time strata in the Extending the Time for Thrombolysis in Emergency Neurological Deficits (EXTEND) and Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) randomized clinical trials. Design, Setting, and Participants: Individual patient meta-analysis of randomized clinical trials performed from August 2001 to June 2018 with 3-month follow-up. Patients had acute ischemic stroke with 4.5-to 9-hours poststroke onset or with wake-up stroke were randomized to alteplase or placebo after perfusion mismatch imaging. Analysis began July 2019 and ended May 2020. Exposures: Reperfusion was defined as more than 90% reduction in time to maximum of more than 6 seconds' lesion volume at 24- to 72-hour follow-up. Main Outcomes and Measures: Ordinal logistic regression adjusted for baseline age and National Institutes of Health Stroke Scale score was used to analyze functional improvement in day 90 modified Rankin Scale score overall, including a reperfusion × time-to-randomization multiplicative interaction term, and in the 4.5- to 6-hours, 6- to 9-hours, and wake-up time strata. Symptomatic hemorrhage was defined as large parenchymal hematoma with a National Institutes of Health Stroke Scale score increase of 4 points or more. Results: Reperfusion was assessable in 270 of 295 patients (92%), 68 of 133 (51%) in the alteplase group, and 38 of 137 (28%) in the placebo reperfused group (P < .001). The median (interquartile range) age was 76 (66-81) years in the reperfusion group vs 74 (64.5-81.0) years in the group with no reperfusion. The median (interquartile range) baseline National Institutes of Health Stroke Scale score was 10 (7-15) in the reperfusion group vs 12 (8.0-17.5) in the no reperfusion group. Overall, reperfusion was associated with improved functional outcome (common odds ratio, 7.7; 95% CI, 4.6-12.8; P < .001). Reperfusion was associated with significantly improved functional outcome in each of the 4.5- to 6-hours, 6- to 9-hours, and wake-up time strata, with no evidence of association between time to randomization and beneficial effect of reperfusion (P = .63). Symptomatic hemorrhage, assessed in all 294 patients, occurred in 3 of 51 (5.9%) in the 4.5- to 6-hours group, 2 of 28 (7.1%) in the 6- to 9-hours group, and 4 of 73 (5.5%) in the wake-up stroke in patients treated with alteplase (Fisher P = .91). Conclusions and Relevance: Strong benefits of reperfusion in all time strata without differential risk in symptomatic hemorrhage support the consistent treatment effect of alteplase in perfusion mismatch-selected patients throughout the 4.5- to 9-hours and wake-up stroke time window.

Nitroglycerin Is Not Associated with Improved Cerebral Perfusion in Acute Ischemic Stroke.

OBJECTIVE: The study was conducted to test the hypothesis that nitroglycerin (NTG) increases cerebral perfusion focally and globally in acute ischemic stroke patients, using serial perfusion-weighted imaging (PWI) magnetic resonance imaging measurements. PATIENTS AND METHODS: Thirty-five patients underwent PWI immediately before and 72 h after administration of a transdermal NTG patch or no treatment. Patients with baseline mean arterial pressure (MAP) > 100 mmHg (NTG group, n = 20) were treated with transdermal NTG (0.2 mg/h) for 72 h, without a nitrate-free interval. Patients with MAP ≤ 100 mmHg (untreated group, n = 15) were not treated. The primary outcome measure was absolute cerebral blood flow (CBF) in the hypoperfused region at 72 h. RESULTS: The mean baseline absolute CBF in the hypoperfused region was similar in the NTG group (33.3 ± 10.2 ml/100 g/min) and untreated (32.7 ± 8.4 ml/100 g/min, p = 0.4) groups. The median (IQR) baseline infarct volume was 10.4 (2.5-49.3) ml in the NTG group and 32.6 (8.6-96.7) ml in the untreated group (p = 0.09). MAP change in the NTG group was 1.2 ± 12.6 and 8 ± 20.7 mmHg at 2 h and 72 h, respectively. Mean absolute CBF in the hypoperfused region at 72 h was similar in the NTG (29.9 ± 12 ml/100 g/min) and untreated groups (24.1 ± 10 ml/100 g/min, p = 0.8). The median infarct volume increased in untreated (11.8 (5.7-44.2) ml) than the NTG group (3.2 (0.5-16.5) ml; p = 0.033) on univariate analysis, however, there was no difference on regression analysis. CONCLUSION: NTG was not associated with improvement in cerebral perfusion in acute ischemic stroke patients.