Yvo B. W. E. M. Roos

Background/Objectives: Computer-aided vessel occlusion detection for acute ischemic stroke is typically developed on early-phase CT angiography (CTA). In late-phase CTA, enhanced venous contrast can mimic arterial occlusions and lead to incorrect occlusion detections. To counteract this, we propose a constraint-based post-processing framework that leverages anatomical and temporal vascular information from CT perfusion (CTP) scans. Methods: Vascular anatomy and relative contrast-arrival times were encoded as time–vessel maps. Three complementary constraints worked on these maps to remove incorrect detections based on distance-to-vessel truncation points, contrast-arrival time, and spatial priors. Constraints were fixed on a 32-case late-phase development subset and applied to an external held-out cohort of late-phase CTA (N = 354). To enable application without CTP, an auxiliary CTA-to-time–vessel map generator was designed to estimate maps directly from CTA. Results: In the external cohort, the framework reduced incorrect occlusions per scan from 3.9 (95% CI 3.6–4.2) to 2.1 (95% CI 1.9–2.3), preserving occlusion-level sensitivity at 80% (95% CI 69–91). The patient-level AUROC was 83 for the baseline versus 88 with post-processing. Improvements were also observed in detectors exposed to late-phase CTA, where post-processing reduced incorrect occlusions per scan from 2.8 to 1.9. As only 51 occlusion-positive cases were present in the external cohort, confidence intervals were wide. Consequently, these estimates should be interpreted with caution. Conclusions: Anatomically and temporally informed post-processing reduced incorrect occlusion detections in late-phase CTA without measurable loss of sensitivity, potentially improving robustness against CTA phase changes in external institutions.

BACKGROUND: Mapping concerns the cross-walking of one health-related quality of life instrument to another. This study aimed to translate the modified Rankin Scale (mRS) score at 3 months after ischemic stroke into 5-level version of the EQ-5D (EQ-5D-5L)–based utility values, which may be used for the derivation of quality-adjusted life years for cost-effectiveness analyses. METHODS: Data from 3 Dutch multicenter phase III clinical trials in ischemic stroke were pooled (MR CLEAN [Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands]-NO-IV, MR CLEAN-MED, and MR CLEAN-LATE). The mRS and EQ-5D-5L were assessed by telephone interview at 3 months poststroke. The correlation (Spearman coefficient) between the mRS and each EQ-5D-5L domain was assessed. Various direct and indirect mapping algorithms were explored. Model performance (predictive ability) was assessed using bootstrapping in the full testing set (mRS score 0–5) and in patients with independent (0–2) and dependent (3–5) mRS scores separately. Results were validated in an external validation set derived from a cross-sectional Dutch study. Final utility estimates per mRS score were assessed in the pooled trial and external validation data set. RESULTS: The EQ-5D-5L dimensions self-care, daily activities, and mobility demonstrated the strongest correlation to the mRS ( ρ =0.46–0.70). Correlation coefficients of the pain and anxiety dimensions were relatively poor ( ρ =0.37–0.45). Indirect mapping with a multinomial logit model was identified as the preferred mapping algorithm. In the pooled data set, the median (interquartile range) age was 71 (62–79), and 56% of patients were male. Mean (SD) fitted utility values per mRS score were; mRS score 0: 0.947 (0.004); mRS score 1: 0.860 (0.009); mRS score 2: 0.758 (0.013); mRS score 3: 0.597 (0.017); mRS score 4: 0.352 (0.017); and mRS score 5: 0.147 (0.017). CONCLUSIONS: The mean utility weights provided in this study may be used for the direct estimation of quality-adjusted life years from mRS scores. Furthermore, the multinomial logit model may be used to derive utility values from new data sets with different country-specific utility tariffs. Our results are ideally suited for application in cost-effectiveness analyses.

In stroke patients directly admitted to thrombectomy-capable centers, the value of intravenous thrombolysis (IVT) with alteplase before thrombectomy is time dependent. While early IVT may improve outcomes, delayed IVT administration lowers the likelihood of benefit. To date, no previous cost-effectiveness study has considered onset-to-treatment time. This study evaluated the cost-effectiveness of intravenous (IV) alteplase plus thrombectomy vs thrombectomy alone in patients admitted directly to thrombectomy-capable centers across 16 countries, stratified by onset-to-IVT time. A decision tree integrated with a Markov model estimated costs, quality-adjusted life years (QALYs), and incremental net monetary benefit (INMB) over 15 years. A willingness-to-pay threshold of one gross domestic product per capita was applied for each country. Effectiveness data were derived from individual patient data from 6 trials including patients with anterior circulation large-vessel occlusion eligible for both IVT and thrombectomy who presented directly to thrombectomy-capable centers. Costs were obtained from a literature review. Onset-to-IVT time was categorized as <140, 140-169, 170-199, and ≥200 minutes. One-way sensitivity and probabilistic sensitivity analyses were performed to check robustness of results. Ninety-day functional outcome distributions from 2,268 patients (median age 71 years; 44% female) were used to model cost-effectiveness in a hypothetical cohort of 10,000 patients. Without accounting for onset-to-IVT time, IV alteplase plus thrombectomy seemed cost-effective in 13 countries (INMB: $85-$3,618; 50-65% probability of cost-effectiveness) and not cost-effective in the United States, China, and Vietnam, with modest health gains (0.06-0.08 QALYs per patient). Time-stratified analyses revealed that IVT plus thrombectomy was cost-effective in 16 countries when onset-to-IVT time was <140 minutes (INMB: $615-$30,645; 82%-98% probability) and at 140-169 minutes (INMB: $86-$16,918; 51%-77% probability). However, IV alteplase plus thrombectomy was no longer cost-effective in 8 countries at 170-199 minutes. Universally, the INMB was negative for onset-to-IVT times exceeding 200 minutes. Cost-effectiveness of IV alteplase plus thrombectomy varies per country and onset-to-IVT time. IV alteplase plus thrombectomy is cost-effective when IVT can be administered within 170 minutes from symptom onset. Cost-effectiveness of IV alteplase plus thrombectomy diminishes progressively with longer onset-to-IVT times and becomes detrimental after 200 minutes.

Subacute lesion growth after acute ischemic stroke is associated with worse functional outcomes. The ischemic lesion severity can be assessed with Net Water Uptake (NWU), a CT-based marker of edema. Pre-treatment NWU has been associated with worse functional outcomes; however, it remains unclear how the temporal changes in NWU influence functional outcomes. In this study, we aimed to determine how associations between NWU and functional outcome vary across imaging times up to 1 week after stroke. We included patients from the MRCLEAN NO-IV trial with anterior circulation large vessel occlusion who were treated with endovascular treatment and had baseline, 24-hour, and 1-week follow-up non-contrast CT scans. Functional outcome at 90 days was evaluated using the modified Rankin Scale (mRS), analyzed both as functional independence (mRS 0-2) and across the full ordinal distribution (mRS 0-6). In the primary analysis, associations between NWU measured at different imaging timepoints and functional independence were examined using univariable and multivariable logistic regression models. To evaluate temporal changes in NWU, ΔNWU was calculated at different time intervals (baseline-24 hours, 24 hours-1 week, and baseline-1 week), and its association with outcomes was analyzed using analogous regression models. Out of 539 MRCLEAN NO-IV patients, 115 were included in this study. The median time from stroke onset to randomization was 92(70-140) minutes. The median NWU evolved from 4.3%(IQR:2.1-6.8%) at baseline to 9.0%(IQR:3.0-13%) at 24 hours and 15%(IQR:11-19%) at 1 week. The median patient-level change (ΔNWU) from baseline to 1 week was 10%(IQR: 5.3-16%). NWU measured at 1 week, but not at baseline or 24 hours, was significantly associated with functional dependence, with an aOR of 0.66(95%CI=0.47-0.90) per 5-percantage-point increase in NWU. Furthermore, a higher increase in NWU from baseline to 1 week imaging was significantly associated with functional dependence, with an aOR of 0.66(95%CI=0.47-0.86) per 5-percentage-point increase in ΔNWU_1wk-BL. In our population, NWU measured at 1 week is associated with 90-day clinical outcomes, suggesting that lesion evolution continues in the first week after stroke onset and may therefore represent a target for secondary treatments to improve clinical outcomes.

Net water uptake (NWU) in the infarct core of patients with ischemic stroke has been correlated with clinical outcome and lesion age, which could aid in treatment selection. Traditional NWU measurement requires CTP, limiting its clinical applicability. We aimed to develop and evaluate an automated method to measure NWU using only NCCT and CTA. We included 90 patients with ischemic stroke with known onset time and available NCCT, CTA, and CTP from the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) Registry and MR CLEAN-LATE trial. Using deep learning, we automatically segmented the infarct core and hypoperfused area from NCCT and CTA images. NWU was calculated as the relative difference in density between these affected regions and their contralateral counterparts. We included the hypoperfused area because it represents potentially salvageable tissue, and additional NWU analyses in this region could provide insights into ischemic injury progression. We compared this automated CTA-NCCT-based approach with the traditional CTP-NCCT-based approach by assessing their agreement (intraclass correlation coefficient [ICC], Bland-Altman analysis) and accuracy in identifying patients within 4.5 hours of stroke onset (receiver operating characteristic analysis, DeLong test for areas under the curve [AUC] comparison). NWU measured in the core (CTP-NCCT-based: median 4.1%, interquartile range [2.7-6.6]; CTA-NCCT-based: 3.2%, [2.1-5.2]) showed good agreement between approaches (ICC 0.81, 95% CI, 0.73-0.87; mean difference 0.43% [-4.6% to +5.5%]). NWU in the hypoperfused area (CTP-NCCT-based: 2.3%, [1.3-4.1]; CTA-NCCT-based: 2.4%, [0.9-3.9]) showed excellent agreement (ICC 0.93, 95% CI, 0.90-0.96; mean difference 0.17%, -1.54% to +1.88%). For core-based NWU, both approaches detected significantly lower values in patients within versus beyond 4.5 hours (CTP-NCCT-based: 3.7% versus 10%; P < .001; CTA-NCCT-based: 3.1% versus 11%; P < .001) with similar accuracy (AUC, 0.87; P = .88). For hypoperfused area-based NWU, neither approach showed significant differences between patients within versus beyond 4.5 hours (CTP-NCCT-based: 2.3% versus 4.4%; P = .31; CTA-NCCT-based: 2.3% versus 4.7%; P = 0.13) and both had lower accuracy than core-based NWU classification (AUC,: CTP-NCCT-based 0.59, CTA-NCCT-based 0.63; P = 0.81). The automated CTA-NCCT-based approach shows good agreement with the traditional CTP-NCCT-based method for NWU measurement and achieves similar accuracy in identifying patients within 4.5 hours of onset. External validation is needed to confirm these findings.

Introduction: Inflammation is important in the pathogenesis of acute ischemic stroke (AIS). The association between CRP and outcomes in patients with large vessel occlusion (LVO) stroke receiving endovascular therapy (EVT) has not been fully elucidated. Patients and methods: We used data from the MR CLEAN Registry (2014–2017), including LVO-AIS patients with intracranial carotid atherosclerotic disease (ICAD), extracranial carotid atherosclerotic disease (ECAD) or atrial fibrillation (AF). The primary outcome was modified Rankin Scale (mRS) score at 90 days. Secondary outcomes included mRS ⩾3 at 90 days, all-cause mortality, successful recanalization, and symptomatic intracranial hemorrhages. CRP was analyzed both dichotomously (>3.0 vs ⩽3.0 mg/L) and continuously, using multivariable regression adjusted for potential confounders. Results: Among 865 included patients (ICAD: 286; ECAD: 154; AF: 425), median CRP level was 3.4 mg/L (IQR: 2.0–6.1) and 446 patients had elevated CRP (>3.0 mg/L). AF patients had higher CRP than ICAD and ECAD patients (4.0–3.0–3.2 mg/L, p = 0.002). CRP >3.0 mg/L was not associated with mRS in the full cohort (acOR 0.983, 95% CI (0.767, 1.260)) or in any etiological subgroups (ICAD: acOR = 0.968, 95% CI (0.626, 1.496), ECAD: acOR = 1.114, 95% CI (0.617, 2.012), AF: acOR = 0.937, 95% CI (0.653, 1.344)). There was also no association between CRP and any of the other outcomes. When analyzed as a continuous variable, CRP was also not associated with any other outcomes. Conclusions: We did not observe an association between CRP levels and clinical and radiological outcomes after LVO stroke.

BACKGROUND: Equipoise persists whether patients with stroke with carotid tandem lesions undergoing endovascular treatment (EVT) should undergo acute carotid stenting, and whether intravenous thrombolysis (IVT) before EVT should influence this decision. We assessed functional and safety outcomes of acute carotid stenting in patients with carotid tandem lesions randomized to IVT plus EVT or EVT alone. METHODS: Individual participant data meta-analysis of 6 randomized clinical trials conducted in Asia, Europe, and Oceania between 2017 and 2021 investigating IVT plus EVT versus EVT alone in patients with carotid tandem lesions presenting directly to EVT-capable centers. The primary outcome was the 90-day modified Rankin Scale score, assessed with mixed-effect ordinal regression models. Safety outcomes were any intracranial hemorrhage and symptomatic intracranial hemorrhage. A secondary analysis used inverse probability of treatment weighting. Treatment effect heterogeneity between IVT plus EVT and EVT alone was assessed in a 2-step meta-analysis. RESULTS: Overall, 340 of 2267 (15%) patients had carotid tandem lesions with 113 of 329 (34%) undergoing acute carotid stenting. Stenting was associated with better 90-day functional outcomes (adjusted common odds ratio, 1.60 [95% CI, 1.03–2.47]), confirmed in inverse probability of treatment weighting analysis (adjusted common odds ratio, 1.66 [95% CI, 1.08–2.54]). Patients undergoing stenting had no statistically significant higher rates of any intracranial hemorrhage (44% versus 35%; adjusted odds ratio, 1.30 [95% CI, 0.79–2.15]) and symptomatic intracranial hemorrhage (6.3% versus 3.7%; adjusted odds ratio, 2.09 [95% CI, 0.78–5.59]). No heterogeneity in treatment effect was observed in patients randomized to IVT plus EVT (adjusted common odds ratio, 2.07 [95% CI, 1.06–4.07]) or EVT alone (1.21 [95% CI, 0.59–2.50]; P interaction=0.81). CONCLUSIONS: In this international individual participant data meta-analysis of patients with carotid tandem lesions randomized to EVT alone or IVT followed by EVT, acute carotid stenting during EVT was associated with better functional outcomes, and this association was not modified by prior treatment with IVT.

Introduction: Endovascular thrombectomy (EVT) procedures and workflow have evolved over the years. We examined trends in patient characteristics, EVT techniques and outcomes over 5 years in the Netherlands. Patients and methods: Data from the MR CLEAN Registry (2014–2018) were analysed, including patients treated with EVT for anterior circulation acute ischaemic stroke (AIS). Patients were grouped by year of inclusion except for the linear regression analysis where the inclusion date was used. Baseline predicted probability of poor outcome (modified Rankin Scale (mRS) score 3–6) was calculated using a validated prediction model. Primary outcome was mRS score at 90 days. Secondary outcomes included workflow times, EVT techniques, successful reperfusion (eTICI ⩾ 2B) and symptomatic intracranial haemorrhage (sICH). Time trends were analysed using multivariable regression models (adjusted common odds ratios (acOR) per year). Results: 5193 patients were included. Median age increased (from 66 in 2014 to 74 years in 2018 [p < 0.001]). Proportion of patients with pre-stroke dependence (mRS ⩾ 3) increased from 2014 through 2018 (9% to 16%, p < 0.001). Baseline predicted probability of poor outcome did not change (60% vs 66%, p = 0.06). Over time, functional outcomes improved (acOR 1.14 per year, 95%CI: 1.09–1.20); mortality decreased (aOR 0.88 per year, 95%CI: 0.83–0.94). EVT under local anaesthesia increased (from 46% in 2014 to 70% in 2018; aOR 1.15, 95%CI: 1.10–1.22), as did use of direct aspiration (13%–36%; aOR 1.43, 95%CI: 1.35–1.53). Successful reperfusion became more frequent (aOR 1.32 per year, 95%CI: 1.25–1.40), despite needing more attempts (1 in 2014 vs 2 in 2018, aOR 0.93 per year, 95%CI: 0.89–0.98). Incidence of sICH remained unchanged (5% vs 5%, aOR 0.99 per year, 95%CI: 0.89–1.09). Time from emergency room to groin puncture reduced by 7 min per year (95%CI: 5–8). Discussion and conclusion: Enhanced workflow and increased EVT experience may have led to shorter time to treatment and more frequent successful reperfusion, with better functional outcomes over 5 years, despite treating older, more dependent patients.

Background: In large vessel occlusion (LVO) stroke, shorter time from stroke onset to endovascular thrombectomy (EVT), and faster recanalization in the early window (<6 hours from last seen well) are associated with better outcomes. This association is less well known for patients with M2 occlusions. Methods: We conducted a pooled analysis of the MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands) MED and NO‐IV trials and analyzed the effect of time delay in EVT‐treated LVO (grouped as intracranial internal carotid artery (ICA), ICA‐Terminus, or M1‐segment) and M2 occlusion patients with known stroke onset times. The primary outcome was the ordinal 90‐day modified Rankin Scale score. Secondary outcomes included 90‐day functional independence (modified Rankin Scale score 0–2) and mortality. Results: We included 94 patients with M2 occlusions and 423 with LVOs. In LVOs, longer times between stroke onset to start of EVT or to successful recanalization were associated with worse functional outcomes (adjusted common odds ratio [acOR], 0.92 [ 95% CI, 0.87–0.98] and acOR, 0.91 [95% CI, 0.86–0.95] per 15 minutes, respectively). Every 15‐minute delay to start of EVT reduced the probability of functional independence by 2.3%. For M2 occlusions, no significant association was found between time to EVT or successful recanalization and functional outcome (acOR, 1.09 [95% CI, 0.97–1.22] and acOR, 1.04 [95% CI, 0.92–1.19] per 15 minutes). Patients with LVOs showed a significant 0.7% increased probability of 90‐day mortality per 15‐minute delay in the start of EVT, whereas patients with M2 occlusions showed no significant association. Conclusions: Treatment delays worsen functional outcomes in patients with LVOs. However, this was not shown in patients with M2 occlusions, suggesting that outcomes after EVT for patients with M2 occlusions in the early window depend less on time to treatment.