Kenneth Faulder

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.

Surgical risks associated with the management of Grade I and II brain arteriovenous malformations.

OBJECTIVE Grade I and II arteriovenous malformations (AVMs) have been considered safe to resect. However, unoperated low-grade AVMs have not been considered in previously reported series. The aim of this study was to examine all cases, both operated and unoperated, to identify any characteristics of low-grade AVMs that comprise a subgroup that might pose a relatively higher risk. METHODS A prospectively enrolled AVM database included 237 patients in Spetzler-Martin Grade I or II. These patients were analyzed on the basis of demographic characteristics, angiographic and magnetic resonance imaging features, clinical presentation, method of treatment, and outcome. RESULTS Surgery was performed in 220 patients in Spetzler-Martin Grade I or II. Seventeen patients did not undergo treatment because of poor neurological condition (six patients), patient refusal (nine patients), and perceived surgical difficulty (AVM size approaching 3 cm adjacent to Brocas area) (two patients). The overall surgical morbidity rate was 0.9%, and the mortality rate was 0.5%. Adverse outcomes occurred in 1 (0.6%) of 180 patients with AVMs located away from eloquent cortex and in 2 (5%) of 40 patients with AVMs adjacent to eloquent cortex. None of 28 surgical patients with deep venous drainage had an adverse outcome. All 219 patients who survived surgery underwent postoperative angiography that confirmed cure. No postoperative hemorrhage has occurred in 1143 patient-years of follow-up (mean follow-up, 5.3 yr). CONCLUSION When considering adverse outcome in the surgical series of Grade I and II AVMs alone, no statistical difference between non-eloquently located AVMs (0.6%) and eloquently located AVMs (5% adverse outcome) can be detected. However, consideration of all Grade I and II AVMs, both surgical and nonsurgical, may prove that a difference in outcome exists between these two groups masked by case selection. Generalization of the chances of adverse outcomes to all Grade I and II AVMs (both operated and unoperated) suggests that the risk of performing surgery on noneloquent brain in our series was 0.6% and that in eloquent brain could have been as high as 9.5%, had all such patients undergone surgery.

Sex differences in intracranial arterial bifurcations

BACKGROUND Subarachnoid hemorrhage (SAH) is a serious condition, occurring more frequently in females than in males. SAH is mainly caused by rupture of an intracranial aneurysm, which is formed by localized dilation of the intracranial arterial vessel wall, usually at the apex of the arterial bifurcation. The female preponderance is usually explained by systemic factors (hormonal influences and intrinsic wall weakness); however, the uneven sex distribution of intracranial aneurysms suggests a possible physiologic factor-a local sex difference in the intracranial arteries. OBJECTIVE The aim of this study was to explore sex variation in the bifurcation anatomy of the middle cerebral artery (MCA) and internal carotid artery (ICA), and the subsequent hemodynamic impact. METHODS Vessel radii and bifurcation angles were measured in patients with MCA and ICA bifurcations. Data from a previously published study of 55 patients undergoing diagnostic cerebral digital subtraction angiography at Dalcross Private Hospital in Sydney, Australia, between 2002 and 2003, were available for analysis. The measurements were used to create idealized, averaged bifurcations of the MCA and ICA for females and males. Computational fluid dynamics simulations were performed to calculate hemodynamic forces in the models. RESULTS The vessel radii and bifurcation angles of 47 MCA and 52 ICA bifurcations in 49 patients (32 females, 17 males; mean age, 53 years; age range, 14-86 years) were measured. Statistically significant sex differences were found in vessel diameter (males larger than females; P < 0.05), but not in bifurcation angle. Computational fluid dynamics simulations revealed higher wall shear stress in the female MCA (19%) and ICA (50%) bifurcations compared with the male bifurcations. CONCLUSIONS This study of MCA and ICA bifurcations in female and male patients suggests that sex differences in vessel size and blood flow velocity result in higher hemodynamic forces acting on the vessel wall in females. This new hypothesis may partly explain why intracranial aneurysms and SAH are more likely to occur in females than in males.

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.)

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.

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

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

Midterm outcomes of paclitaxel-eluting stents for the treatment of intracranial posterior circulation stenoses.

reference year 2014). Results There were 70 patients, 35 in each arm, mean age 69, median NIHSS 15 (IQR 12–19). The median (IQR) disability-weighted utility score at 90 days was 0.65 (0.00–0.91) in the alteplase-only versus 0.91 (0.65–1.00) in the endovascular group (p = 0.005). Modeled life expectancy was greater in the endovascular versus alteplase-only group (median 15.6 versus 11.2 years, p = 0.02). The endovascular thrombectomy group had fewer simulated DALYs lost over 15 years [median (IQR) 5.5 (3.2–8.7) versus 8.9 (4.7–13.8), p = 0.02] and more QALY gained [median (IQR) 9.3 (4.2–13.1) versus 4.9 (0.3–8.5), p = 0.03]. Endovascular patients spent less time in hospital [median (IQR) 5 (3–11) days versus 8 (5–14) days, p = 0.04] and rehabilitation [median (IQR) 0 (0–28) versus 27 (0–65) days, p = 0.03]. The estimated inpatient costs in the first 90 days were less in the thrombectomy group (average US

Turning Point of Acute Stroke Therapy: Mechanical Thrombectomy as a Standard of Care

15,689 versus US