Andrew M. Demchuk

Endovascular Therapy after Intravenous t-PA versus t-PA Alone for Stroke

BACKGROUND Endovascular therapy is increasingly used after the administration of intravenous tissue plasminogen activator (t-PA) for patients with moderate-to-severe acute ischemic stroke, but whether a combined approach is more effective than intravenous t-PA alone is uncertain. METHODS We randomly assigned eligible patients who had received intravenous t-PA within 3 hours after symptom onset to receive additional endovascular therapy or intravenous t-PA alone, in a 2:1 ratio. The primary outcome measure was a modified Rankin scale score of 2 or less (indicating functional independence) at 90 days (scores range from 0 to 6, with higher scores indicating greater disability). RESULTS The study was stopped early because of futility after 656 participants had undergone randomization (434 patients to endovascular therapy and 222 to intravenous t-PA alone). The proportion of participants with a modified Rankin score of 2 or less at 90 days did not differ significantly according to treatment (40.8% with endovascular therapy and 38.7% with intravenous t-PA; absolute adjusted difference, 1.5 percentage points; 95% confidence interval [CI], -6.1 to 9.1, with adjustment for the National Institutes of Health Stroke Scale [NIHSS] score [8-19, indicating moderately severe stroke, or ≥20, indicating severe stroke]), nor were there significant differences for the predefined subgroups of patients with an NIHSS score of 20 or higher (6.8 percentage points; 95% CI, -4.4 to 18.1) and those with a score of 19 or lower (-1.0 percentage point; 95% CI, -10.8 to 8.8). Findings in the endovascular-therapy and intravenous t-PA groups were similar for mortality at 90 days (19.1% and 21.6%, respectively; P=0.52) and the proportion of patients with symptomatic intracerebral hemorrhage within 30 hours after initiation of t-PA (6.2% and 5.9%, respectively; P=0.83). CONCLUSIONS The trial showed similar safety outcomes and no significant difference in functional independence with endovascular therapy after intravenous t-PA, as compared with intravenous t-PA alone. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00359424.).

Validity and reliability of a quantitative computed tomography score in predicting outcome of hyperacute stroke before thrombolytic therapy

Summary Background Computed tomography (CT) must be done before thrombolytic treatment of hyperacute ischaemic stroke, but the significance of early ischaemic change on CT is unclear. We tested a quantitative CT score, the Alberta Stroke Programme Early CT Score (ASPECTS). Methods 203 consecutive patients with ischaemic stroke were treated with intravenous alteplase within 3 h of symptom onset in two North American teaching hospitals. All pretreatment CT scans were prospectively scored. The score divides the middle-cerebral-artery territory into ten regions of interest. Primary outcomes were symptomatic intracerebral haemorrhage and 3-month functional outcome. The sensitivity and specificity of ASPECTS for the primary outcomes were calculated. Logistic regression was used to test the association between the score on ASPECTS and the primary outcomes. Findings Ischaemic changes on the baseline CT were seen in 117 (75%) of 156 treated patients with anteriorcirculation ischaemia included in the analysis (23 had ischaemia in the posterior circulation and 24 were treated outside the protocol). Baseline ASPECTS value correlated inversely with the severity of stroke on the National Institutes of Health Stroke Scale (r=� 0·56, p<0·001). Baseline ASPECTS value predicted functional outcome and symptomatic intracerebral haemorrhage (p<0·001, p=0·012, respectively). The sensitivity of ASPECTS for functional outcome was 0·78 and specificity 0·96; the values for symptomatic intracerebral haemorrhage were 0·90 and 0·62. Agreement between observers for ASPECTS, with knowledge of the affected hemisphere, was good (� statistic 0·71–0·89). Interpretation This CT score is simple and reliable and identifies stroke patients unlikely to make an independent recovery despite thrombolytic treatment.

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.

Magnetic resonance imaging and computed tomography in emergency assessment of patients with suspected acute stroke: a prospective comparison

BACKGROUND Although the use of magnetic resonance imaging (MRI) for the diagnosis of acute stroke is increasing, this method has not proved more effective than computed tomography (CT) in the emergency setting. We aimed to prospectively compare CT and MRI for emergency diagnosis of acute stroke. METHODS We did a single-centre, prospective, blind comparison of non-contrast CT and MRI (with diffusion-weighted and susceptibility weighted images) in a consecutive series of patients referred for emergency assessment of suspected acute stroke. Scans were independently interpreted by four experts, who were unaware of clinical information, MRI-CT pairings, and follow-up imaging. RESULTS 356 patients, 217 of whom had a final clinical diagnosis of acute stroke, were assessed. MRI detected acute stroke (ischaemic or haemorrhagic), acute ischaemic stroke, and chronic haemorrhage more frequently than did CT (p<0.0001, for all comparisons). MRI was similar to CT for the detection of acute intracranial haemorrhage. MRI detected acute ischaemic stroke in 164 of 356 patients (46%; 95% CI 41-51%), compared with CT in 35 of 356 patients (10%; 7-14%). In the subset of patients scanned within 3 h of symptom onset, MRI detected acute ischaemic stroke in 41 of 90 patients (46%; 35-56%); CT in 6 of 90 (7%; 3-14%). Relative to the final clinical diagnosis, MRI had a sensitivity of 83% (181 of 217; 78-88%) and CT of 26% (56 of 217; 20-32%) for the diagnosis of any acute stroke. INTERPRETATION MRI is better than CT for detection of acute ischaemia, and can detect acute and chronic haemorrhage; therefore it should be the preferred test for accurate diagnosis of patients with suspected acute stroke. Because our patient sample encompassed the range of disease that is likely to be encountered in emergency cases of suspected stroke, our results are directly applicable to clinical practice.

Why are stroke patients excluded from tPA therapy? An analysis of patient eligibility.

Background: Thrombolytic therapy for acute stroke (<3 hours) will not have a major impact on death and dependency unless it is accessible to more patients. Objective: To determine why patients with ischemic stroke did not receive IV TPA and assess the availability of this therapy to patients with ischemic stroke. Methods: Consecutive patients with acute ischemic stroke were prospectively identified at a university teaching hospital between October 1996 and December 1999. Additional patients with ischemic stroke were identified that were admitted to one of three other hospitals in the Calgary region during the study period. The Oxford Community Stroke Programme Classification was used to record type and side of stroke. Results: Of 2165 stroke patients presenting to the university hospital, 1168 (53.9%) were diagnosed with ischemic stroke, 31.8% with intracranial hemorrhage (intracerebral, subarachnoid, or subdural), and 13.9% with TIA. Delay in presentation to emergency department beyond 3 hours excluded 73.1% (854/1168). Major reasons for delay included uncertain time of onset (24.2%), patients waited to see if symptoms would improve (29%), delay caused by transfer from an outlying hospital (8.9%), and inaccessibility of treating hospital (5.7%). Twenty-seven percent of patients with ischemic stroke (314/1168) were admitted within 3 hours of sympton onset and of these 84 (26.7%) patients received IV TPA. The major reasons for exclusion in this group of patients (<3 hours) were mild stroke (13.1%), clinical improvement (18.2%), perceived protocol exclusions (13.6%), emergency department referral delay (8.9%), and significant comorbidity (8.3%). Of those patients who were considered too mild or were documented to have had significant improvement, 32% either remained dependent at hospital discharge or died during hospital admission. Throughout the region there was a total of 1806 ischemic stroke patients (admitted to all four Calgary hospitals). During this study period, 4.7% received IV TPA. Conclusions: The majority of patients are unable to receive TPA for acute ischemic stroke because they do no not reach the hospital soon enough. Of those patients presenting within 3 hours, 27% received the therapy but a further 31% were excluded because their symptoms were either considered too mild or were rapidly improving. Subsequently, a third of these patients were left either dependent or dead, bringing into question the initial decision not to treat.

Site of Arterial Occlusion Identified by Transcranial Doppler Predicts the Response to Intravenous Thrombolysis for Stroke

Background and Purpose— The objective of this study was to examine clinical outcomes and recanalization rates in a multicenter cohort of stroke patients receiving intravenous tissue plasminogen activator by site of occlusion localized with bedside transcranial Doppler. Angiographic studies with intraarterial thrombolysis suggest more proximal occlusions carry greater thrombus burden and benefit less from local therapy. Methods— Using validated transcranial Doppler criteria for specific arterial occlusion (Thrombolysis in Brain Ischemia flow grades), we compared the rate of dramatic recovery (National Institutes of Health Stroke Scale score ≤2 at 24 hours) and favorable outcomes at 3 months (modified Rankin Scale ≤1) for each occlusion site. We determined the likelihood of recanalization at various occlusion sites and its predictors. Then, stepwise logistic regression was used to determine predictors of complete recanalization. Results— Three hundred thirty-five patients had a mean age 69±13 years and 48.5% were women (median baseline National Institutes of Health Stroke Scale score 16 [range, 3 to 32], mean time to transcranial Doppler 140±84 minutes, and mean time to intravenous tissue plasminogen activator 145±68 minutes). Distal middle cerebral artery occlusion had an OR of 2 for complete recanalization (50 of 113 [44.2%], 95% CI: 1.1 to 3.1, P=0.005), proximal middle cerebral artery 0.7 (49 of 163 [30%], 95% CI: 0.4 to 1.1, P=0.13), terminal internal carotid artery 0.1 (one of 17 [5.9%], 95% CI: 0.015 to 0.8, P=0.015), tandem cervical internal carotid artery/middle cerebral artery 0.7 (6 of 22 [27%], 95% CI: 0.3 to 1.9, P=0.5), and basilar artery 0.96 (3 of 10 [30%], 95% CI: 0.2 to 4, P=0.9). Prerecombinant tissue plasminogen activator National Institutes of Health Stroke Scale score, systolic blood pressure, glucose, and Thrombolysis in Brain Ischemia flow grade at the occlusion site were the negative independent predictors for complete recanalization in the final model. There were no associations among time to treatment, stroke mechanisms, or recanalization rate. Patients with no flow (Thrombolysis in Brain Ischemia 0) at the occlusion site had less probability of complete recanalization than patients with dampened flow (Thrombolysis in Brain Ischemia 3) (ORadj: 0.256, 95% CI: 0.11 to 0.595, P=0.002). Continuous transcranial Doppler monitoring (exposure to ultrasound) was a positive predictor for complete recanalization (ORadj: 3.02, 95% CI: 1.396 to 6.514, P=0.005). National Institutes of Health Stroke Scale score ≤2 at 24 hours was achieved in 66 of 305 patients (22%): distal middle cerebral artery 33% (35 of 107), tandem cervical internal carotid artery/middle cerebral artery 24% (5 of 21), proximal middle cerebral artery 16% (24 of 155), basilar artery 25% (2 of 8), and none of the patients with terminal internal carotid artery had dramatic recovery (0%, n=14; P=0.003). Modified Rankin Scale score ≤1 was achieved in 90 of 260 patients (35%): distal middle cerebral artery 52% (50 of 96), proximal middle cerebral artery 25% (33 of 131), tandem cervical internal carotid artery/middle cerebral artery 21% (3 of 14), terminal internal carotid artery 18% (2 of 11), and basilar artery 25% (2 of 8) (P<0.001). Patients with distal middle cerebral artery occlusion were twice as likely to have a good long-term outcome as patients with proximal middle cerebral artery (OR: 2.1, 95% CI: 1.1 to 4, P=0.025). Conclusions— Clinical response to thrombolysis is influenced by the site of occlusion. Patients with no detectable residual flow signals as well as those with terminal internal carotid artery occlusions are least likely to respond early or long term.

Comparison of MRI and CT for Detection of Acute Intracerebral Hemorrhage

CONTEXT Noncontrast computed tomography (CT) is the standard brain imaging study for the initial evaluation of patients with acute stroke symptoms. Multimodal magnetic resonance imaging (MRI) has been proposed as an alternative to CT in the emergency stroke setting. However, the accuracy of MRI relative to CT for the detection of hyperacute intracerebral hemorrhage has not been demonstrated. OBJECTIVE To compare the accuracy of MRI and CT for detection of acute intracerebral hemorrhage in patients presenting with acute focal stroke symptoms. DESIGN, SETTING, AND PATIENTS A prospective, multicenter study was performed at 2 stroke centers (UCLA Medical Center and Suburban Hospital, Bethesda, Md), between October 2000 and February 2003. Patients presenting with focal stroke symptoms within 6 hours of onset underwent brain MRI followed by noncontrast CT. MAIN OUTCOME MEASURES Acute intracerebral hemorrhage and any intracerebral hemorrhage diagnosed on gradient recalled echo (GRE) MRI and CT scans by a consensus of 4 blinded readers. RESULTS The study was stopped early, after 200 patients were enrolled, when it became apparent at the time of an unplanned interim analysis that MRI was detecting cases of hemorrhagic transformation not detected by CT. For the diagnosis of any hemorrhage, MRI was positive in 71 patients with CT positive in 29 (P<.001). For the diagnosis of acute hemorrhage, MRI and CT were equivalent (96% concordance). Acute hemorrhage was diagnosed in 25 patients on both MRI and CT. In 4 other patients, acute hemorrhage was present on MRI but not on the corresponding CT--each of these 4 cases was interpreted as hemorrhagic transformation of an ischemic infarct. In 3 patients, regions interpreted as acute hemorrhage on CT were interpreted as chronic hemorrhage on MRI. In 1 patient, subarachnoid hemorrhage was diagnosed on CT but not on MRI. In 49 patients, chronic hemorrhage, most often microbleeds, was visualized on MRI but not on CT. CONCLUSION MRI may be as accurate as CT for the detection of acute hemorrhage in patients presenting with acute focal stroke symptoms and is more accurate than CT for the detection of chronic intracerebral hemorrhage.

Fast assessment of stroke and transient ischaemic attack to prevent early recurrence (FASTER): a randomised controlled pilot trial

BACKGROUND Patients with transient ischaemic attack (TIA) or minor stroke are at high immediate risk of stroke. The optimum early treatment options for these patients are not known. METHODS Within 24 h of symptom onset, we randomly assigned, in a factorial design, 392 patients with TIA or minor stroke to clopidogrel (300 mg loading dose then 75 mg daily; 198 patients) or placebo (194 patients), and simvastatin (40 mg daily; 199 patients) or placebo (193 patients). All patients were also given aspirin and were followed for 90 days. Descriptive analyses were done by intention to treat. The primary outcome was total stroke (ischaemic and haemorrhagic) within 90 days. Safety outcomes included haemorrhage related to clopidogrel and myositis related to simvastatin. This study is registered as an International Standard Randomised Controlled Trial (number 35624812) and with ClinicalTrials.gov (NCT00109382). FINDINGS The median time to stroke outcome was 1 day (range 0-62 days). The trial was stopped early due to a failure to recruit patients at the prespecified minimum enrolment rate because of increased use of statins. 14 (7.1%) patients on clopidogrel had a stroke within 90 days compared with 21 (10.8%) patients on placebo (risk ratio 0.7 [95% CI 0.3-1.2]; absolute risk reduction -3.8% [95% CI -9.4 to 1.9]; p=0.19). 21 (10.6%) patients on simvastatin had a stroke within 90 days compared with 14 (7.3%) patients on placebo (risk ratio 1.3 [0.7-2.4]; absolute risk increase 3.3% [-2.3 to 8.9]; p=0.25). The interaction between clopidogrel and simvastatin was not significant (p=0.64). Two patients on clopidogrel had intracranial haemorrhage compared with none on placebo (absolute risk increase 1.0% [-0.4 to 2.4]; p=0.5). There was no difference between groups for the simvastatin safety outcomes. INTERPRETATION Immediately after TIA or minor stroke, patients are at high risk of stroke, which might be reduced by using clopidogrel in addition to aspirin. The haemorrhagic risks of the combination of aspirin and clopidogrel do not seem to offset this potential benefit. We were unable to provide evidence of benefit of simvastatin in this setting. This aggressive prevention approach merits further study.

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.

Thrombolysis in Brain Ischemia (TIBI) Transcranial Doppler Flow Grades Predict Clinical Severity, Early Recovery, and Mortality in Patients Treated With Intravenous Tissue Plasminogen Activator

Background and Purpose— TIMI angiographic classification measures coronary residual flow and recanalization. We developed a Thrombolysis in Brain Ischemia (TIBI) classification by using transcranial Doppler (TCD) to noninvasively monitor intracranial vessel residual flow signals. We examined whether the emergent TCD TIBI classification correlated with stroke severity and outcome in patients treated with intravenously administered tPA (IV-tPA). Methods— TCD examination occurred acutely and on day 2. TIBI flows were determined at distal MCA and basilar artery depths, depending on occlusion site. TIBI waveforms were graded as follows: 0, absent; 1, minimal; 2, blunted; 3, dampened; 4, stenotic; and 5, normal. National Institutes of Health Stroke Scale (NIHSS) scores were obtained at baseline and 24 hours after administration of tPA. Results— One hundred nine IV tPA patients were studied. Mean±SD age was 68±16 years; median NIHSS score before administration of tPA (pre-tPA) was 17.5. The tPA bolus was administered 143±58 minutes and the TCD examination 141±57 minutes after symptom onset. Pre-tPA NIHSS scores were higher in patients with TIBI grade 0 than TIBI grade 4 or 5 flow. TIBI flow improvement to grade 4 or 5 occurred in 35% of patients (19/54) with an initial grade of 0 or 1 and in 52% (12/23) with initial grade 2 or 3. The 24-hour NIHSS scores were higher in follow-up in patients with TIBI grade 0 or 1 than those with TIBI grade 4 or 5 flow. TIBI flow recovery correlated with NIHSS score improvement. Lack of flow recovery predicted worsening or no improvement. In-hospital mortality was 71% (5/7) for patients with posterior circulation occlusions; it was 22% (11/51) for patients with pre-tPA TIBI 0 or 1 compared with 5% (1/19) for those with pre-tPA TIBI 2 or 3 anterior circulation occlusions. Conclusions— Emergent TCD TIBI classification correlates with initial stroke severity, clinical recovery, and mortality in IV-tPA–treated stroke patients. A flow-grade improvement correlated with clinical improvement.