Brendan Steinfort

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.

The detrimental clinical impact of severe angiographic vasospasm may be diminished by maximal medical therapy and intensive endovascular treatment

Objective Severe angiographic vasospasm (aVSP) is a risk factor for poor functional outcome following subarachnoid hemorrhage. We investigated the impact of angiographic surveillance and intensive endovascular treatment using transluminal balloon angioplasty (TBA) and/or verapamil infusion for severe aVSP through comparison of clinical outcomes in patients of similar presenting grade but with no/mild vasospasm. Methods This was an analysis of prospectively acquired clinical trial data. World Federation of Neurosurgical Societies (WFNS) grade 1–2 patients presenting within 72 h were included. Angiographic screening for vasospasm was undertaken at days 5–7 or in response to clinical deterioration. Severe aVSP was defined as >50% luminal narrowing on digital subtraction angiography. Treatment was instituted on the basis of radiographic findings and/or clinical deterioration. Discharge destination and favorable clinical outcomes (discharge Glasgow Outcome Score (GOS) 4–5, 90 day modified Rankin Scale (mRS) score 0–2, and GOS 4–5) for patients with severe aVSP were compared with those without significant vasospasm. Statistical analysis was undertaken using Fishers exact test. Results 63 WFNS grade 1–2 patients with minimal vasospasm were compared with 17 WFNS grade 1–2 patients with severe aVSP treated with induced hypertension and endovascular therapy. Results were available in 62 and 16 patients, respectively. Rates of favorable outcome did not differ significantly between the two groups. For patients with treated severe vasospasm, 90 day mRS 0–2 was seen in 15/17 (88.2%) and GOS 4–5 was achieved in 16/17 (94.1%). Conclusions An intensive endovascular approach of TBA and/or intra-arterial verapamil in combination with induced hypertension for severe aVSP may result in comparable clinical outcomes to those without vasospasm.

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.)

Rates of local procedural-related structural injury following clipping or coiling of anterior communicating artery aneurysms.

Background Surgical clipping and endovascular coiling yield similar functional outcomes for the treatment of saccular aneurysms of the anterior communicating (ACOM) artery. However, surgical treatment may be associated with greater rates of cognitive impairment due to injury of adjacent structures. We aimed to quantify the rates of injury (infarction/hemorrhage) for both clipping and coiling of ACOM aneurysms. Methods This was a retrospective dual-center radiological investigation of a consecutive series of patients with ruptured and unruptured ACOM aneurysms treated between January 2011 and October 2014. Post-treatment CT or MRI was assessed for new ischemic or hemorrhagic injury. Injury relating to the primary hemorrhage or vasospasm was differentiated. Univariate analysis using χ2 tests and multivariate analysis using binary logistic regression was used. Results 66 patients treated with clipping were compared with 93 patients treated with coiling. 32/66 (48.5%) patients in the clipping group suffered treatment-related injury (31 ischemic, 1 hemorrhagic) compared with 4/93 (4.4%) patients in the coiling group (3 ischemic, 1 hemorrhagic) (p<0.0001). For patients with subarachnoid hemorrhage, the multivariate OR for infarction for clipping over coiling was 24.42 (95% CI 5.84 to 102.14), p<0.0001. The most common site of infarction was the basal forebrain (28/66 patients, 42.4%), with bilateral infarction in 4. There was injury of the septal/subcallosal region in 12/66 patients (18%). Conclusions Clipping of ACOM aneurysms is associated with significantly higher rates of structural injury than coiling, and this may be a reason for superior cognitive outcomes in patients treated with coiling in previously published studies.

Thrombosis of a Developmental Venous Anomaly Causing Venous Infarction and Pontine Hemorrhage

Developmental venous anomalies are often incidental findings on brain imaging. We report a case of a thrombosed developmental venous anomaly with venous congestion and pontine hemorrhage that improved after anticoagulation therapy.

Bioactive versus bare platinum coils for the endovascular treatment of intracranial aneurysms: systematic review and meta-analysis of randomized clinical trials

Background Bioactive coils were introduced in 2002 in an attempt to improve aneurysm healing and durability of angiographic results. Evidence demonstrating superior efficacy to justify the routine use of bioactive coils over bare coils is limited. We compared the periprocedural and clinical outcome after bioactive and bare platinum coiling for intracranial aneurysms. Methods MEDLINE, EMBASE, Cochrane Library, and ISI Web of Knowledge Conference Proceedings Citation Index—Science were searched for randomized clinical trials (RCTs) comparing bioactive and bare coils. The methodological quality was evaluated to assess bias risk. Periprocedural outcomes and mid-term outcomes were compared. Results Five independent RCTs comparing bioactive (n=1084) and bare coils (n=1084) were identified. Periprocedural outcome was similar for both groups. Bioactive coiling increased the rate of complete aneurysm occlusion (47% vs 40%; RR 1.17 (95% CI 1.05 to 1.31); p=0.006) and reduced the rate of residual aneurysm neck at 10 months compared with bare coiling in the mid-term (26% vs 31%; RR 0.82 (95% CI 0.70 to 0.96); p=0.01). There were no differences in aneurysm recurrence, aneurysm rupture, stroke, neurological death, modified Rankin Scale score and reinterventions. Subgroup analysis for the three RCTs on hydrogel coils demonstrated reduction of residual aneurysms compared with bare coiling (25% vs 34%; RR 0.76 (95% CI 0.58 to 0.99); p=0.04). Conclusions Bioactive coils ensure a higher rate of medium-term complete aneurysm occlusion while reducing the rate of residual neck aneurysms compared with bare coiling in the mid-term. Hydrogel coils reduce residual aneurysms compared with bare coils. While there is level 1a evidence to show more complete aneurysm occlusion, longer term follow-up is needed to determine if this translates into clinical significance.

Tenecteplase versus alteplase before endovascular thrombectomy (EXTEND-IA TNK): A multicenter, randomized, controlled study

Background and hypothesis Intravenous thrombolysis with alteplase remains standard care prior to thrombectomy for eligible patients within 4.5 h of ischemic stroke onset. However, alteplase only succeeds in reperfusing large vessel arterial occlusion prior to thrombectomy in a minority of patients. We hypothesized that tenecteplase is non-inferior to alteplase in achieving reperfusion at initial angiogram, when administered within 4.5 h of ischemic stroke onset, in patients planned to undergo endovascular therapy. Study design EXTEND-IA TNK is an investigator-initiated, phase II, multicenter, prospective, randomized, open-label, blinded-endpoint non-inferiority study. Eligibility requires a diagnosis of ischemic stroke within 4.5 h of stroke onset, pre-stroke modified Rankin Scale≤3 (no upper age limit), large vessel occlusion (internal carotid, basilar, or middle cerebral artery) on multimodal computed tomography and absence of contraindications to intravenous thrombolysis. Patients are randomized to either IV alteplase (0.9 mg/kg, max 90 mg) or tenecteplase (0.25 mg/kg, max 25 mg) prior to thrombectomy. Study outcomes The primary outcome measure is reperfusion on the initial catheter angiogram, assessed as modified treatment in cerebral infarction 2 b/3 or the absence of retrievable thrombus. Secondary outcomes include modified Rankin Scale at day 90 and favorable clinical response (reduction in National Institutes of Health Stroke Scale by ≥8 points or reaching 0–1) at day 3. Safety outcomes are death and symptomatic intracerebral hemorrhage. Trial registration ClinicalTrials.gov NCT02388061

Delayed infarction following aneurysmal subarachnoid hemorrhage: Can the role of severe angiographic vasospasm really be dismissed?

Background The recent literature pertaining to delayed cerebral ischemia following aneurysmal subarachnoid hemorrhage has downplayed the role of angiographic vasospasm. However, it is our hypothesis that angiographic vasospasm has a significant pathophysiological role in this disease. We undertook an observational radiographic study of patients who presented in a delayed manner (>72 h from ictus) with evidence of severe angiographic vasospasm on initial angiography in order to describe an apparent association between vasospasm and infarct location. Methods This was a retrospective study of consecutive patients treated at our unit. Initial, subsequent, and follow-up cross-sectional imaging with CT or MRI was analyzed in conjunction with initial angiography. Sites of angiographic narrowing, angiographic hypoperfusion, and subsequent sites of infarction were assessed. Results Thirteen patients (6 women, 7 men) of mean age 49 years were assessed. Mean time to presentation was 6 days. All had severe angiographic vasospasm. Nine of the 13 patients suffered infarction; the infarcts in seven of the nine patients were large. There was correlation between sites of angiographic narrowing and infarction in all cases and eight of the nine cases showed angiographic hypoperfusion in a location corresponding to eventual infarct location. Conclusions Severe angiographic vasospasm may be linked to infarction in patients who present late. These infarcts are mostly large despite maximal treatment. We question the notion that proximal vasospasm has a minor role in delayed ischemia.

Institution of sustained endovascular treatment prior to clinical deterioration in patients with severe angiographic vasospasm: A retrospective observational study of clinico-radiological outcomes

UNLABELLED Severe angiographic vasospasm (aVSP) is a risk factor for infarction following subarachnoid haemorrhage and infarction is strongly associated with poor outcome. We present the clinico-radiological results of cohort with severe aVSP who underwent a program of angiographic surveillance and sustained endovascular treatment using multiple verapamil infusions and/or transluminal balloon angioplasty (TBA). METHODS This was a dual-centre retrospective observational study. Angiographic screening for vasospasm was undertaken at days 5-7 post-ictus. Treatment was instituted principally on the basis of radiographic findings. The rate of infarction was evaluated on follow-up CT. Clinical outcome was assessed using the modified Rankin Scale (mRS). RESULTS Fifty-seven WFNS grades 1-5 patients were studied. The mean number of procedures/patient was 6, range 2-13. Mean verapamil dose administered to the ICA was 14 mg and VA was 12 mg. Thirty-one patients underwent TBA (52.6%). The rate of proximal vessel infarction was 3/45 (6.7%) for patients presenting <72 hours. Rates of favourable outcome (mRS 0-2) were 16/19 (84.2%) for WFNS grades 1-2, 12/19 (63.2%) for grades 3-4 and 5/19 (26.3%) for grade 5 patients. Delayed presentation >72 hours was the only factor on multivariate analysis to significantly predict aVSP-infarction [OR19.3 (3.2-116.6) P=0.0012]. Large aVSP-infarction [OR19.0 (1.7-216.4) 0.0179] and poor WFNS grade [OR 6.6 (1.3-33.9) P = 0.0233] were significant predictors of poor outcome on multivariate analysis. CONCLUSION This approach may result in low rates of aVSP-infarction and encouraging rates of favourable outcome when compared to literature benchmarks. Delayed presentation, however, predicts infarction and large infarct and poor initial grade significantly influence functional outcome.

Endovascular thrombectomy for ischemic stroke increases disability-free survival, quality of life, and life expectancy and reduces cost

Background Endovascular thrombectomy improves functional outcome in large vessel occlusion ischemic stroke. We examined disability, quality of life, survival and acute care costs in the EXTEND-IA trial, which used CT-perfusion imaging selection. Methods Large vessel ischemic stroke patients with favorable CT-perfusion were randomized to endovascular thrombectomy after alteplase versus alteplase-only. Clinical outcome was prospectively measured using 90-day modified Rankin scale (mRS). Individual patient expected survival and net difference in Disability/Quality-adjusted life years (DALY/QALY) up to 15 years from stroke were modeled using age, sex, 90-day mRS, and utility scores. Level of care within the first 90 days was prospectively measured and used to estimate procedure and inpatient care costs (US