Tissa Wijeratne

Endovascular Therapy for Ischemic Stroke with Perfusion-Imaging Selection

BACKGROUND Trials of endovascular therapy for ischemic stroke have produced variable results. We conducted this study to test whether more advanced imaging selection, recently developed devices, and earlier intervention improve outcomes. METHODS We randomly assigned patients with ischemic stroke who were receiving 0.9 mg of alteplase per kilogram of body weight less than 4.5 hours after the onset of ischemic stroke either to undergo endovascular thrombectomy with the Solitaire FR (Flow Restoration) stent retriever or to continue receiving alteplase alone. All the patients had occlusion of the internal carotid or middle cerebral artery and evidence of salvageable brain tissue and ischemic core of less than 70 ml on computed tomographic (CT) perfusion imaging. The coprimary outcomes were reperfusion at 24 hours and early neurologic improvement (≥8-point reduction on the National Institutes of Health Stroke Scale or a score of 0 or 1 at day 3). Secondary outcomes included the functional score on the modified Rankin scale at 90 days. RESULTS The trial was stopped early because of efficacy after 70 patients had undergone randomization (35 patients in each group). The percentage of ischemic territory that had undergone reperfusion at 24 hours was greater in the endovascular-therapy group than in the alteplase-only group (median, 100% vs. 37%; P<0.001). Endovascular therapy, initiated at a median of 210 minutes after the onset of stroke, increased early neurologic improvement at 3 days (80% vs. 37%, P=0.002) and improved the functional outcome at 90 days, with more patients achieving functional independence (score of 0 to 2 on the modified Rankin scale, 71% vs. 40%; P=0.01). There were no significant differences in rates of death or symptomatic intracerebral hemorrhage. CONCLUSIONS In patients with ischemic stroke with a proximal cerebral arterial occlusion and salvageable tissue on CT perfusion imaging, early thrombectomy with the Solitaire FR stent retriever, as compared with alteplase alone, improved reperfusion, early neurologic recovery, and functional outcome. (Funded by the Australian National Health and Medical Research Council and others; EXTEND-IA ClinicalTrials.gov number, NCT01492725, and Australian New Zealand Clinical Trials Registry number, ACTRN12611000969965.).

A multicentre, randomized, double-blinded, placebo-controlled phase III study to investigate EXtending the time for Thrombolysis in Emergency Neurological Deficits (EXTEND)

Background and hypothesis Thrombolytic therapy with tissue plasminogen activator is effective for acute ischaemic stroke within 4·5 h of onset. Patients who wake up with stroke are generally ineligible for stroke thrombolysis. We hypothesized that ischaemic stroke patients with significant penumbral mismatch on either magnetic resonance imaging or computer tomography at three- (or 4·5 depending on local guidelines) to nine-hours from stroke onset, or patients with wake-up stroke within nine-hours from midpoint of sleep duration, would have improved clinical outcomes when given tissue plasminogen activator compared to placebo. Study design EXtending the time for Thrombolysis in Emergency Neurological Deficits is an investigator-driven, Phase III, randomized, multicentre, double-blind, placebo-controlled study. Ischaemic stroke patients presenting after the three- or 4·5-h treatment window for tissue plasminogen activator and within nine-hours of stroke onset or with wake-up stroke within nine-hours from the midpoint of sleep duration, who fulfil clinical (National Institutes of Health Stroke Score ≥4–26 and prestroke modified Rankin Scale <2) will undergo magnetic resonance imaging or computer tomography. Patients who also meet imaging criteria (infarct core volume <70 ml, perfusion lesion : infarct core mismatch ratio >1·2, and absolute mismatch >10 ml) will be randomized to either tissue plasminogen activator or placebo. Study outcome The primary outcome measure will be modified Rankin Scale 0–1 at day 90. Clinical secondary outcomes include categorical shift in modified Rankin Scale at 90 days, reduction in the National Institutes of Health Stroke Score by 8 or more points or reaching 0–1 at day 90, recurrent stroke, or death. Imaging secondary outcomes will include symptomatic intracranial haemorrhage, reperfusion and or recanalization at 24 h and infarct growth at day 90.

A multicenter, randomized, controlled study to investigate EXtending the time for Thrombolysis in Emergency Neurological Deficits with Intra-Arterial therapy (EXTEND-IA)

Background and Hypothesis Thrombolysis with tissue plasminogen activator is proven to reduce disability when given within 4.5 h of ischemic stroke onset. However, tissue plasminogen activator only succeeds in recanalizing large vessel arterial occlusion in a minority of patients. We hypothesized that anterior circulation ischemic stroke patients, selected with ‘dual target’ vessel occlusion and evidence of salvageable brain using computed tomography or magnetic resonance imaging ‘mismatch’ within 4.5 h of onset, would have improved reperfusion and early neurological improvement when treated with intra-arterial clot retrieval after intravenous tissue plasminogen activator compared with intravenous tissue plasminogen activator alone. Study Design EXTEND-IA is an investigator-initiated, phase II, multicenter prospective, randomized, open-label, blinded-endpoint study. Ischemic stroke patients receiving standard 0.9 mg/kg intravenous tissue plasminogen activator within 4.5 h of stroke onset who have good prestroke functional status (modified Rankin Scale <2, no upper age limit) will undergo multimodal computed tomography or magnetic resonance imaging. Patients who also meet dual target imaging criteria: vessel occlusion (internal carotid or middle cerebral artery) and mismatch (perfusion lesion: ischemic core mismatch ratio >1.2, absolute mismatch >10 ml, ischemic core volume <70 ml) will be randomized to either clot retrieval with the Solitaire FR device after full dose intravenous tissue plasminogen activator, or tissue plasminogen activator alone. Study Outcomes The coprimary outcome measure will be reperfusion at 24 h and favorable clinical response (reduction in National Institutes of Health Stroke Scale by ≥8 points or reaching 0–1) at day 3. Secondary outcomes include modified Rankin Scale at day 90, death, and symptomatic intracranial hemorrhage.

Systematic Review of Guidelines for the Management of Asymptomatic and Symptomatic Carotid Stenosis.

Background and Purpose— We systematically compared and appraised contemporary guidelines on management of asymptomatic and symptomatic carotid artery stenosis. Methods— We systematically searched for guideline recommendations on carotid endarterectomy (CEA) or carotid angioplasty/stenting (CAS) published in any language between January 1, 2008, and January 28, 2015. Only the latest guideline per writing group was selected. Each guideline was analyzed independently by 2 to 6 authors to determine clinical scenarios covered, recommendations given, and scientific evidence used. Results— Thirty-four eligible guidelines were identified from 23 different regions/countries in 6 languages. Of 28 guidelines with asymptomatic carotid artery stenosis procedural recommendations, 24 (86%) endorsed CEA (recommended it should or may be provided) for ≈50% to 99% average-surgical-risk asymptomatic carotid artery stenosis, 17 (61%) endorsed CAS, 8 (29%) opposed CAS, and 1 (4%) endorsed medical treatment alone. For asymptomatic carotid artery stenosis patients considered high-CEA-risk because of comorbidities, vascular anatomy, or undefined reasons, CAS was endorsed in 13 guidelines (46%). Thirty-one of 33 guidelines (94%) with symptomatic carotid artery stenosis procedural recommendations endorsed CEA for patients with ≈50% to 99% average-CEA-risk symptomatic carotid artery stenosis, 19 (58%) endorsed CAS and 9 (27%) opposed CAS. For high-CEA-risk symptomatic carotid artery stenosis because of comorbidities, vascular anatomy, or undefined reasons, CAS was endorsed in 27 guidelines (82%). Guideline procedural recommendations were based only on results of trials in which patients were randomized 12 to 34 years ago, rarely reflected medical treatment improvements and often understated potential CAS hazards. Qualifying terminology summarizing recommendations or evidence lacked standardization, impeding guideline interpretation, and comparison. Conclusions— This systematic review has identified many opportunities to modernize and otherwise improve carotid stenosis management guidelines.

The Spot Sign and Tranexamic Acid on Preventing ICH Growth – AUStralasia Trial (STOP-AUST): Protocol of a Phase II Randomized, Placebo-Controlled, Double-Blind, Multicenter Trial

Rationale No evidence-based acute therapies exist for intracerebral hemorrhage. Intracerebral hemorrhage growth is an important determinant of patient outcome. Tranexamic acid is known to reduce hemorrhage in other conditions. Aim The study aims to test the hypothesis that intracerebral hemorrhage patients selected with computed tomography angiography contrast extravasation ‘spot sign’ will have lower rates of hematoma growth when treated with intravenous tranexamic acid within 4·5-hours of stroke onset compared with placebo. Design The Spot sign and Tranexamic acid On Preventing ICH growth – AUStralasia Trial is a multicenter, prospective, 1:1 randomized, double-blind, placebo-controlled, investigator-initiated, academic Phase II trial. Intracerebral hemorrhage patients fulfilling clinical criteria (e.g. Glasgow Coma Scale >7, intracerebral hemorrhage volume <70 ml, no identified secondary cause of intracerebral hemorrhage, no thrombotic events within the previous 12 months, no planned surgery) and demonstrating contrast extravasation on computed tomography angiography will receive either intravenous tranexamic acid 1 g 10-min bolus followed by 1 g eight-hour infusion or placebo. A second computed tomography will be performed at 24 ± 3 hours to evaluate intracerebral hemorrhage growth and patients followed up for three-months. Study outcomes The primary outcome measure is presence of intracerebral hemorrhage growth by 24 ± 3 hours, defined as either >33% or >6 ml increase from baseline, and will be adjusted for baseline intracerebral hemorrhage volume. Secondary outcome measures include growth as a continuous measure, thromboembolic events, and the three-month modified Rankin Scale score. Discussion This is the first trial to evaluate the efficacy of tranexamic acid in intracerebral hemorrhage patients selected based on an imaging biomarker of high likelihood of hematoma growth. The trial is registered as NCT01702636.

Why Calls for More Routine Carotid Stenting Are Currently Inappropriate: An International, Multispecialty, Expert Review and Position Statement

Why Calls for More Routine Carotid Stenting Are Currently Inappropriate An International, Multispecialty, Expert Review and Position Statement

Tenecteplase versus Alteplase before Thrombectomy for Ischemic Stroke

BACKGROUND Intravenous infusion of alteplase is used for thrombolysis before endovascular thrombectomy for ischemic stroke. Tenecteplase, which is more fibrin‐specific and has longer activity than alteplase, is given as a bolus and may increase the incidence of vascular reperfusion. METHODS We randomly assigned patients with ischemic stroke who had occlusion of the internal carotid, basilar, or middle cerebral artery and who were eligible to undergo thrombectomy to receive tenecteplase (at a dose of 0.25 mg per kilogram of body weight; maximum dose, 25 mg) or alteplase (at a dose of 0.9 mg per kilogram; maximum dose, 90 mg) within 4.5 hours after symptom onset. The primary outcome was reperfusion of greater than 50% of the involved ischemic territory or an absence of retrievable thrombus at the time of the initial angiographic assessment. Noninferiority of tenecteplase was tested, followed by superiority. Secondary outcomes included the modified Rankin scale score (on a scale from 0 [no neurologic deficit] to 6 [death]) at 90 days. Safety outcomes were death and symptomatic intracerebral hemorrhage. RESULTS Of 202 patients enrolled, 101 were assigned to receive tenecteplase and 101 to receive alteplase. The primary outcome occurred in 22% of the patients treated with tenecteplase versus 10% of those treated with alteplase (incidence difference, 12 percentage points; 95% confidence interval [CI], 2 to 21; incidence ratio, 2.2; 95% CI, 1.1 to 4.4; P=0.002 for noninferiority; P=0.03 for superiority). Tenecteplase resulted in a better 90‐day functional outcome than alteplase (median modified Rankin scale score, 2 vs. 3; common odds ratio, 1.7; 95% CI, 1.0 to 2.8; P=0.04). Symptomatic intracerebral hemorrhage occurred in 1% of the patients in each group. CONCLUSIONS Tenecteplase before thrombectomy was associated with a higher incidence of reperfusion and better functional outcome than alteplase among patients with ischemic stroke treated within 4.5 hours after symptom onset. (Funded by the National Health and Medical Research Council of Australia and others; EXTEND‐IA TNK ClinicalTrials.gov number, NCT02388061.)

The influence of left and right hemisphere brain damage on configural and featural processing of affective faces

The literature about the lateralization of facial emotion perception according to valence (positive, negative) is conflicting; investigating the underlying processes may shed light on why some studies show right-hemisphere dominance across valence and other studies demonstrate hemispheric differences according to valence. This is the first clinical study to examine whether the use of configural and featural cues underlies hemispheric differences in affective face perception. Right brain-damaged (RBD; n = 17), left brain-damaged (LBD; n = 17) and healthy control (HC; n = 34) participants completed an affective face discrimination task that tested configural processing using whole faces and featural processing using partial faces. No group differences in expression perception according to valence or processing strategy were found. Across emotions, the RBD group was less accurate than the HC group in discriminating whole faces, whilst the RBD and LBD groups were less accurate than HCs in discriminating partial faces. This suggests that the right hemisphere processes facial expressions from configural and featural information, whereas the left hemisphere relies more heavily on featural facial information.

The perception of positive and negative facial expressions by unilateral stroke patients.

There remains conflict in the literature about the lateralisation of affective face perception. Some studies have reported a right hemisphere advantage irrespective of valence, whereas others have found a left hemisphere advantage for positive, and a right hemisphere advantage for negative, emotion. Differences in injury aetiology and chronicity, proportion of male participants, participant age, and the number of emotions used within a perception task may contribute to these contradictory findings. The present study therefore controlled and/or directly examined the influence of these possible moderators. Right brain-damaged (RBD; n=17), left brain-damaged (LBD; n=17), and healthy control (HC; n=34) participants completed two face perception tasks (identification and discrimination). No group differences in facial expression perception according to valence were found. Across emotions, the RBD group was less accurate thanthe HC group, however RBD and LBD group performancedid not differ. The lack of difference between RBD and LBD groups indicates that both hemispheres are involved in positive and negative expression perception. The inclusion of older adults and the well-defined chronicity range of the brain-damaged participants may have moderated these findings. Participant sex and general face perception ability did not influence performance. Furthermore, while the RBD group was less accurate than the LBD group when the identification task tested two emotions, performance of the two groups was indistinguishable when the number of emotions increased (four or six). This suggests that task demand moderates a studys ability to find hemispheric differences in the perception of facial emotion.

Deconstruction of Interhospital Transfer Workflow in Large Vessel Occlusion: Real-World Data in the Thrombectomy Era

Background and Purpose— Interhospital transfer is a critical component in the treatment of acute anterior circulation large vessel occlusive stroke transferred for mechanical thrombectomy. Real-world data for benchmarking and theoretical modeling are limited. We sought to characterize transfer workflow from primary stroke center (PSC) to comprehensive stroke center after the publication of positive thrombectomy trials. Methods— Consecutive patients transferred from 3 high-volume PSCs to a single comprehensive stroke center between January 2015 and August 2016 were included in a retrospective study. Factors associated with key time metrics were analyzed with emphasis on PSC intrahospital workflow. Results— Sixty-seven patients were identified. Median age was 74 years (interquartile range [IQR], 63.5–78) and National Institutes of Health Stroke Scale 17 (IQR, 12–21). Median transfer time measured by PSC-door-to-comprehensive stroke center-door was 128 minutes (IQR, 107–164), of which 82.8% was spent at PSCs (door-in-door-out [DIDO]; 106 minutes; IQR, 86–143). The lengthiest component of DIDO was computed-tomography-to-retrieval-request (median 59.5 minutes; IQR, 44–83). The 37.3% had DIDO exceeding 120 minutes. DIDO times differed significantly between PSCs (P=0.01). In multivariate analyses, rerecruiting the initial ambulance crew for transfer (P<0.01) and presentation during working hours (P=0.04) were associated with shorter DIDO times. Conclusions— In a metropolitan hub-and-spoke network, PSC-door-to-comprehensive stroke center-door and DIDO times are long even in high-volume PSCs. Improving PSC workflow represents a major opportunity to expedite mechanical thrombectomy and improve patient outcomes.