Value of thrombus CT Characteristics in Patients with Acute Ischemic Stroke

BACKGROUND AND PURPOSE: Thrombus CT characteristics might be useful for patient selection for intra-arterial treatment. Our objective was to study the association of thrombus CT characteristics with outcome and treatment effect in patients with acute ischemic stroke. MATERIALS AND METHODS: We included 199 patients for whom thin-section NCCT and CTA within 30 minutes from each other were available in the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute ischemic stroke in the Netherlands (MR CLEAN) study. We assessed the following thrombus characteristics: location, distance from ICA terminus to thrombus, length, volume, absolute and relative density

A replication study of genetic risk loci for ischemic stroke in a Dutch population: A case-control study

We aimed to replicate reported associations of 10 SNPs at eight distinct loci with overall ischemic stroke (IS) and its subtypes in an independent cohort of Dutch IS patients. We included 1,375 IS patients enrolled in a prospective multicenter hospital-based cohort in the Netherlands, and 1,533 population-level controls of Dutch descent. We tested these SNPs for association with overall IS and its subtypes (large artery atherosclerosis, small vessel disease and cardioembolic stroke (CE), as classified by TOAST) using an additive multivariable logistic regression model, adjusting for age and sex. We obtained odds ratios (OR) with 95% confidence intervals (95% CI) for the risk allele of each SNP analyzed and exact p-values by permutation. We confirmed the association at 4q25 (PITX2) (OR 1.43; 95% CI, 1.13-1.81, p = 0.029) and 16q22 (ZFHX3) (OR 1.62; 95% CI, 1.26-2.07, p = 0.001) as risk loci for CE. Locus 16q22 was also associated with overall IS (OR 1.24; 95% CI, 1.08-1.42, p = 0.016). Other loci previously associated with IS and/or its subtypes were not confirmed. In conclusion, we validated two loci (4q25, 16q22) associated with CE. In addition, our study may suggest that the association of locus 16q22 may not be limited to CE, but also includes overall IS

Follow-up infarct volume as a mediator of endovascular treatment effect on functional outcome in ischaemic stroke

Objective: The putative mechanism for the favourable effect of endovascular treatment (EVT) on functional outcome after acute ischaemic stroke is preventing follow-up infarct volume (FIV) progression. We aimed to assess to what extent difference in FIV explains the effect of EVT on functional outcome in a randomised trial of EVT versus no EVT (MR CLEAN). Methods: FIV was assessed on non-contrast CT scan 5–7 days after stroke. Functional outcome was the score on the modified Rankin Scale at 3 months. We tested the causal pathway from intervention, via FIV to functional outcome with a mediation model, using linear and ordinal regression, adjusted for relevant baseline covariates, including stroke severity. Explained effect was assessed by taking the ratio of the log odds ratios of treatment with and without adjustment for FIV. Results: Of the 500 patients included in MR CLEAN, 60 died and four patients underwent hemicraniectomy before FIV was assessed, leaving 436 patients for analysis. Patients in the intervention group had better functional outcomes (adjusted common odds ratio (acOR) 2.30 (95% CI 1.62–3.26) than controls and smaller FIV (median 53 vs. 81 ml) (difference 28 ml; 95% CI 13–41). Smaller FIV was associated with better outcome (acOR per 10 ml 0.60, 95% CI 0.52–0.68). After adjustment for FIV the effect of intervention on functional outcome decreased but remained substantial (acOR 2.05, 95% CI 1.44–2.91). This implies that preventing FIV progression explains 14% (95% CI 0–34) of the beneficial effect of EVT on outcome. Conclusion: The effect of EVT on FIV explains only part of the treatment effect on functional outcome. Key Points: • Endovascular treatment in acute ischaemic stroke patients prevents progression of follow-up infarct volume on non-contrast CT at 5–7 days.• Follow-up infarct volume was related to functional outcome, but only explained a modest part of the effect of intervention on functional outcome.• A large proportion of treatment effect on functional outcome remains unexplained, suggesting FIV alone cannot be used as an early surrogate imaging marker of functional outcome

Repeated Endovascular Thrombectomy in Patients With Acute Ischemic Stroke: Results From a Nationwide Multicenter Database

Background and Purpose- Patients with acute ischemic stroke treated with endovascular thrombectomy may be treated with repeat endovascular thrombectomy (rEVT) in case of recurrent large vessel occlusion. Data on safety and efficacy of these interventions is scarce. Our aim is to report on frequency, timing, and outcome of rEVT in a large nation-wide multicenter registry. Methods- In the Netherlands, all patients with endovascular thrombectomy have been registered since 2002 (MR CLEAN Pretrial registry, MR CLEAN Trial [Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands], and MR CLEAN Registry). We retrospectively reviewed these databases for anterior circulation rEVT cases. Patient characteristics, procedural data, and functional outcome (modified Rankin Scale at 90 days) were analyzed. Results- Of 3928 patients treated between 2002 and 2017, 27 (0.7%) underwent rEVT. Median time between first and second procedure was 78 (1-1122) days; 11/27 patients were re-treated within 30 days. Cardioembolism was the most common etiology (18 patients [67%]). In 19 patients (70%), recurrent occlusion occurred ipsilateral to previous occlusion. At 90 days after rEVT procedure, 44% of the patients had achieved functional independence (modified Rankin Scale score of 0-2), and 33% had died. Adverse events were 2/27 (7.4%) intracranial hemorrhage, 1/27 (3.7%) stroke progression, and 1/27 (3.7%) pneumonia. Conclusions- In this large nationwide cohort of patients with acute ischemic stroke treated with endovascular thrombectomy, rEVT was rare. Stroke cause was mainly cardio-embolic, and most recurrent large vessel occlusions in which rEVT was performed occurred ipsilateral. Although there probably is a selection bias on repeated treatment in case of recurrent large vessel occlusion, rEVT appears safe, with similar outcome as in single-treated cases

Endovascular Treatment for Acute Ischemic Stroke in Patients on Oral Anticoagulants: Results from the MR CLEAN Registry

Background and Purpose - The use of oral anticoagulants (OAC) is considered a contra-indication for intravenous thrombolytics as acute treatment of ischemic stroke. However, little is known about the risks and benefits of endovascular treatment in patients on prior OAC. We aim to compare outcomes after endovascular treatment between patients with and without prior use of OAC. Methods - Data of patients with acute ischemic stroke caused by an intracranial anterior circulation occlusion, included in the nationwide, prospective, MR CLEAN Registry between March 2014 and November 2017, were analyzed. Outcomes of interest included symptomatic intracranial hemorrhage and functional outcome at 90 days (modified Rankin Scale score). Outcomes between groups were compared with (ordinal) logistic regression analyses, adjusted for prognostic factors. Results - Three thousand one hundred sixty-two patients were included in this study, of whom 502 (16%) used OAC. There was no significant difference in the occurrence of symptomatic intracranial hemorrhage between patients with and without prior OACs (5% versus 6%; adjusted odds ratio, 0.63 [95% CI, 0.38-1.06]). Patients on OACs had worse functional outcomes than patients without OACs (common odds ratio, 0.57 [95% CI, 0.47-0.66]). However, this observed difference in functional outcome disappeared after adjustment for prognostic factors (adjusted common odds ratio, 0.91 [95% CI, 0.74-1.13]). Conclusions - Prior OAC use in patients treated with endovascular treatment for ischemic stroke is not associated with an increased risk of symptomatic intracranial hemorrhage or worse functional outcome compared with no prior OAC use. Therefore, prior OAC use should not be a contra-indication for endovascular treatment

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 Body Mass Index on Outcome after Endovascular Treatment in Acute Ischemic Stroke Patients: A Post Hoc Analysis of the MR

Background: Though obesity is a well-known risk factor for vascular disease, the impact of obesity on stroke outcome has been disputed. Several studies have shown that obesity is associated with better functional outcome after stroke. Whether obesity influences the benefit of endovascular treatment (EVT) in stroke patients is unknown. We evaluated the association between body mass index (BMI) and outcome in acute ischemic stroke patients with large vessel-occlusion (LVO), and assessed whether BMI affects the-benefit of EVT. Methods: This is a post hoc analysis of the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands trial (-ISRCTN10888758). BMI was used as a continuous and categorical variable, distinguishing underweight and normal weight (BMI <25), overweight (BMI 25-30), and obesity (BMI ≥30). We used multivariable ordinal logistic regression analysis to estimate the association of BMI with functional outcome (shift analysis), assessed with modified Rankin Scale (mRs) at 90 days. The impact of BMI on EVT effect was tested by the use of a multiplicative interaction term. Results: Of 366 patients, 160 (44%) were underweight or normal weight, 145 (40%) overweight, and 61 (17%) were obese. In multivariable analysis with BMI as a continuous variable, we found a shift toward better functional outcome with higher BMI (mRS adjusted common OR 1.04; 95% CI 1.0-1.09), and mortality was inversely related to BMI (aOR 0.92; 95% CI 0.85-0.99). Safety analysis showed that higher BMI was associated with lower risk of stroke progression (aOR 0.92, 95% CI 0.87-0.99). Additional analysis showed no interaction between BMI and EVT effect on functional outcome, mortality, and other safety outcomes. Conclusion: Our study confirms the effect of obesity on outcome in acute ischemic stroke patients with LVO, meaning better functional outcome, lower mortality, and lower risk of stroke progression for patients with higher BMI. As we found no interaction between BMI and EVT effect, all BMI classes may expect the same benefit from EVT

Distribution of Cardioembolic Stroke: A Cohort Study

Background: A cardiac origin in ischemic stroke is more frequent than previously assumed, but it is not clear which patients benefit from cardiac work-up if obvious cardiac pathology is absent. We hypothesized that thromboembolic stroke with a cardiac source occurs more frequently in the posterior circulation compared with thromboembolic stroke of another etiology. Methods: We performed a multicenter observational study in 3,311 consecutive patients with ischemic stroke who were enrolled in an ongoing prospective stroke registry of 8 University hospitals between September 2009 and November 2014 in The Netherlands. In thi

National Institutes of Health Stroke Scale: An Alternative Primary Outcome Measure for Trials of Acute Treatment for Ischemic Stroke

Background and Purpose- The modified Rankin Scale (mRS) at 3 months is the most commonly used primary outcome measure in stroke treatment trials, but it lacks specificity and requires long-term follow-up interviews, which consume time and resources. An alternative may be the National Institutes of Health Stroke Scale (NIHSS), early after stroke. Our aim was to evaluate whether the NIHSS assessed within 1 week after treatment could serve as a primary outcome measure for trials of acute treatment for ischemic stroke. Methods- We used data from 2 randomized controlled trials of endovascular treatment for ischemic stroke: the positive MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands; N=500) and the neutral IMS (Interventional Management of Stroke) III trial (N=656). We used a causal mediation model, with linear and ordinal logistic regression adjusted for confounders, to evaluate the NIHSS 24 hours and 5 to 7 days after endovascular treatment as primary outcome measures (instead of the mRS at 3 months) in both trials. Patients who had died before the NIHSS was assessed received the maximum score of 42. NIHSS+1 was then log10-transformed. Results- In both trials, there was a significant correlation between the NIHSS at 24 hours and 5 to 7 days and the mRS. In MR CLEAN, we found a significant effect of endovascular treatment on the mRS and on the NIHSS at 24 hours and 5 to 7 days. After adjustment for NIHSS at 24 hours and 5 to 7 days, the effect of endovascular treatment on the mRS decreased from common odds ratio 1.68 (95% CI, 1.22-2.32) to respectively 1.36 (95% CI, 0.97-1.91) and 1.24 (95% CI, 0.87-1.79), indicating that treatment effect on the mRS is in large part mediated by the NIHSS. In the IMS III trial there was no treatment effect on the NIHSS at 24 hours and 5 to 7 days, corresponding with the absence of a treatment effect on the mRS. Conclusions- The NIHSS within 1 week satisfies the requirements for a surrogate end point and may be used as a primary outcome measure in trials of acute treatment for ischemic stroke, particularly in phase II(b) trials. This could reduce stroke-outcome assessment to its essentials (ie, neurological deficit), and reduce trial duration and costs. Whether and under which conditions it could be used in phase III trials requires a debate in the field with all parties. Clinical Trial Registration- URL: http://www.isrctn.com. Unique identifier: ISRCTN10888758; https://www.clinicaltrials.gov. Unique identifier: NCT00359424