Intracranial Carotid Artery Calcification and Effect of Endovascular Stroke Treatment

Background and Purpose- Previous studies suggest that intracranial carotid artery calcification (ICAC) volume might influence the clinical outcome of patients after endovascular treatment (EVT) for acute ischemic stroke. Importantly, ICAC can be subtyped into a medial or intimal pattern that may differentially influence the effect of EVT in patients with acute ischemic stroke. Methods- All 500 patients included in the MR CLEAN (Multicenter Randomized Clinical trial of Endovascular treatment for acute ischemic stroke in the Netherlands) were evaluated. Volume (mm3) and location pattern (tunica intima or tunica media) of ICAC could be determined on baseline noncontrast computed tomography in 344 patients. Functional outcome at 90 days was assessed with the modified Rankin Scale. Next, we investigated the association of ICAC volume and pattern with functional outcome using adjusted ordinal logistic regression models. Effect modification by EVT was assessed with an interaction term between treatment allocation and ICAC aspect. Results- We found evidence for treatment effect modification by ICAC pattern ( P interaction=0.04). Patients with predominantly medial calcification had better functional outcome with EVT than without this treatment (adjusted common odds ratio, 2.32; 95% CI, 1.23-4.39), but we observed no effect of EVT in patients with predominantly intimal calcifications (adjusted common odds ratio, 0.82; 95% CI, 0.40-1.68). We did not find an association of ICAC volume with functional outcome (adjusted common odds ratio per unit increase ICAC volume 1.01 (95% CI, 0.89-1.13). Moreover, we found no evidence for effect modification by ICAC volume ( P interaction=0.61). Conclusions- The benefit of EVT in acute ischemic stroke patients with a medial calcification pattern is larger than the benefit in patients with an intimal calcification pattern. Clinical Trial Registration- URL: http://www.trialregister.nl . Unique identifier: NTR1804. URL: http://www.isrctn.com . Unique identifier: ISRCTN10888758

Observer variability of absolute and relative thrombus density measurements in patients with acute ischemic stroke

Introduction: Thrombus density may be a predictor for acute ischemic stroke treatment success. However, only limited data on observer variability for thrombus density measurements exist. This study assesses the variability and bias of four common thrombus density measurement methods by expert and non-expert observers. Methods: For 132 consecutive patients with acute ischemic stroke, three experts and two trained observers determined thrombus density by placing three standardized regions of interest (ROIs) in the thrombus and corresponding contralateral arterial segment. Subsequently, absolute and relative thrombus densities were determined using either one or three ROIs. Intraclass correlation coefficient (ICC) was determined, and Bland–Altman analysis was performed to evaluate interobserver and intermethod agreement. Accuracy of the trained observer was evaluated with a reference expert observer using the same statistical analysis. Results: The highest interobserver agreement was obtained for absolute thrombus measurements using three ROIs (ICCs ranging from 0.54 to 0.91). In general, interobserver agreement was lower for relative measurements, and for using one instead of three ROIs. Interobserver agreement of trained non-experts and experts was similar. Accuracy of the trained observer measurements was comparable to the expert interobserver agreement and was better for absolute measurements and with three ROIs. The agreement between the one ROI and three ROI methods was good. Conclusion: Absolute thrombus density measurement has superior interobserver agreement compared to relative density measurement. Interobserver variation is smaller when multiple ROIs are used. Trained non-expert observers can accurately and reproducibly assess absolute thrombus densities using three ROIs

Penumbral imaging and functional outcome in patients with anterior circulation ischaemic stroke treated with endovascular thrombectomy versus medical therapy: a meta-analysis of individual patient-level data

Background: CT perfusion (CTP) and diffusion or perfusion MRI might assist patient selection for endovascular thrombectomy. We aimed to establish whether imaging assessments of irreversibly injured ischaemic core and potentially salvageable penumbra volumes were associated with functional outcome and whether they interacted with the treatment effect of endovascular thrombectomy on functional outcome. Methods: In this systematic review and meta-analysis, the HERMES collaboration pooled patient-level data from all randomised controlled trials that compared endovascular thrombectomy (predominantly using stent retrievers) with standard medical therapy in patients with anterior circulation ischaemic stroke, published in PubMed from Jan 1, 2010, to May 31, 2017. The primary endpoint was functional outcome, assessed by the modified Rankin Scale (mRS) at 90 days after stroke. Ischaemic core was estimated, before treatment with either endovascular thrombectomy or standard medical therapy, by CTP as relative cerebral blood flow less than 30% of normal brain blood flow or by MRI as an apparent diffusion coefficient less than 620 μm2/s. Critically hypoperfused tissue was estimated as the volume of tissue with a CTP time to maximum longer than 6 s. Mismatch volume (ie, the estimated penumbral volume) was calculated as critically hypoperfused tissue volume minus ischaemic core volume. The association of ischaemic core and penumbral volumes with 90-day mRS score was analysed with multivariable logistic regression (functional independence, defined as mRS score 0–2) and ordinal logistic regression (functional improvement by at least one mRS category) in all patients and in a subset of those with more than 50% endovascular reperfusion, adjusted for baseline prognostic variables. The meta-analysis was prospectively designed by the HERMES executive committee, but not registered. Findings: We identified seven studies with 1764 patients, all of which were included in the meta-analysis. CTP was available and assessable for 591 (34%) patients and diffusion MRI for 309 (18%) patients. Functional independence was worse in patients who had CTP versus those who had diffusion MRI, after adjustment for ischaemic core volume (odds ratio [OR] 0·47 [95% CI 0·30–0·72], p=0·0007), so the imaging modalities were not pooled. Increasing ischaemic core volume was associated with reduced likelihood of functional independence (CTP OR 0·77 [0·69–0·86] per 10 mL, pinteraction=0·29; diffusion MRI OR 0·87 [0·81–0·94] per 10 mL, pinteraction=0·94). Mismatch volume, examined only in the CTP group because of the small numbers of patients who had perfusion MRI, was not associated with either functional independence or functional improvement. In patients with CTP with more than 50% endovascular reperfusion (n=186), age, ischaemic core volume, and imaging-to-reperfusion time were independently associated with functional improvement. Risk of bias between studies was generally low. Interpretation: Estimated ischaemic core volume was independently associated with functional independence and functional improvement but did not modify the treatment benefit of endovascular thrombectomy over standard medical therapy for improved functional outcome. Combining ischaemic core volume with age and expected imaging-to-reperfusion time will improve assessment of prognosis and might inform endovascular thrombectomy treatment decisions. Funding: Medtronic

Automated entire thrombus density measurements for robust and comprehensive thrombus characterization in patients with acute ischemic stroke

Background and Purpose: In acute ischemic stroke (AIS) management, CT-based thrombus density has been associated with treatment success. However, currently used thrombus measurements are prone to inter-observer variability and oversimplify the heterogeneous thrombus composition. Our aim was first to introduce an automated method to assess the entire thrombus density and then to compare the measured entire thrombus density with respect to current standard manual measurements. Materials and Method: In 135 AIS patients, the density distribution of the entire thrombus was determined. Density distributions were described usingmedians, interquartile ranges (IQR), kurtosis, and skewedness. Differences between themedian of entire thrombusmeasurements and commonly applied manualmeasurements using 3 regions of interest were determined using linear regression. Results: Density distributions varied considerably with medians ranging from 20.0 to 62.8 HU and IQRs ranging from 9.3 to 55.8 HU. The average median of the thrombus density distributions (43.5 ± 10.2 HU) was lower than the manual assessment (49.6 ± 8.0 HU) (p<0.05). The difference between manual measurements and median density of entire thrombus decreased with increasing density (r = 0.64; p<0.05), revealing relatively higher manual measurements for low density thrombi such that manual density measurement tend overestimates the real thrombus density. Conclusions: Automatic measurements of the full thrombus expose a wide variety of thrombi density distribution, which is not grasped with currently used manual measurement. Furthermore, d

Two-year clinical follow-up of the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in The Netherlands (MR CLEAN): Design and statistical analysis plan of the extended follow-up study

Background: MR CLEAN was the first randomized trial to demonstrate the short-term clinical effectiveness of endovascular treatment in patients with acute ischemic stroke caused by large vessel occlusion in the anterior circulation. Several other trials confirmed that endovascular treatment improves clinical outcome at three months. However, limited data are available on long-term clinical outcome. We aimed to estimate the effect of endovascular treatment on functional outcome at two-year follow-up in patients with acute ischemic stroke. Secondly, we aimed to assess the effect of endovascular treatment on major vascular events and mortality during two years of follow-up. Methods: MR CLEAN is a multicenter clinical trial with randomized treatment allocation, open-label treatment, and blinded endpoint evaluation. Patients included were 18 years or older with acute ischemic stroke caused by a proven anterior proximal artery occlusion who could be treated within six hours after stroke onset. The intervention contrast was endovascular treatment and usual care versus no endovascular treatment and usual care. The current study extended the follow-up duration from three months to two years. The primary outcome is the score on the modified Rankin scale at two years. Secondary outcomes include all-cause mortality and the occurrence of major vascular events within two years of follow-up. Discussion: The results of our study provide information on the long-term clinical effectiveness of endovascular treatment, which may have implications for individual treatment decisions and estimates of cost-effectiveness. Trial registration:NTR1804. Registered on 7 May 2009; ISRCTN10888758. Registered on 24 July 2012 (main MR CLEAN trial); NTR5073. Registered on 26 February 2015 (extended follow-up study)

The effect of age on outcome after intraarterial treatment in acute ischemic stroke: a MR CLEAN pretrial study

Background: In recent randomized controlled trials (RCTs) intra-arterial treatment (IAT) has been proven effective and safe for patients with acute ischemic stroke (AIS). So far, there seemed to be no interaction between older age (>80) and main treatment effect. We studied the association of older age with outcome and adverse events after IAT in a cohort of intra arterially treated patients. Methods and findings: Data from all AIS patients with proven proximal anterior circulation cerebral artery occlusion who were intra arterially treated between 2002 until the start of the MR CLEAN trial were studied retrospectively. Duration of the procedure, recanalization (Thrombolysis In Cerebral Infarction score (TICI)), early neurological recovery (i.e. decrease on NIHSS of ≥ 8 points) after one week or at discharge, good functional outcome at discharge by modified Rankin Scale (mRS ≤ 2) and the occurrence of neurological and non-neurological adverse events were assessed and the association with age was investigated. In total 315 patients met our inclusion criteria. Median age was 63 years (range 22-93) and 17 patients (5.4 %) were over 80. Age was inversely associated with good functional outcome (adjusted Odds Ratio (aOR) 0.80, 95 % CI: 0.66-0.98) for every 10 years increase of age. Age was not associated with longer duration of the procedure, lower recanalization rate or less early neurological recovery. The risk of all adverse events (aOR 1.27; 95 % CI: 1.08-1.50) and non-neurological adverse events (aOR 1.34; 95 % CI: 1.11-1.61) increased, but that of peri-procedural adverse events (aOR 0.79; 95 % CI: 0.66-0.94) decreased with age. Conclusion: Higher age is inversely associated with good functional outcome after IAT in

The effect of age on outcome after intra-arterial treatment in acute ischemic stroke : A MR CLEAN pretrial study

Background: In recent randomized controlled trials (RCTs) intra-arterial treatment (IAT) has been proven effective and safe for patients with acute ischemic stroke (AIS). So far, there seemed to be no interaction between older age (>80) and main treatment effect. We studied the association of older age with outcome and adverse events after IAT in a cohort of intra arterially treated patients. Methods and findings: Data from all AIS patients with proven proximal anterior circulation cerebral artery occlusion who were intra arterially treated between 2002 until the start of the MR CLEAN trial were studied retrospectively. Duration of the procedure, recanalization (Thrombolysis In Cerebral Infarction score (TICI)), early neurological recovery (i.e. decrease on NIHSS of ≥ 8 points) after one week or at discharge, good functional outcome at discharge by modified Rankin Scale (mRS ≤ 2) and the occurrence of neurological and non-neurological adverse events were assessed and the association with age was investigated. In total 315 patients met our inclusion criteria. Median age was 63 years (range 22-93) and 17 patients (5.4 %) were over 80. Age was inversely associated with good functional outcome (adjusted Odds Ratio (aOR) 0.80, 95 % CI: 0.66-0.98) for every 10 years increase of age. Age was not associated with longer duration of the procedure, lower recanalization rate or less early neurological recovery. The risk of all adverse events (aOR 1.27; 95 % CI: 1.08-1.50) and non-neurological adverse events (aOR 1.34; 95 % CI: 1.11-1.61) increased, but that of peri-procedural adverse events (aOR 0.79; 95 % CI: 0.66-0.94) decreased with age. Conclusion: Higher age is inversely associated with good functional outcome after IAT in patients with AIS. However, treatment related adverse events are not related to age. These findings may help decision making when considering treatment of older patients with AIS

Intracranial Carotid Artery Calcification and Effect of Endovascular Stroke Treatment: MR CLEAN Subgroup Analysis

Background and Purpose-Previous studies suggest that intracranial carotid artery calcification (ICAC) volume might influence the clinical outcome of patients after endovascular treatment (EVT) for acute ischemic stroke. Importantly, ICAC can be subtyped into a medial or intimal pattern that may differentially influence the effect of EVT in patients with acute ischemic stroke. Methods-All 500 patients included in the MR CLEAN (Multicenter Randomized Clinical trial of Endovascular treatment for acute ischemic stroke in the Netherlands) were evaluated. Volume (mm(3)) and location pattern (tunica intima or tunica media) of ICAC could be determined on baseline noncontrast computed tomography in 344 patients. Functional outcome at 90 days was assessed with the modified Rankin Scale. Next, we investigated the association of ICAC volume and pattern with functional outcome using adjusted ordinal logistic regression models. Effect modification by EVT was assessed with an interaction term between treatment allocation and ICAC aspect. Results-We found evidence for treatment effect modification by ICAC pattern (P interaction=0.04). Patients with predominantly medial calcification had better functional outcome with EVT than without this treatment (adjusted common odds ratio, 2.32; 95% CI, 1.23-4.39), but we observed no effect of EVT in patients with predominantly intimal calcifications (adjusted common odds ratio, 0.82; 95% CI, 0.40-1.68). We did not find an association of ICAC volume with functional outcome (adjusted common odds ratio per unit increase ICAC volume 1.01 (95% CI, 0.89-1.13). Moreover, we found no evidence for effect modification by ICAC volume (P interaction=0.61). Conclusions-The benefit of EVT in acute ischemic stroke patients with a medial calcification pattern is larger than the benefit in patients with an intimal calcification pattern

Type of Anesthesia and Differences in Clinical Outcome After Intra-Arterial Treatment for Ischemic Stroke

Intra-arterial treatment (IAT) in patients with acute ischemic stroke (AIS) can be performed with or without general anesthesia (GA). Previous studies suggested that IAT without the use of GA (non-GA) is associated with better clinical outcome. Nevertheless, no consensus exists about the anesthetic management during IAT of AIS patients. This study investigates the association between type of anesthesia and clinical outcome in a large cohort of patients with AIS treated with IAT. All consecutive patients with AIS of the anterior circulation who received IAT between 2002 and 2013 in 16 Dutch hospitals were included in the study. Primary outcome was functional outcome on the modified Rankin Scale at discharge. Difference in primary outcome between GA and non-GA was estimated using multiple ordinal regression analysis, adjusting for age, stroke severity, occlusion of the internal carotid artery terminus, previous stroke, atrial fibrillation, and diabetes mellitus. Three hundred forty-eight patients were included in the analysis; 70 patients received GA and 278 patients did not receive GA. Non-GA was significantly associated with good clinical outcome (odds ratio 2.1, 95% confidence interval 1.02-4.31). After adjusting for prespecified prognostic factors, the point estimate remained similar; statistical significance, however, was lost (odds ratio 1.9, 95% confidence interval 0.89-4.24). Our study suggests that patients with AIS of the anterior circulation undergoing IAT without GA have a higher probability of good clinical outcome compared with patients treated with general anesthesi