Clinical Outcome After Endovascular Treatment in Patients With Active Cancer and Ischemic Stroke: A MR CLEAN Registry Substudy

Objective:To explore clinical and safety outcomes of patients with acute ischemic stroke (AIS) and active cancer after endovascular treatment (EVT).Methods:Using data from the MR CLEAN Registry, we compared patients with active cancer (defined as cancer diagnosed within 12 months prior to stroke, metastatic disease, or current cancer treatment) to patients without cancer. Outcomes were 90-day modified Rankin Scale (mRS) score, mortality, successful reperfusion (eTICI scores≥2b), symptomatic intracranial hemorrhage (sICH), and recurrent stroke. Subgroup analyses were performed in patients with a pre-stroke mRS score of 0 or 1 and according to treatment setting (curative or palliative). Analyses were adjusted for prognostic variables.Results:Of 2583 patients who underwent EVT, 124 (4.8%) had active cancer. They more often had pre-stroke disability (mRS≥2: 34.1% vs. 16.6%). The treatment setting was palliative in 25.3% of the patients. There was a shift towards worse functional outcome at 90 days in patients with active cancer (adjusted common OR 2.2, 95% CI 1.5-3.2). At 90 days, patients with active cancer were less often independent (mRS 0-2: 22.6% vs. 42.0%, aOR 0.5, 95% CI 0.3-0.8), and more often dead (52.2% vs. 26.5%, aOR 3.2, 95% CI 2.1-4.9). Successful reperfusion (67.8% vs. 60.5%, aOR 1.4, 95% CI 1.0-2.1) and sICH rates (6.5% vs. 5.9%, aOR 1.1, 95 %CI 0.5-2.3) did not differ. Recurrent stroke within 90 days was more common in patients with active cancer (4.0% vs. 1.3%, aOR 3.1, 95% CI 1.2-8.1). The sensitivity analysis of patients with a pre-stroke mRS of 0 or 1 showed that patients with active cancer still had a worse outcome at 90 days (acOR 1.9, 95% CI 1.2-3.0). Patients with active cancer in a palliative treatment setting regained functional independence less often compared to patients in a curative setting (18.2% vs. 32.1%) and mortality was also higher (81.8% vs. 39.3%).Conclusions:Despite similar technical success, patients with active cancer had significantly worse outcomes after EVT for AIS. Moreover, they had an increased risk of recurrent stroke. Nevertheless, about a quarter of the patients regained functional independence and the risk of other complications, most notably sICH, was not increased.Classification of Evidence:This study provides Class I evidence that patients with active cancer undergoing EVT for AIS have worse functional outcomes at 90 days compared to those without active cancer.

Hospital Variation in Time to Endovascular Treatment for Ischemic Stroke: What Is the Optimal Target for Improvement?

Background Time to reperfusion in patients with ischemic stroke is strongly associated with functional outcome and may differ between hospitals and between patients within hospitals. Improvement in time to reperfusion can be guided by between‐hospital and within‐hospital comparisons and requires insight in specific targets for improvement. We aimed to quantify the variation in door‐to‐reperfusion time between and within Dutch intervention hospitals and to assess the contribution of different time intervals to this variation. Methods and Results We used data from the MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) Registry. The door‐to‐reperfusion time was subdivided into time intervals, separately for direct patients (door‐to‐computed tomography, computed tomography‐to‐computed tomography angiography [CTA], CTA‐to‐groin, and groin‐to‐reperfusion times) and for transferred patients (door‐to‐groin and groin‐to‐reperfusion times). We used linear mixed models to distinguish the variation in door‐to‐reperfusion time between hospitals and between patients. The proportional change in variance was used to estimate the amount of variance explained by each time interval. We included 2855 patients of 17 hospitals providing endovascular treatment. Of these patients, 44% arrived directly at an endovascular treatment hospital. The between‐hospital variation in door‐to‐reperfusion time was 9%, and the within‐hospital variation was 91%. The contribution of case‐mix variables on the variation in door‐to‐reperfusion time was marginal (2%–7%). Of the between‐hospital variation, CTA‐to‐groin time explained 83%, whereas groin‐to‐reperfusion time explained 15%. Within‐hospital variation was mostly explained by CTA‐to‐groin time (33%) and groin‐to‐reperfusion time (42%). Similar results were found for transferred patients. Conclusions Door‐to‐reperfusion time varies between, but even more within, hospitals providing endovascular treatment for ischemic stroke. Quality of stroke care improvements should not only be guided by between‐hospital comparisons, but also aim to reduce variation between patients within a hospital, and should specifically focus on CTA‐to‐groin time and groin‐to‐reperfusion time.

Mehanička trombektomija – nova metoda liječenja akutnog ishemijskog moždanog udara

U zadnjem desetljeću paradigma liječenja akutnog ishemijskog moždanog udara značajno je promijenjena. Za razliku od nekadašnjeg pasivnog pristupa koji je podrazumijevao medikamentoznu terapiju i medicinsko praćenje, danas se primjenjuje aktivno liječenje koje uključuje intravensku trombolizu i mehaničku trombektomiju. Mehanička trombektomija počela se provoditi početkom ovog stoljeća, no značajan procvat metode započeo je objavom nekoliko multicentričnih randomiziranih studija (MR CLEAN, ESCAPE, SWIFT PRIME, REVASCAT, THRACE, PISTE) koje su 2015. godine potvrdile dobrobit ove metode liječenja. Danas je dokazano da je mehanička trombektomija povoljna i poželjna metoda liječenja bolesnika s akutnim ishemijskim moždanim udarom. Razvoj novih dijagnostičkih uređaja i standardizacija protokola snimanja omogućila je objektivniju procjenu stupnja oštećenja parenhima mozga, što je izravno utjecalo na odluku o daljnjem liječenju. Danas je postupak mehaničke trombektomije moguće provesti unutar 24 sata od nastupa simptoma, što su potvrdile i multicentrične randomizirane studije, DAWN i DEFUSE 3. Svakodnevni napredak mehaničke trombektomije doveo je do liječenja i distalnijih okluzija, poput M2 i M3 segmenta srednje moždane arterije i proksimalnih okluzija anteriorne i posteriorne moždane cirkulacije. Istovremeno je neurointervencijski tim postao veoma važna karika u lancu liječenja bolesnika s moždanim udarom. Nedavnom implementacijom mehaničke trombektomije u standardan protokol liječenja bolesnika s akutnim ishemijskim moždanim udarom u sve kliničke bolničke centre u Republici Hrvatskoj, bolesnicima koji borave u Republici Hrvatskoj omogućeno je liječenje najsuvremenijom metodom, sukladno najnovijim smjernicama.

Study Criteria Applied to Real Life—A Multicenter Analysis of Stroke Patients Undergoing Endovascular Treatment in Clinical Practice

Background Randomized controlled clinical trials (RCT) have demonstrated the efficacy of endovascular treatment in anterior circulation large vessel occlusions. However, outcome of patients treated in daily practice differs from the results of the clinical trials. We hypothesize that this is attributable to the study criteria and that application of the criteria on patients undergoing endovascular therapy in daily routine would improve their outcome. Methods and Results Data from a multicenter prospective registry of GSR‐ET (German Stroke Registry – Endovascular Treatment) was used. Inclusion criteria and selectivity of SWIFT‐PRIME (Solitaire with the Intention for Thrombectomy as Primary Endovascular Treatment trial), MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands trial), ESCAPE (Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion with Emphasis on Minimizing CT to Recanalization Times trial), DAWN (DWI or CTP Assessment with Clinical Mismatch in the Triage of Wake‐Up and Late Presenting Strokes Undergoing Neurointervention with Trevo trial) and DEFUSE‐3 (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke trial) trials were analyzed. Baseline characteristics, procedural and outcome data of patients from GSR‐ET before and after selection were compared with the results of the RCTs. Furthermore, outcome of patients who underwent endovascular treatment despite not fulfilling the RCT criteria was analyzed. A total of 2611 patients were included (median age, 75 years; 49.6% women; median National Institute of Health Stroke Scale, 16). A minority of patients met all inclusion criteria, ranging from 3% (DEFUSE‐3 criteria) to 35% (MR CLEAN criteria). Of the patients fulfilling the MR CLEAN criteria, 41% of patients had a good clinical outcome, compared with 34% of patients that did not fulfill MR CLEAN criteria. Conclusions The RCTs represent a selected population with higher rates of good clinical outcome compared with daily practice. The good outcomes of RCTs can be reproduced in clinical routine in patients who fulfill the RCT inclusion criteria. Furthermore, patients who did not meet the criteria of the RCT still had substantial rates of good clinical outcome.

Brain atrophy and endovascular treatment effect in acute ischemic stroke: a secondary analysis of the MR CLEAN trial

Background Brain atrophy is suggested to impair the potential for functional recovery after acute ischemic stroke. We assessed whether the effect of endovascular treatment is modified by brain atrophy in patients with acute ischemic stroke due to large vessel occlusion. Methods We used data from MR CLEAN, a multicenter trial including patients with acute ischemic stroke due to anterior circulation large vessel occlusion randomized to endovascular treatment plus medical care (intervention) versus medical care alone (control). We segmented total brain volume (TBV) and intracranial volume (ICV) on baseline non-contrast computed tomography (n = 410). Next, we determined the degree of atrophy as the proportion of brain volume in relation to head size (1 − TBV/ICV) × 100%, analyzed as continuous variable and in tertiles. The primary outcome was a shift towards better functional outcome on the modified Rankin Scale expressed as adjusted common odds ratio. Treatment effect modification was tested using an interaction term between brain atrophy (as continuous variable) and treatment allocation. Results We found that brain atrophy significantly modified the effect of endovascular treatment on functional outcome (P for interaction = 0.04). Endovascular treatment led to larger shifts towards better functional outcome in the higher compared to the lower range of atrophy (adjusted common odds ratio, 1.86 [95% CI: 0.97–3.56] in the lowest tertile vs. 1.97 [95% CI: 1.03–3.74] in the middle tertile vs. 3.15 [95% CI: 1.59–6.24] in the highest tertile). Conclusion Benefit of endovascular treatment is larger in the higher compared to the lower range of atrophy, demonstrating that advanced atrophy should not be used as an argument to withhold endovascular treatment.

Added Value of a Blinded Outcome Adjudication Committee in an Open-Label Randomized Stroke Trial

Background and Purpose: Blinded outcome assessment in trials with prospective randomized open blinded end point design is challenging. Unblinding can result in misclassified outcomes and biased treatment effect estimates. An outcome adjudication committee assures blinded outcome assessment, but the added value for trials with prospective randomized open blinded end point design and subjective outcomes is unknown. We aimed to assess the degree of misclassification of modified Rankin Scale (mRS) scores by a central assessor and its impact on treatment effect estimates in a stroke trial with prospective randomized open blinded end point design. Methods: We used data from the MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands). The primary outcome was the mRS at 90 days. Standardized, algorithm-based telephone interviews to assess the mRS were conducted from a central location by an experienced research nurse, unaware but not formally blinded to treatment allocation (central assessor). Masked reports of these interviews were adjudicated by a blinded outcome committee. Misclassification was defined as an incorrect classification of the mRS by the central assessor. The effect of endovascular treatment on the mRS was assessed with multivariable ordinal logistic regression. Results: In MR CLEAN, 53/500 (10.6%) of the mRS scores were misclassified. The degree and direction of misclassification did not differ between treatment arms ( P =0.59). Benefit of endovascular treatment was shown on the mRS when scored by the central assessor (adjusted common odds ratio, 1.60 [95% CI, 1.16–2.21]) and the outcome adjudication committee (adjusted common odds ratio, 1.67 [95% CI, 1.21–2.20]). Conclusions: Misclassification by the central assessor was small, randomly distributed over treatment arms, and did not affect treatment effect estimates. This study suggests that the added value of a blinded outcome adjudication committee is limited in a stroke trial with prospective randomized open blinded end point design applying standardized, algorithm-based outcome assessment by a central assessor, who is unaware but not formally blinded to treatment allocation. REGISTRATION: URL: https://www.isrctn.com ; Unique identifier: ISRCTN10888758.

Diagnostic performance of an algorithm for automated large vessel occlusion detection on CT angiography

BackgroundMachine learning algorithms hold the potential to contribute to fast and accurate detection of large vessel occlusion (LVO) in patients with suspected acute ischemic stroke. We assessed the diagnostic performance of an automated LVO detection algorithm on CT angiography (CTA).MethodsData from the MR CLEAN Registry and PRESTO were used including patients with and without LVO. CTA data were analyzed by the algorithm for detection and localization of LVO (intracranial internal carotid artery (ICA)/ICA terminus (ICA-T), M1, or M2). Assessments done by expert neuroradiologists were used as reference. Diagnostic performance was assessed for detection of LVO and per occlusion location by means of sensitivity, specificity, and area under the curve (AUC).ResultsWe analyzed CTAs of 1110 patients from the MR CLEAN Registry (median age (IQR) 71 years (60–80); 584 men; 1110 with LVO) and of 646 patients from PRESTO (median age (IQR) 73 years (62–82); 358 men; 141 with and 505 without LVO). For detection of LVO, the algorithm yielded a sensitivity of 89% in the MR CLEAN Registry and a sensitivity of 72%, specificity of 78%, and AUC of 0.75 in PRESTO. Sensitivity per occlusion location was 88% for ICA/ICA-T, 94% for M1, and 72% for M2 occlusion in the MR CLEAN Registry, and 80% for ICA/ICA-T, 95% for M1, and 49% for M2 occlusion in PRESTO.ConclusionThe algorithm provided a high detection rate for proximal LVO, but performance varied significantly by occlusion location. Detection of M2 occlusion needs further improvement.

The Role of Edema in Subacute Lesion Progression After Treatment of Acute Ischemic Stroke

Background: Ischemic lesions commonly continue to progress even days after treatment, and this lesion growth is associated with unfavorable functional outcome in acute ischemic stroke patients. The aim of this study is to elucidate the role of edema in subacute lesion progression and its influence on unfavorable functional outcome by quantifying net water uptake.Methods: We included all 187 patients from the MR CLEAN trial who had high quality follow-up non-contrast CT at 24 h and 1 week. Using a CT densitometry-based method to calculate the net water uptake, we differentiated total ischemic lesion volume (TILV) into edema volume (EV) and edema-corrected infarct volume (ecIV). We calculated these volumes at 24 h and 1 week after stroke and determined their progression in the subacute period. We assessed the effect of 24-h lesion characteristics on EV and ecIV progression. We evaluated the influence of edema and edema-corrected infarct progression on favorable functional outcome after 90 days (modified Rankin Scale: 0–2) after correcting for potential confounders. Lastly, we compared these volumes between subgroups of patients with and without successful recanalization using the Mann–Whitney U-test.Results: Median TILV increased from 37 (IQR: 18–81) ml to 68 (IQR: 30–130) ml between 24 h and 1 week after stroke, while the net water uptake increased from 22 (IQR: 16–26)% to 27 (IQR: 22–32)%. The TILV progression of 20 (8.8–40) ml was mostly caused by ecIV with a median increase of 12 (2.4–21) ml vs. 6.5 (2.7–15) ml of EV progression. Larger TILV, EV, and ecIV volumes at 24 h were all associated with more edema and lesion progression. Edema progression was associated with unfavorable functional outcome [aOR: 0.53 (0.28–0.94) per 10 ml; p-value: 0.05], while edema-corrected infarct progression showed a similar, non-significant association [aOR: 0.80 (0.62–0.99); p-value: 0.06]. Lastly, edema progression was larger in patients without successful recanalization, whereas ecIV progression was comparable between the subgroups.Conclusion: EV increases in evolving ischemic lesions in the period between 1 day and 1 week after acute ischemic stroke. This progression is larger in patients without successful recanalization and is associated with unfavorable functional outcome. However, the extent of edema cannot explain the total expansion of ischemic lesions since edema-corrected infarct progression is larger than the edema progression.