Bijoy K. Menon

Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials

BACKGROUND In 2015, five randomised trials showed efficacy of endovascular thrombectomy over standard medical care in patients with acute ischaemic stroke caused by occlusion of arteries of the proximal anterior circulation. In this meta-analysis we, the trial investigators, aimed to pool individual patient data from these trials to address remaining questions about whether the therapy is efficacious across the diverse populations included. METHODS We formed the HERMES collaboration to pool patient-level data from five trials (MR CLEAN, ESCAPE, REVASCAT, SWIFT PRIME, and EXTEND IA) done between December, 2010, and December, 2014. In these trials, patients with acute ischaemic stroke caused by occlusion of the proximal anterior artery circulation were randomly assigned to receive either endovascular thrombectomy within 12 h of symptom onset or standard care (control), with a primary outcome of reduced disability on the modified Rankin Scale (mRS) at 90 days. By direct access to the study databases, we extracted individual patient data that we used to assess the primary outcome of reduced disability on mRS at 90 days in the pooled population and examine heterogeneity of this treatment effect across prespecified subgroups. To account for between-trial variance we used mixed-effects modelling with random effects for parameters of interest. We then used mixed-effects ordinal logistic regression models to calculate common odds ratios (cOR) for the primary outcome in the whole population (shift analysis) and in subgroups after adjustment for age, sex, baseline stroke severity (National Institutes of Health Stroke Scale score), site of occlusion (internal carotid artery vs M1 segment of middle cerebral artery vs M2 segment of middle cerebral artery), intravenous alteplase (yes vs no), baseline Alberta Stroke Program Early CT score, and time from stroke onset to randomisation. FINDINGS We analysed individual data for 1287 patients (634 assigned to endovascular thrombectomy, 653 assigned to control). Endovascular thrombectomy led to significantly reduced disability at 90 days compared with control (adjusted cOR 2.49, 95% CI 1.76-3.53; p<0.0001). The number needed to treat with endovascular thrombectomy to reduce disability by at least one level on mRS for one patient was 2.6. Subgroup analysis of the primary endpoint showed no heterogeneity of treatment effect across prespecified subgroups for reduced disability (pinteraction=0.43). Effect sizes favouring endovascular thrombectomy over control were present in several strata of special interest, including in patients aged 80 years or older (cOR 3.68, 95% CI 1.95-6.92), those randomised more than 300 min after symptom onset (1.76, 1.05-2.97), and those not eligible for intravenous alteplase (2.43, 1.30-4.55). Mortality at 90 days and risk of parenchymal haematoma and symptomatic intracranial haemorrhage did not differ between populations. INTERPRETATION Endovascular thrombectomy is of benefit to most patients with acute ischaemic stroke caused by occlusion of the proximal anterior circulation, irrespective of patient characteristics or geographical location. These findings will have global implications on structuring systems of care to provide timely treatment to patients with acute ischaemic stroke due to large vessel occlusion. FUNDING Medtronic.

Low Rates of Acute Recanalization With Intravenous Recombinant Tissue Plasminogen Activator in Ischemic Stroke: Real-World Experience and a Call for Action

Background and Purpose— Acute rates of recanalization after intravenous (IV) recombinant tissue plasminogen activator (rt-PA) in proximal vessel occlusion have been estimated sparingly, typically using transcranial Doppler (TCD). We aimed to study acute recanalization rates of IV rt-PA in CT angiogram-proven proximal (internal carotid artery [ICA], M1 middle cerebral artery [MCA], M2-MCA, and basilar artery) occlusions and their effects on outcome. Materials and Methods— The CT angiogram database of the Calgary stroke program was reviewed for the period 2002 to 2009. All patients with proximal vessel occlusions receiving IV rt-PA who were assessed for recanalization by TCD or angiogram (for acute endovascular treatment) were included for analysis. Rates of acute recanalization as observed on TCD/first run of angiogram and postendovascular therapy recanalization rates were noted. Modified Rankin Scale score ≤2 at 3 months was used as a good outcome. Results— Among 1341 patients in the CT angiogram database, 388 patients with proximal occlusion were identified. Of these, 216 patients had received IV rt-PA; 127 patients underwent further imaging to assess recanalization. Among the patients undergoing TCD (n=46) and cerebral angiogram (n=103), only 27 (21.25%) patients had acute recanalization. By occlusion subtype, the rates of recanalization were: distal ICA (with or without ICA neck occlusion or stenotic disease) 1 of 24 (4.4%); M1-MCA (with or without ICA neck occlusion or stenotic disease) 21 of 65 (32.3%); M2-MCA 4 of 13 (30.8%); and basilar artery 1 of 25 (4%). Onset to rt-PA time was comparable in patients with and without recanalization. Recanalization (P<0.0001; risk ratio, 2.7; 95% confidence interval, 1.5–4.6) was the strongest predictor of outcome (adjusted for age and National Institutes of Health Stroke Scale score). Conclusions— A low rate of acute recanalization was observed with IV rt-PA in proximal vessel occlusions identified by baseline CT angiogram. Recanalization was the strongest predictor of good outcome.

Time to Treatment With Endovascular Thrombectomy and Outcomes From Ischemic Stroke: A Meta-analysis

IMPORTANCE Endovascular thrombectomy with second-generation devices is beneficial for patients with ischemic stroke due to intracranial large-vessel occlusions. Delineation of the association of treatment time with outcomes would help to guide implementation. OBJECTIVE To characterize the period in which endovascular thrombectomy is associated with benefit, and the extent to which treatment delay is related to functional outcomes, mortality, and symptomatic intracranial hemorrhage. DESIGN, SETTING, AND PATIENTS Demographic, clinical, and brain imaging data as well as functional and radiologic outcomes were pooled from randomized phase 3 trials involving stent retrievers or other second-generation devices in a peer-reviewed publication (by July 1, 2016). The identified 5 trials enrolled patients at 89 international sites. EXPOSURES Endovascular thrombectomy plus medical therapy vs medical therapy alone; time to treatment. MAIN OUTCOMES AND MEASURES The primary outcome was degree of disability (mRS range, 0-6; lower scores indicating less disability) at 3 months, analyzed with the common odds ratio (cOR) to detect ordinal shift in the distribution of disability over the range of the mRS; secondary outcomes included functional independence at 3 months, mortality by 3 months, and symptomatic hemorrhagic transformation. RESULTS Among all 1287 patients (endovascular thrombectomy + medical therapy [n = 634]; medical therapy alone [n = 653]) enrolled in the 5 trials (mean age, 66.5 years [SD, 13.1]; women, 47.0%), time from symptom onset to randomization was 196 minutes (IQR, 142 to 267). Among the endovascular group, symptom onset to arterial puncture was 238 minutes (IQR, 180 to 302) and symptom onset to reperfusion was 286 minutes (IQR, 215 to 363). At 90 days, the mean mRS score was 2.9 (95% CI, 2.7 to 3.1) in the endovascular group and 3.6 (95% CI, 3.5 to 3.8) in the medical therapy group. The odds of better disability outcomes at 90 days (mRS scale distribution) with the endovascular group declined with longer time from symptom onset to arterial puncture: cOR at 3 hours, 2.79 (95% CI, 1.96 to 3.98), absolute risk difference (ARD) for lower disability scores, 39.2%; cOR at 6 hours, 1.98 (95% CI, 1.30 to 3.00), ARD, 30.2%; cOR at 8 hours,1.57 (95% CI, 0.86 to 2.88), ARD, 15.7%; retaining statistical significance through 7 hours and 18 minutes. Among 390 patients who achieved substantial reperfusion with endovascular thrombectomy, each 1-hour delay to reperfusion was associated with a less favorable degree of disability (cOR, 0.84 [95% CI, 0.76 to 0.93]; ARD, -6.7%) and less functional independence (OR, 0.81 [95% CI, 0.71 to 0.92], ARD, -5.2% [95% CI, -8.3% to -2.1%]), but no change in mortality (OR, 1.12 [95% CI, 0.93 to 1.34]; ARD, 1.5% [95% CI, -0.9% to 4.2%]). CONCLUSIONS AND RELEVANCE In this individual patient data meta-analysis of patients with large-vessel ischemic stroke, earlier treatment with endovascular thrombectomy + medical therapy compared with medical therapy alone was associated with lower degrees of disability at 3 months. Benefit became nonsignificant after 7.3 hours.

Multiphase CT Angiography: A New Tool for the Imaging Triage of Patients with Acute Ischemic Stroke

PURPOSE To describe the use of an imaging selection tool, multiphase computed tomographic (CT) angiography, in patients with acute ischemic stroke (AIS) and to demonstrate its interrater reliability and ability to help determine clinical outcome. MATERIALS AND METHODS The local ethics board approved this study. Data are from the pilot phase of PRoveIT, a prospective observational study analyzing utility of multimodal imaging in the triage of patients with AIS. Patients underwent baseline unenhanced CT, single-phase CT angiography of the head and neck, multiphase CT angiography, and perfusion CT. Multiphase CT angiography generates time-resolved images of pial arteries. Pial arterial filling was scored on a six-point ordinal scale, and interrater reliability was tested. Clinical outcomes included a 50% or greater decrease in National Institutes of Health Stroke Scale (NIHSS) over 24 hours and 90-day modified Rankin Scale (mRS) score of 0-2. The ability to predict clinical outcomes was compared between single-phase CT angiography, multiphase CT angiography, and perfusion CT by using receiver operating curve analysis, Akaike information criterion (AIC), and Bayesian information criterion (BIC). RESULTS A total of 147 patients were included. Interrater reliability for multiphase CT angiography is excellent (n = 30, κ = 0.81, P < .001). At receiver operating characteristic curve analysis, the ability to predict clinical outcome is modest (C statistic = 0.56, 95% confidence interval [CI]: 0.52, 0.63 for ≥50% decrease in NIHSS over 24 hours; C statistic = 0.6, 95% CI: 0.53, 0.68 for 90-day mRS score of 0-2) but better than that of models using single-phase CT angiography and perfusion CT (P < .05 overall). With AIC and BIC, models that use multiphase CT angiography are better than models that use single-phase CT angiography and perfusion CT for a decrease of 50% or more in NIHSS over 24 hours (AIC = 166, BIC = 171.7; values were lowest for multiphase CT angiography) and a 90-day mRS score of 0-2 (AIC = 132.1, BIC = 137.4; values were lowest for multiphase CT angiography). CONCLUSION Multiphase CT angiography is a reliable tool for imaging selection in patients with AIS.

Anesthetic management and outcome in patients during endovascular therapy for acute stroke.

Background: Studies of endovascular treatment for acute ischemic stroke have identified general anesthesia as a predictor for poor outcome in comparison with local anesthesia/sedation. This retrospective study attempts to identify modifiable factors associated with poor outcome, while adjusting for baseline stroke severity, in patients receiving general anesthesia. Methods: We reviewed charts of 129 patients treated between January 2003 and September 2009. The primary outcome was the modified Rankin Score of 0–2 for 3 months poststroke. Predictors of neurologic outcome included baseline National Institutes of Health Stroke Scale score, blood glucose concentration, and age. Additional risk factors evaluated were prolonged stroke onset-treatment interval and systolic blood pressure less than 140 mmHg. Choice of local anesthesia or general anesthesia was recorded. Results: The study group was 96 out of 129 patients for whom modified Rankin Scale scores were available; 48 patients received general anesthesia and 48 local anesthesia. The proportion of patients with “good” outcomes were 15% and 60% in the general anesthesia group and local anesthesia group, respectively (P < 0.001). Lowest systolic blood pressure and general anesthesia were correlated (r = −0.7, P < 0.001). Independent predictors for good neurologic outcome were local anesthesia, systolic blood pressure greater than 140 mmHg, and low baseline stroke scores. Conclusions: Adjusted for stroke severity, patients who received general anesthesia for treatment are less likely to have a good outcome than those managed with local anesthesia. This may be due to preintervention risk not included in the stroke severity measures. Hypotension, more frequent in the general anesthesia patients, may also contribute.

Regional Leptomeningeal Score on CT Angiography Predicts Clinical and Imaging Outcomes in Patients with Acute Anterior Circulation Occlusions

BACKGROUND AND PURPOSE: The regional leptomeningeal score is a strong and reliable imaging predictor of good clinical outcomes in acute anterior circulation ischemic strokes and can therefore be used for imaging based patient selection. Efforts to determine biological determinants of collateral status are needed if techniques to alter collateral behavior and extend time windows are to succeed. MATERIALS AND METHODS: This was a retrospective Institutional Review Board–approved study of patients with acute ischemic stroke and M1 middle cerebral artery+/− intracranial internal carotid artery occlusion at our center from 2003 to 2009. The rLMC score is based on scoring pial and lenticulostriate arteries (0, no; 1, less; 2, equal or more prominent compared with matching region in opposite hemisphere) in 6 ASPECTS regions (M1–6) plus anterior cerebral artery region and basal ganglia. Pial arteries in the Sylvian sulcus are scored 0, 2, or 4. Good clinical outcome was defined as mRS ≤2 at 90 days. RESULTS: The analysis included 138 patients: 37.6% had a good (17–20), 40.5% a medium (11–16), and 21.7% a poor (0–10) rLMC score. Interrater reliability was high, with an intraclass correlation coefficient of 0.87 (95% CI, 0.77%–0.95%). On univariate analysis, no single vascular risk factor was associated with the presence of poor rLMCs (P ≥ .20 for all comparisons). In multivariable analysis, the rLMC score (good versus poor: OR, 16.7; 95% CI, 2.9%–97.4%; medium versus poor: OR, 9.2, 95% CI, 1.7%–50.6%), age (<80 years), baseline ASPECTS (≥8), and clot burden score (≥8) were independent predictors of good clinical outcome. CONCLUSIONS: The rLMC score is a strong imaging parameter on CT angiography for predicting clinical outcomes in patients with acute ischemic strokes.

Collaterals at Angiography and Outcomes in the Interventional Management of Stroke (IMS) III Trial

Background and Purpose— Endovascular strategies provide unique opportunity to correlate angiographic measures of collateral circulation at the time of endovascular therapy. We conducted systematic analyses of collaterals at conventional angiography on recanalization, reperfusion, and clinical outcomes in the endovascular treatment arm of the Interventional Management of Stroke (IMS) III trial. Methods— Prospective evaluation of angiographic collaterals was conducted via central review of subjects treated with endovascular therapy in IMS III (n=331). Collateral grade before endovascular therapy was assessed with the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology scale, blinded to all other data. Statistical analyses investigated the association between collaterals with baseline clinical variables, angiographic measures of recanalization, reperfusion and clinical outcomes. Results— Adequate views of collateral circulation to the ischemic territory were available in 276 of 331 (83%) subjects. Collateral grade was strongly related to both recanalization of the occluded arterial segment (P=0.0016) and downstream reperfusion (P<0.0001). Multivariable analyses confirmed that robust angiographic collateral grade was a significant predictor of good clinical outcome (modified Rankin Scale score ⩽2) at 90 days (P=0.0353), adjusted for age, history of diabetes mellitus, National Institutes of Health Stroke Scale strata, and Alberta Stroke Program Early CT Score. The relationship between collateral flow and clinical outcome may depend on the degree of reperfusion. Conclusions— More robust collateral grade was associated with better recanalization, reperfusion, and subsequent better clinical outcomes. These data, from the largest endovascular trial to date, suggest that collaterals are an important consideration in future trial design. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00359424.

Effect of Baseline CT Scan Appearance and Time to Recanalization on Clinical Outcomes in Endovascular Thrombectomy of Acute Ischemic Strokes

Background and Purpose— The Penumbra Pivotal Stroke Trial reported a 25% good outcome (modified Rankin scale score ≤2) despite an 81% recanalization rate. We evaluated the association of a favorable initial noncontrast CT and a short time to recanalization in predicting good outcome. Methods— Data were from the Penumbra Pivotal Stroke Trial. Baseline scans were evaluated by 2 experienced readers blinded to outcomes using ASPECTS. ASPECTS scores were dichotomized into >7 and ≤7 for primary analysis. Data on degree of recanalization based on thrombolysis in myocardial infarction scores, stroke onset to recanalization, and CT to recanalization times were obtained. Primary outcome was modified Rankin scale score ≤2 at 3 months. Results— Median baseline NIHSS was 18 (range, 8–34) and median baseline ASPECTS score was 6 (range, 0–10); 81.2% achieved recanalization (thrombolysis in myocardial infarction, 2–3) and (27.7%) achieved good outcome. Good outcome was significantly higher in the ASPECTS score >7 group when compared to the ASPECTS score ≤7 group (50% vs 15%; RR, 3.3; 95% CI, 1.6–6.8; P=0.0001). No patient with an ASPECTS score ≤4 (n=28) or without recanalization (n=16) had a good outcome. There was an interaction between baseline ASPECTS score (>7 and ≤7) and onset to recanalization time (≤300 minutes and >300 minutes) in predicting good outcome (P=0.06). Conclusion— Patients with baseline CT ASPECTS score ≤4 do not benefit from recanalization. Fast recanalization may benefit patients with evident damage on the CT scan (ASPECTS score >4). Overall, patients benefit the most with early recanalization and a favorable baseline CT scan (ASPECTS score >7).

Risk Score for Intracranial Hemorrhage in Patients With Acute Ischemic Stroke Treated With Intravenous Tissue-Type Plasminogen Activator

Background and Purpose— There are few validated models for prediction of risk of symptomatic intracranial hemorrhage (sICH) after intravenous tissue-type plasminogen activator treatment for ischemic stroke. We used data from Get With The Guidelines–Stroke (GWTG-Stroke) to derive and validate a prediction tool for determining sICH risk. Methods— The population consisted of 10 242 patients from 988 hospitals who received intravenous tissue-type plasminogen activator within 3 hours of symptom onset from January 2009 to June 2010. This sample was randomly divided into derivation (70%) and validation (30%) cohorts. Multivariable logistic regression identified predictors of intravenous tissue-type plasminogen activator-related sICH in the derivation sample; model &bgr; coefficients were used to assign point scores for prediction. Results— sICH within 36 hours was noted in 496 patients (4.8%). Multivariable adjusted independent predictors of sICH were increasing age (17 points), higher baseline National Institutes of Health Stroke Scale (42 points), higher systolic blood pressure (21 points), higher blood glucose (8 points), Asian race (9 points), and male sex (4 points). The C-statistic was 0.71 in the derivation sample and 0.70 in the independent internal validation sample. Plots of observed versus predicted sICH showed good model calibration in the derivation and validation cohorts. The model was externally validated in National Institute of Neurological Disorders and Stroke trial patients with a C-statistic of 0.68. Conclusions— The GWTG-Stroke sICH risk “GRASPS” score provides clinicians with a validated method to determine the risk of sICH in patients treated with intravenous tissue-type plasminogen activator within 3 hours of stroke symptom onset.

Assessment of leptomeningeal collaterals using dynamic CT angiography in patients with acute ischemic stroke

Whole-brain dynamic time-resolved computed tomography angiography (CTA) is a technique developed on the new 320-detector row CT scanner capable of generating time-resolved cerebral angiograms from skull base to vertex. Unlike a conventional cerebral angiogram, this technique visualizes pial arterial filling in all vascular territories, thereby providing additional hemodynamic information. Ours was a retrospective study of consecutive patients with ischemic stroke and M1 middle cerebral artery +/– intracranial internal carotid artery occlusions presenting to our center from June 2010 and undergoing dynamic time-resolved CTA and perfusion CT within 6 hours of symptom onset. Leptomeningeal collateral status was assessed by determining relative prominence of pial arteries in the ischemic region, rate and extent of retrograde flow, and various topographical patterns of pial arterial filling. Twenty-five patients were included in the study. We demonstrate the existence of the following novel properties of leptomeningeal collaterals in humans: (a) posterior (posterior cerebral artery (PCA)–MCA) dominant collateralization, (b) intra-territorial ‘within MCA region’ leptomeningeal collaterals, and (c) significant variability in size, extent, and retrograde filling time in pial arteries. We also describe a simple and reliable collateral grading template that, for the first time on dynamic CTA, incorporates back-filling time as well as size and extent of collateral filling.