Richard Libman

Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial.

BACKGROUND The clinical benefit of preventive eradication of unruptured brain arteriovenous malformations remains uncertain. A Randomised trial of Unruptured Brain Arteriovenous malformations (ARUBA) aims to compare the risk of death and symptomatic stroke in patients with an unruptured brain arteriovenous malformation who are allocated to either medical management alone or medical management with interventional therapy. METHODS Adult patients (≥18 years) with an unruptured brain arteriovenous malformation were enrolled into this trial at 39 clinical sites in nine countries. Patients were randomised (by web-based system, in a 1:1 ratio, with random permuted block design [block size 2, 4, or 6], stratified by clinical site) to medical management with interventional therapy (ie, neurosurgery, embolisation, or stereotactic radiotherapy, alone or in combination) or medical management alone (ie, pharmacological therapy for neurological symptoms as needed). Patients, clinicians, and investigators are aware of treatment assignment. The primary outcome is time to the composite endpoint of death or symptomatic stroke; the primary analysis is by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00389181. FINDINGS Randomisation was started on April 4, 2007, and was stopped on April 15, 2013, when a data and safety monitoring board appointed by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health recommended halting randomisation because of superiority of the medical management group (log-rank Z statistic of 4·10, exceeding the prespecified stopping boundary value of 2·87). At this point, outcome data were available for 223 patients (mean follow-up 33·3 months [SD 19·7]), 114 assigned to interventional therapy and 109 to medical management. The primary endpoint had been reached by 11 (10·1%) patients in the medical management group compared with 35 (30·7%) in the interventional therapy group. The risk of death or stroke was significantly lower in the medical management group than in the interventional therapy group (hazard ratio 0·27, 95% CI 0·14-0·54). No harms were identified, other than a higher number of strokes (45 vs 12, p<0·0001) and neurological deficits unrelated to stroke (14 vs 1, p=0·0008) in patients allocated to interventional therapy compared with medical management. INTERPRETATION The ARUBA trial showed that medical management alone is superior to medical management with interventional therapy for the prevention of death or stroke in patients with unruptured brain arteriovenous malformations followed up for 33 months. The trial is continuing its observational phase to establish whether the disparities will persist over an additional 5 years of follow-up. FUNDING National Institutes of Health, National Institute of Neurological Disorders and Stroke.

Quality improvement in acute stroke: The New York State Stroke Center Designation Project

Background: Many hospitals lack the infrastructure required to treat patients with acute stroke. The Brain Attack Coalition (BAC) published guidelines for the establishment of primary stroke centers. Objective: To determine if stroke center designation and selective triage of acute stroke patients improve quality of care. Methods: Baseline chart abstraction was performed on all stroke patients admitted to 32 hospitals serving Brooklyn and Queens, NY, from March to May 2002. Hospitals were invited to meet BAC guideline-based criteria. Adherence was verified by on-site visits. After designation, acute stroke patients were selectively triaged. Remeasurement data were collected from August to October 2003. Results: The authors abstracted 1,598 charts at baseline and 1,442 charts at remeasurement. From baseline to remeasurement, median times decreased for door to physician contact (25 vs 15 minutes, p = 0.001), CT performance for potential tissue plasminogen activator (t-PA) candidates (68 vs 32 minutes, p < 0.001), and t-PA administration (109 vs 98 minutes (p = NS). IV t-PA utilization increased from 2.4 to 5.2% (p < 0.005), select t-PA protocol violations decreased from 11.1 to 7.9% (p = NS), and the stroke unit admission rate increased from 16 to 39% (p < 0.001). In stroke centers (n = 14) vs nondesignated hospitals (n = 18), there were shorter median times from door to physician contact (10 vs 25 minutes, p < 0.001), CT performance for potential t-PA candidates (31 vs 40 minutes, p = NS), and t-PA administration (95 vs 115 minutes, p < 0.05). Stroke centers, compared with nondesignated centers, admitted acute stroke patients to stroke units more often (55.9 vs 10.9%, p < 0.001). Conclusions: Stroke center designation and selective triage of acute stroke patients improved the quality of care, including access to timely thrombolytic therapy and stroke units.

The Combined Approach to Lysis Utilizing Eptifibatide and rt-PA in Acute Ischemic Stroke The CLEAR Stroke Trial

Background and Purpose— Multiple approaches are being studied to enhance the rate of thrombolysis for acute ischemic stroke. Treatment of myocardial infarction with a combination of a reduced-dose fibrinolytic agent and a glycoprotein (GP) IIb/IIIa receptor antagonist has been shown to improve the rate of recanalization versus fibrinolysis alone. The combined approach to lysis utilizing eptifibatide and recombinant tissue-type plasminogen activator (rt-PA) (CLEAR) stroke trial assessed the safety of treating acute ischemic stroke patients within 3 hours of symptom onset with this combination. Methods— The CLEAR trial was a National Institutes of Health/National Institute of Neurological Disorders and Stroke–funded multicenter, double-blind, randomized, dose-escalation and safety study. Patients were randomized 3:1 to either low-dose rt-PA (tier 1=0.3 mg/kg, tier 2=0.45 mg/kg) plus eptifibatide (75 &mgr;g/kg bolus followed by 0.75 &mgr;g/kg per min infusion for 2 hours) or standard-dose rt-PA (0.9 mg/kg). The primary safety end point was the incidence of symptomatic intracerebral hemorrhage within 36 hours. Secondary analyses were performed regarding clinical efficacy. Results— Ninety-four patients (40 in tier 1 and 54 in tier 2) were enrolled. The combination group of the 2 dose tiers (n=69) had a median age of 71 years and a median baseline National Institutes of Health Stroke Scale (NIHSS) score of 14, and the standard-dose rt-PA group (n=25) had a median age of 61 years and a median baseline NIHSS score of 10 (P=0.01 for NIHSS score). Fifty-two (75%) of the combination treatment group and 24 (96%) of the standard treatment group had a baseline modified Rankin scale score of 0 (P=0.04). There was 1 (1.4%; 95% CI, 0% to 4.3%) symptomatic intracranial hemorrhage in the combination group and 2 (8.0%; 95% CI, 0% to 19.2%) in the rt-PA–only arm (P=0.17). During randomization in tier 2, a review by the independent data safety monitoring board demonstrated that the safety profile of combination therapy at the tier 2 doses was such that further enrollment was statistically unlikely to indicate inadequate safety for the combination treatment group, the ultimate outcome of the study. Thus, the study was halted. There was a trend toward increased clinical efficacy of standard-dose rt-PA compared with the combination treatment group. Conclusions— The safety of the combination of reduced-dose rt-PA plus eptifibatide justifies further dose-ranging trials in acute ischemic stroke.

Phase IIB/III Trial of Tenecteplase in Acute Ischemic Stroke. Results of a Prematurely Terminated Randomized Clinical Trial

Background and Purpose— Intravenous alteplase (rtPA) remains the only approved treatment for acute ischemic stroke, but its use remains limited. In a previous pilot dose-escalation study, intravenous tenecteplase showed promise as a potentially safer alternative. Therefore, a Phase IIB clinical trial was begun to (1) choose a best dose of tenecteplase to carry forward; and (2) to provide evidence for either promise or futility of further testing of tenecteplase versus rtPA. If promise was established, then the trial would continue as a Phase III efficacy trial comparing the selected tenecteplase dose to standard rtPA. Methods— The trial began as a small, multicenter, randomized, double-blind, controlled clinical trial comparing 0.1, 0.25, and 0.4 mg/kg tenecteplase with standard 0.9 mg/kg rtPA in patients with acute stroke within 3 hours of onset. An adaptive sequential design used an early (24-hour) assessment of major neurological improvement balanced against occurrence of symptomatic intracranial hemorrhage to choose a “best” dose of tenecteplase to carry forward. Once a “best” dose was established, the trial was to continue until at least 100 pairs of the selected tenecteplase dose versus standard rtPA could be compared by 3-month outcome using the modified Rankin Scale in an interim analysis. Decision rules were devised to yield a clear recommendation to either stop for futility or to continue into Phase III. Results— The trial was prematurely terminated for slow enrollment after only 112 patients had been randomized at 8 clinical centers between 2006 and 2008. The 0.4-mg/kg dose was discarded as inferior after only 73 patients were randomized, but the selection procedure was still unable to distinguish between 0.1 mg/kg and 0.25 mg/kg as a propitious dose at the time the trial was stopped. There were no statistically persuasive differences in 3-month outcomes between the remaining tenecteplase groups and rtPA. Symptomatic intracranial hemorrhage rates were highest in the discarded 0.4-mg/kg tenecteplase group and lowest (0 of 31) in the 0.1-mg/kg tenecteplase group. Neither promise nor futility could be established. Conclusion— This prematurely terminated trial has demonstrated the potential efficiency of a novel design in selecting a propitious dose for future study of a new thrombolytic agent for acute stroke. Given the truncation of the trial, no convincing conclusions can be made about the promise of future study of tenecteplase in acute stroke.

Diffuse cerebral vasoconstriction (Call–Fleming syndrome) and stroke associated with antidepressants

Call–Fleming syndrome is a reversible segmental vasoconstriction of cerebral arteries manifested by a “thunderclap” headache and focal neurologic symptoms. Although of unknown etiology, it has been reported in association with vasoactive sympathomimetic drugs. The authors report Call–Fleming syndrome in two patients with history of antidepressant use. Although the association is hypothetical, the authors suggest consideration of Call–Fleming syndrome in patients presenting with headache, focal deficits, and evidence of cerebral ischemia during antidepressant use.

Central retinal artery occlusion from carotid dissection diagnosed by cervical computed tomography.

Background Carotid dissection may lead to many different types of neurological deficits, both transient and permanent. Case Description We present a patient with an isolated central retinal artery occlusion who was found to have an ipsilateral carotid dissection by neck computed tomographic scan, later confirmed by angiography. Conclusions This is the first reported case of carotid dissection causing central retinal artery occlusion without any other neurological deficits. It demonstrates the diagnostic usefulness of computed tomographic imaging in such cases.

Use and Outcomes of Intravenous Thrombolysis for Acute Ischemic Stroke in Patients ≥90 Years of Age

Background and Purpose— Intravenous tissue-type plasminogen activator (tPA) is a proven treatment for acute ischemic stroke, but there has been limited evaluation among patients aged ≥90 years. Methods— We analyzed data from the Get With The Guidelines–Stroke national quality improvement registry from January 2009 to April 2013. Frequency, determinants, and outcomes of tPA use were compared among patients aged ≥90 and 3 younger age groups (18–64, 65–79, and 80–89 years). Results— Among 35 708 patients from 1178 sites who arrived within 2 hours of time last known well and received tPA, 2585 (7.2%) were ≥90 years. Compared with younger patients, the rate of tPA use among patients without a documented contraindication was lower among patients aged ≥90 years (67.4% versus 84.1% in 18–89-year olds; P<0.0001). Discharge outcomes among individuals aged ≥90 years included discharge to home or acute rehabilitation in 31.4%, independent ambulation at discharge in 13.4%, symptomatic hemorrhage in 6.1%, and in-hospital mortality or hospice discharge in 36.4%. On multivariable analysis, good functional outcomes generally occurred less often and mortality more often among patients aged ≥90 years. The risk of symptomatic hemorrhage was increased compared with patients <65 years but was not significantly different than the risk in 66- to 89-year olds. Conclusions— The use of intravenous tPA among those aged ≥90 years is lower than in younger patients. When fibrinolytic therapy is used, the risk of symptomatic hemorrhage is not higher than in 66- to 89-year olds; however, mortality is higher and functional outcomes are lower.

Thrombolysis for Ischemic Stroke during Pregnancy: A Case Report and Review of the Literature

BACKGROUND AND PURPOSE Our knowledge of the safety of thrombolytic therapy in pregnancy stems from individual case reports and series. We report the successful use of intravenous alteplase (tissue plasminogen activator; tPA) thrombolysis in a pregnant woman with acute cardioembolic stroke presumed to be paradoxical embolism through a patent foramen ovale. METHODS A literature review found several case reports and case series of pregnant patients treated with either intravenous or intra-arterial tPA for acute ischemic stroke. RESULTS A literature review yielded 10 cases of intravenous tPA administration and 5 cases of intra-arterial tPA. In total, there were 3 cases of asymptomatic intracerebral hemorrhage and 1 case of maternal and fetal death. CONCLUSIONS Our patient improved clinically with no residual deficits. There was no evidence of placental or fetal injury following administration of tPA on follow-up obstetrical evaluations.

Pulsatile tinnitus from a redundant arterial loop.

A 21-year-old woman presented with a 5-month history of right-sided pulsatile tinnitus. A general medical and neurologic evaluation revealed no abnormalities and no cervical or cranial bruits. She perceived the pulsatile tinnitus during the examination, and it corresponded to her pulse. Studies with normal results included carotid Doppler, transcranial Doppler, MRI and angiography of …

Functional impairments for outcomes in a randomized trial of unruptured brain AVMs

Objective: To investigate the effects of medical vs interventional management on functional outcome in A Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA). Methods: We used the initial results of a nonblinded, randomized, controlled, parallel-group trial involving adults ≥18 years of age with an unruptured brain arteriovenous malformation (AVM) to compare the effects of medical management (MM) with or without interventional therapy (IT) on functional impairment, defined by a primary outcome of death or symptomatic stroke causing modified Rankin Scale (mRS) score ≥2. ARUBA closed recruitment on April 15, 2013. Results: After a median of 33.3 months of follow-up (interquartile range 16.3–49.8 months), of the 223 enrolled in the trial, those in the MM arm were less likely to experience primary outcomes with an mRS score ≥2 than those who underwent IT. The results applied for both those as randomized (MM n = 109 vs IT n = 114) (hazard ratio [HR] 0.25, 95% confidence interval [CI] 0.11–0.57, p = 0.001) and as treated (MM n = 125 vs IT n = 98) (HR 0.10, 95% CI 0.04–0.28, p < 0.001). Functional impairment for the outcomes showed no significant difference by Spetzler-Martin grade for MM but was more frequent with increasing grades for IT (p < 0.001). Conclusion: Death or stroke with functional impairment in ARUBA after a median follow-up of 33 months was significantly lower for those in the MM arm both as randomized and as treated compared with those with IT. Functional severity of outcomes was lower in the MM arm, regardless of Spetzler-Martin grades. ClinicalTrials.gov identifier: NCT00389181. Classification of evidence: This study provides Class II evidence that for adults with unruptured brain AVMs, interventional management compared to MM increases the risk of disability and death over ≈3 years.