White Matter Lesions and Outcomes After Endovascular Treatment for Acute Ischemic Stroke:MR CLEAN Registry Results

BACKGROUND: Cerebral white matter lesions (WMLs) have been associated with a greater risk of poor functional outcome after ischemic stroke. We assessed the relations between WML burden and radiological and clinical outcomes in patients treated with endovascular treatment in routine practice. METHODS: We analyzed data from the MR CLEAN Registry (Multicenter Randomized Controlled Trial of Endovascular Treatment for Acute Ischaemic Stroke in the Netherlands)-a prospective, multicenter, observational cohort study of patients treated with endovascular treatment in the Netherlands. WMLs were graded on baseline noncontrast computed tomography using a visual grading scale. The primary outcome was the score on the modified Rankin Scale at 90 days. Secondary outcomes included early neurological recovery, successful reperfusion (extended Thrombolysis in Cerebral Infarction ≥2b), futile recanalization (modified Rankin Scale score ≥3 despite successful reperfusion), and occurrence of symptomatic intracranial hemorrhage. We used multivariable logistic regression models to assess associations between WML severity and outcomes, taking the absence of WML on noncontrast computed tomography as the reference category. RESULTS: Of 3180 patients included in the MR CLEAN Registry between March 2014 and November 2017, WMLs were graded for 3046 patients and categorized as none (n=1855; 61%), mild (n=608; 20%), or moderate to severe (n=588; 19%). Favorable outcome (modified Rankin Scale score, 0-2) was achieved in 838 patients (49%) without WML, 192 patients (34%) with mild WML, and 130 patients (24%) with moderate-to-severe WML. Increasing WML grades were associated with a shift toward poorer functional outcome in a dose-dependent manner (adjusted common odds ratio, 1.34 [95% CI, 1.13-1.60] for mild WML and 1.67 [95% CI, 1.39-2.01] for moderate-to-severe WML; Ptrend, <0.001). Increasing WML grades were associated with futile recanalization (Ptrend, <0.001) and were inversely associated with early neurological recovery (Ptrend, 0.041) but not with the probability of successful reperfusion or symptomatic intracranial hemorrhage. CONCLUSIONS: An increasing burden of WML at baseline is associated with poorer clinical outcomes after endovascular treatment for acute ischemic stroke but not with the probability of successful reperfusion or symptomatic intracranial hemorrhage

Time Since Stroke Onset, Quantitative Collateral Score, and Functional Outcome After Endovascular Treatment for Acute Ischemic Stroke

BACKGROUND AND OBJECTIVES: In patients with ischemic stroke undergoing endovascular treatment (EVT), time to treatment and collateral status are important prognostic factors and may be correlated. We aimed to assess the relation between time to CT angiography (CTA) and a quantitatively determined collateral score and to assess whether the collateral score modified the relation between time to recanalization and functional outcome. METHODS: We analyzed data from patients with acute ischemic stroke included in the Multicenter Randomized Controlled Trial of Endovascular Treatment for Acute Ischemic Stroke Registry between 2014 and 2017, who had a carotid terminus or M1 occlusion and were treated with EVT within 6.5 hours of symptom onset. A quantitative collateral score (qCS) was determined from baseline CTA using a validated automated image analysis algorithm. We also determined a 4-point visual collateral score (vCS). Multivariable regression models were used to assess the relations between time to imaging and the qCS and between the time to recanalization and functional outcome (90-day modified Rankin Scale score). An interaction term (time to recanalization × qCS) was entered in the latter model to test whether the qCS modifies this relation. Sensitivity analyses were performed using the vCS. RESULTS: We analyzed 1,813 patients. The median time from symptom onset to CTA was 91 minutes (interquartile range [IQR] 65–150 minutes), and the median qCS was 49% (IQR 25%–78%). Longer time to CTA was not associated with the log-transformed qCS (adjusted β per 30 minutes, 0.002, 95% CI −0.006 to 0.011). Both a higher qCS (adjusted common odds ratio [acOR] per 10% increase: 1.06, 95% CI 1.03–1.09) and shorter time to recanalization (acOR per 30 minutes: 1.17, 95% CI 1.13–1.22) were independently associated with a shift toward better functional outcome. The qCS did not modify the relation between time to recanalization and functional outcome (p for interaction: 0.28). Results from sensitivity analyses using the vCS were similar. DISCUSSION: In the first 6.5 hours of ischemic stroke caused by carotid terminus or M1 occlusion, the collateral status is unaffected by time to imaging, and the benefit of a shorter time to recanalization is independent of baseline collateral status

Cerebral Collateral Circulation in the Era of Reperfusion Therapies for Acute Ischemic Stroke

Clinical outcomes of patients with acute ischemic stroke depend in part on the extent of their collateral circulation. A good collateral circulation has also been associated with greater benefit of intravenous thrombolysis and endovascular treatment. Treatment decisions for these reperfusion therapies are increasingly guided by a combination of clinical and imaging parameters, particularly in later time windows. Computed tomography and magnetic resonance imaging enable a rapid assessment of both the collateral extent and cerebral perfusion. Yet, the role of the collateral circulation in clinical decision-making is currently limited and may be underappreciated due to the use of rather coarse and rater-dependent grading methods. In this review, we discuss determinants of the collateral circulation in patients with acute ischemic stroke, report on commonly used and emerging neuroimaging techniques for assessing the collateral circulation, and discuss the therapeutic and prognostic implications of the collateral circulation in relation to reperfusion therapies for acute ischemic stroke

Collateral status and recanalization after endovascular treatment for acute ischemic stroke

Background: Successful recanalization and good collateral status are associated with good clinical outcomes after endovascular treatment (EVT) for acute ischemic stroke, but the relationships among them are unclear. Objective: To assess if collateral status is associated with recanalization after EVT and if collateral status modifies the association between successful recanalization and functional outcome. Methods: We retrospectively analyzed data from the MR CLEAN Registry, a multicenter prospective cohort study of patients with a proximal anterior occlusion who underwent EVT in the Netherlands. We determined collateral status with a previously validated four-point visual grading scale and defined successful recanalization as an extended Thrombolysis in Cerebral Infarction score ≥2B. Functional outcome was determined using the modified Rankin Scale score at 90 days. We assessed, with multivariable logistic regression models, the associations between (1) collateral status and successful recanalization, (2) successful recanalization and functional outcome, (3) collateral status and functional outcome. An interaction of collateral status and successful recanalization was assessed. Subgroup analyses were performed for patients treated with intravenous thrombolysis. Results: We included 2717 patients, of whom 1898 (70%) had successful recanalization. There was no relationship between collateral status and successful recanalization (adjusted common OR (95% CI) of grades 1, 2, and 3 vs 0: 1.19 (0.82 to 1.72), 1.20 (0.83 to 1.75), and 1.10 (0.74 to 1.63), respectively). Successful recanalization (acOR (95% CI): 2.15 (1.84 to 2.52)) and better collateral grades (acOR (95% CI) of grades 1, 2, and 3 vs 0: 2.12 (1.47 to 3.05), 3.46 (2.43 to 4.92), and 4.16 (2.89 to 5.99), respectively) were both associated with a shift towards better functional outcome, without an interaction between collateral status and successful recanalization. Results were similar for the subgroup of thrombolysed patients. Conclusions: Collateral status is not associated with the probability of successful recanalization after EVT and does not modify the association between successful recanalization and functional outcome

White Matter Lesions and Outcomes after Endovascular Treatment for Acute Ischemic Stroke: MR CLEAN Registry Results

Background: Cerebral white matter lesions (WMLs) have been associated with a greater risk of poor functional outcome after ischemic stroke. We assessed the relations between WML burden and radiological and clinical outcomes in patients treated with endovascular treatment in routine practice. Methods: We analyzed data from the MR CLEAN Registry (Multicenter Randomized Controlled Trial of Endovascular Treatment for Acute Ischaemic Stroke in the Netherlands) - a prospective, multicenter, observational cohort study of patients treated with endovascular treatment in the Netherlands. WMLs were graded on baseline noncontrast computed tomography using a visual grading scale. The primary outcome was the score on the modified Rankin Scale at 90 days. Secondary outcomes included early neurological recovery, successful reperfusion (extended Thrombolysis in Cerebral Infarction ≥2b), futile recanalization (modified Rankin Scale score ≥3 despite successful reperfusion), and occurrence of symptomatic intracranial hemorrhage. We used multivariable logistic regression models to assess associations between WML severity and outcomes, taking the absence of WML on noncontrast computed tomography as the reference category. Results: Of 3180 patients included in the MR CLEAN Registry between March 2014 and November 2017, WMLs were graded for 3046 patients and categorized as none (n=1855; 61%), mild (n=608; 20%), or moderate to severe (n=588; 19%). Favorable outcome (modified Rankin Scale score, 0-2) was achieved in 838 patients (49%) without WML, 192 patients (34%) with mild WML, and 130 patients (24%) with moderate-to-severe WML. Increasing WML grades were associated with a shift toward poorer functional outcome in a dose-dependent manner (adjusted common odds ratio, 1.34 [95% CI, 1.13-1.60] for mild WML and 1.67 [95% CI, 1.39-2.01] for moderate-to-severe WML; Ptrend, <0.001). Increasing WML grades were associated with futile recanalization (Ptrend, <0.001) and were inversely associated with early neurological recovery (Ptrend, 0.041) but not with the probability of successful reperfusion or symptomatic intracranial hemorrhage. Conclusions: An increasing burden of WML at baseline is associated with poorer clinical outcomes after endovascular treatment for acute ischemic stroke but not with the probability of successful reperfusion or symptomatic intracranial hemorrhage

White Matter Lesions and Outcomes after Endovascular Treatment for Acute Ischemic Stroke: MR CLEAN Registry Results

Background: Cerebral white matter lesions (WMLs) have been associated with a greater risk of poor functional outcome after ischemic stroke. We assessed the relations between WML burden and radiological and clinical outcomes in patients treated with endovascular treatment in routine practice. Methods: We analyzed data from the MR CLEAN Registry (Multicenter Randomized Controlled Trial of Endovascular Treatment for Acute Ischaemic Stroke in the Netherlands) - a prospective, multicenter, observational cohort study of patients treated with endovascular treatment in the Netherlands. WMLs were graded on baseline noncontrast computed tomography using a visual grading scale. The primary outcome was the score on the modified Rankin Scale at 90 days. Secondary outcomes included early neurological recovery, successful reperfusion (extended Thrombolysis in Cerebral Infarction ≥2b), futile recanalization (modified Rankin Scale score ≥3 despite successful reperfusion), and occurrence of symptomatic intracranial hemorrhage. We used multivariable logistic regression models to assess associations between WML severity and outcomes, taking the absence of WML on noncontrast computed tomography as the reference category. Results: Of 3180 patients included in the MR CLEAN Registry between March 2014 and November 2017, WMLs were graded for 3046 patients and categorized as none (n=1855; 61%), mild (n=608; 20%), or moderate to severe (n=588; 19%). Favorable outcome (modified Rankin Scale score, 0-2) was achieved in 838 patients (49%) without WML, 192 patients (34%) with mild WML, and 130 patients (24%) with moderate-to-severe WML. Increasing WML grades were associated with a shift toward poorer functional outcome in a dose-dependent manner (adjusted common odds ratio, 1.34 [95% CI, 1.13-1.60] for mild WML and 1.67 [95% CI, 1.39-2.01] for moderate-to-severe WML; Ptrend, <0.001). Increasing WML grades were associated with futile recanalization (Ptrend, <0.001) and were inversely associated with early neurological recovery (Ptrend, 0.041) but not with the probability of successful reperfusion or symptomatic intracranial hemorrhage. Conclusions: An increasing burden of WML at baseline is associated with poorer clinical outcomes after endovascular treatment for acute ischemic stroke but not with the probability of successful reperfusion or symptomatic intracranial hemorrhage

Diagnostic performance of an algorithm for automated collateral scoring on computed tomography angiography

Objectives: Outcome of endovascular treatment in acute ischemic stroke patients depends on collateral circulation to provide blood supply to the ischemic territory. We evaluated the performance of a commercially available algorithm for assessing the collateral score (CS) in acute ischemic stroke patients. Methods: Retrospectively, baseline CTA scans (≤ 3-mm slice thickness) with an intracranial carotid artery (ICA), middle cerebral artery segment M1 or M2 occlusion, from the MR CLEAN Registry (n = 1627) were evaluated. All CTA scans were evaluated for visual CS (0–3) by eight expert radiologists (reference standard). A Web-based AI algorithm quantified the collateral circulation (0–100%) for correctly detected occlusion sides. Agreement between visual CS and categorized automated CS (0: 0%, 1: > 0– ≤ 50%, 2: > 50– < 100%, 3: 100%) was assessed. Area under the curve (AUC) values for classifying patients in having good (CS: 2–3) versus poor (CS: 0–1) collaterals and for predicting functional independence (90-day modified Rankin Scale 0–2) were computed. Influence of CTA acquisition timing after contrast material administration was reported. Results: In the analyzed scans (n = 1024), 59% agreement was found between visual CS and automated CS. An AUC of 0.87 (95% CI: 0.85–0.90) was found for discriminating good versus poor CS. Timing of CTA acquisition did not influence discriminatory performance. AUC for predicting functional independence was 0.66 (95% CI 0.62–0.69) for automated CS, similar to visual CS 0.64 (95% CI 0.61–0.68). Conclusions: The automated CS performs similar to radiologists in determining a good versus poor collateral score and predicting functional independence in acute ischemic stroke patients with a large vessel occlusion. Key Points: • Software for automated quantification of intracerebral collateral circulation on computed tomography angiography performs similar to expert radiologists in determining a good versus poor collateral score. • Software for automated quantification of intracerebral collateral circulation on computed tomography angiography performs similar to expert radiologists in predicting functional independence in acute ischemic stroke patients with a large vessel occlusion. • The timing of computed tomography angiography acquisition after contrast material administration did not influence the performance of automated quantification of the collateral status

Admission blood pressure and clinical outcomes in patients with acute ischaemic stroke treated with intravenous alteplase and endovascular treatment versus endovascular treatment alone: A MR CLEAN-NO IV substudy

Introduction: High systolic blood pressure (SBP) is associated with poor functional outcome. We analysed whether the association of SBP with outcomes after endovascular treatment (EVT) is modified by prior intravenous thrombolysis (IVT). Patients and methods: This was a post-hoc analysis of MR CLEAN-NO IV, a randomised trial of IVT with alteplase followed by EVT versus EVT alone, within 4.5 h from stroke onset. SBP was recorded on hospital admission. The primary outcome was 90-day modified Rankin Scale (mRS) score and secondary outcomes included symptomatic intracranial haemorrhage (sICH) and successful reperfusion (eTICI 2b-3), analysed with (ordinal) logistic regression. Estimates were calculated per 10 mmHg change in SBP. We assessed whether IVT modified the associations of SBP with these outcomes using multiplicative interaction terms. Results: Of 539 randomised patients, 266 received IVT. The association of SBP with mRS score was J-shaped, with an inflection point at 150 mmHg. Using 150 mmHg as a reference point, SBPs higher than 150 mmHg were associated with poor functional outcome (acOR: 1.23, 95% CI: 1.09–1.38), but lower SBPs were not (acOR: 1.14, 95% CI: 0.99–1.30). Higher SBP was not associated with the risk of sICH (aOR: 1.09, 95% CI: 0.93–1.27) nor with the probability of successful reperfusion (aOR: 1.00, 95% CI: 0.91–1.10). Our main result was that we found no effect modification by IVT (p-values for interaction, mRS = 0.94; sICH = 0.26; successful reperfusion = 0.58). Discussion and conclusion: There was no effect modification of IVT with SBP for any of the clinical outcomes. Therefore, the level of SBP (if ⩽185/110 mmHg) should not guide IVT decisions in patients otherwise eligible for both IVT and EVT within the 4.5-h time window. Trial registration: ISRCTN80619088, https://www.isrctn.com/ISRCTN80619088

Prehospital transdermal glyceryl trinitrate in patients with presumed acute stroke (MR ASAP): an ambulance-based, multicentre, randomised, open-label, blinded endpoint, phase 3 trial

Background: Pooled analyses of previous randomised studies have suggested that very early treatment with glyceryl trinitrate (also known as nitroglycerin) improves functional outcome in patients with acute ischaemic stroke or intracerebral haemorrhage, but this finding was not confirmed in a more recent trial (RIGHT-2). We aimed to assess whether patients with presumed acute stroke benefit from glyceryl tr initrate started within 3 h after symptom onset. Methods: MR ASAP was a phase 3, randomised, open-label, blinded endpoint trial done at six ambulance services serving 18 hospitals in the Netherlands. Eligible participants (aged ≥18 years) had a probable diagnosis of acute stroke (as assessed by a paramedic), a face-arm-speech-time test score of 2 or 3, systolic blood pressure of at least 140 mm Hg, and could start treatment within 3 h of symptom onset. Participants were randomly assigned (1:1) by ambulance personnel, using a secure web-based electronic application with random block sizes stratified by ambulance service, to receive either transdermal glyceryl trinitrate 5 mg/day for 24 h plus standard care (glyceryl trinitrate group) or to standard care alone (control group) in the prehospital setting. Informed consent was deferred until after arrival at the hospital. The primary outcome was functional outcome assessed with the modified Rankin Scale (mRS) at 90 days. Safety outcomes included death within 7 days, death within 90 days, and serious adverse events. Analyses were based on modified intention to treat, and treatment effects were expressed as odds ratios (ORs) or common ORs, with adjustment for baseline prognostic factors. We separately analysed the total population and the target population (ie, patients with intracerebral haemorrhage, ischaemic stroke, or transient ischaemic attack). The target sample size was 1400 patients. The trial is registered as ISRCTN99503308. Findings: On June 24, 2021, the MR ASAP trial was prematurely terminated on the advice of the data and safety monitoring board, with recruitment stopped because of safety concerns in patients with intracerebral haemorrhage. Between April 4, 2018, and Feb 12, 2021, 380 patients were randomly allocated to a study group. 325 provided informed consent or died before consent could be obtained, of whom 170 were assigned to the glyceryl trinitrate group and 155 to the control group. These patients were included in the total population. 201 patients (62%) had ischaemic stroke, 34 (10%) transient ischaemic attack, 56 (17%) intracerebral haemorrhage, and 34 (10%) a stroke-mimicking condition. In the total population (n=325), the median mRS score at 90 days was 2 (IQR 1–4) in both the glyceryl trinitrate and control groups (adjusted common OR 0·97 [95% CI 0·65–1·47]). In the target population (n=291), the 90-day mRS score was 2 (2–4) in the glyceryl trinitrate group and 3 (1–4) in the control group (0·92 [0·59–1·43]). In the total population, there were no differences between the two study groups with respect to death within 90 days (adjusted OR 1·07 [0·53–2·14]) or serious adverse events (unadjusted OR 1·23 [0·76–1·99]). In patients with intracerebral haemorrhage, 12 (34%) of 35 patients allocated to glyceryl trinitrate versus two (10%) of 21 allocated to the control group died within 7 days (adjusted OR 5·91 [0·78–44·81]); death within 90 days occurred in 16 (46%) of 35 in the glyceryl trinitrate group and 11 (55%) of 20 in the control group (adjusted OR 0·87 [0·18–4·17]). Interpretation: We found no sign of benefit of transdermal glyceryl trinitrate started within 3 h of symptom onset in the prehospital setting in patients with presumed acute stroke. The signal of potential early harm of glyceryl trinitrate in patients with intracerebral haemorrhage suggests that glyceryl trinitrate should be avoided in this setting. Funding: The Collaboration for New Treatments of Acute Stroke consortium, the Brain Foundation Netherlands, the Ministry of Economic Affairs, Stryker, Medtronic, Cerenovus, and the Dutch Heart Foundation

Blood Pressure in the First 6 Hours Following Endovascular Treatment for Ischemic Stroke Is Associated With Outcome

BACKGROUND AND PURPOSE: Optimal blood pressure (BP) management in the acute phase of ischemic stroke remains an unresolved issue. It is uncertain whether guidelines for BP management during and after intravenous alteplase can be extrapolated to endovascular treatment (EVT) for stroke due to large artery occlusion in the anterior circulation. We evaluated the associations between systolic BP (SBP) in the first 6 hours following EVT and functional outcome as well as symptomatic intracranial hemorrhage. METHODS: Patients of 8 MR CLEAN (Multicenter Randomized Controlled Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) Registry centers, with available data on SBP in the 6 hours following EVT, were analyzed. We evaluated maximum, minimum, and mean SBP. Study outcomes were functional outcome (modified Rankin Scale) at 90 days and symptomatic intracranial hemorrhage. We used multivariable ordinal and binary regression analysis to adjust for important prognostic factors and studied possible effect modification by successful reperfusion. RESULTS: Post-EVT SBP data were available for 1161/1796 patients. Higher maximum SBP (per 10 mmHg increments) was associated with worse functional outcome (adjusted common odds ratio, 0.93 [95% CI, 0.88–0.98]) and a higher rate of symptomatic intracranial hemorrhage (adjusted odds ratio, 1.17 [95% CI, 1.02–1.36]). The association between minimum SBP and functional outcome was nonlinear with an inflection point at 124 mmHg. Minimum SBP lower and higher than the inflection point were associated with worse functional outcomes (adjusted common odds ratio, 0.85 per 10 mmHg decrements [95% CI, 0.76–0.95] and adjusted common odds ratio, 0.81 per 10 mmHg increments [95% CI, 0.71–0.92]). No association between mean SBP and functional outcome was observed. Successful reperfusion did not modify the relation of SBP with any of the outcomes. CONCLUSIONS: Maximum SBP in the first 6 hours following EVT is positively associated with worse functional outcome and an increased risk of symptomatic intracranial hemorrhage. Both lower and higher minimum SBP are associated with worse outcomes. A randomized trial to evaluate whether modifying post-intervention SBP results in better outcomes after EVT for ischemic stroke seems justified