Janice Carrozzella

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.).

Genetic and Environmental Risk Factors for Intracerebral Hemorrhage Preliminary Results of a Population-Based Study

Background and Purpose— Intracerebral hemorrhage (ICH) has a 30-day mortality rate of 40% to 50% and lacks a proven treatment. We report a preplanned, midpoint analysis of the first population-based, case-control study that examines both genetic and environmental risk factors of ICH. Methods— We prospectively identified cases of hemorrhagic stroke at all 16 hospitals in the Greater Cincinnati/Northern Kentucky region. All cases underwent medical record and neuroimaging review. Cases enrolled in the direct interview and genetic sampling arm of the study were matched to population-based control subjects by age, race, and sex. Multivariable logistic regression was performed to identify significant independent risk factors. Results— We enrolled 188 cases of ICH (67 lobar, 121 nonlobar) and 366 control subjects in the direct interview arm of the study. Significant independent risk factors for lobar ICH included the presence of an apolipoprotein E2 or E4 allele, frequent alcohol use, prior stroke, and first-degree relative with ICH. Significant independent risk factors for nonlobar ICH were hypertension, prior stroke, and first-degree relative with ICH. An increasing level of education was associated with a decreased risk of nonlobar ICH. The attributable risk of apolipoprotein E2 or E4 for lobar ICH was 29%, and the attributable risk of hypertension for nonlobar ICH was 54%. Conclusions— There is significant epidemiological evidence that the pathophysiology of ICH varies by location. We estimate that a third of all cases of lobar ICH are attributable to possession of an apolipoprotein E4 or E2 allele and that half of all cases of nonlobar ICH are attributable to hypertension.

Time to angiographic reperfusion and clinical outcome after acute ischaemic stroke: an analysis of data from the Interventional Management of Stroke (IMS III) phase 3 trial

BACKGROUND The IMS III trial did not show a clinical benefit of endovascular treatment compared with intravenous alteplase (recombinant tissue plasminogen activator) alone for moderate or severe ischaemic strokes. Late reperfusion of tissue that was no longer salvageable could be one explanation, as suggested by previous exploratory studies that showed an association between time to reperfusion and good clinical outcome. We sought to validate this association in a preplanned analysis of data from the IMS III trial. METHODS We used data for patients with complete proximal arterial occlusions in the anterior circulation who received endovascular treatment and achieved angiographic reperfusion (score on Thrombolysis in Cerebral Infarction scale of grade 2-3) during the endovascular procedure (within 7 h of symptom onset). We used logistic regression to model good clinical outcome (defined as a modified Rankin Scale score of 0-2 at 3 months) as a function of the time to reperfusion. We prespecified variables to be considered for adjustment, including age, baseline National Institutes of Health Stroke Scale score, sex, and baseline blood glucose concentration. FINDINGS Of 240 patients who were otherwise eligible for inclusion in our analysis, 182 (76%) achieved angiographic reperfusion. Mean time from symptom onset to reperfusion (ie, procedure end) was 325 min (SD 52). Increased time to reperfusion was associated with a decreased likelihood of good clinical outcome (unadjusted relative risk for every 30-min delay 0·85 [95% CI 0·77-0·94]; adjusted relative risk 0·88 [0·80-0·98]). INTERPRETATION Delays in time to angiographic reperfusion lead to a decreased likelihood of good clinical outcome in patients after moderate to severe stroke. Rapid reperfusion could be crucial for the success of future acute endovascular trials. FUNDING US National Institutes of Health and National Institute of Neurological Disorders and Stroke.

Methodology of the Interventional Management of Stroke III Trial

Rationale The Interventional Management of Stroke (IMS) I and II pilot trials demonstrated that the combined intravenous (i.v.) and intraarterial (i.a.) approach to recanalization may be more effective than standard i.v. rt-PA (Activase®) alone for moderate-to-large National Institutes of Health Stroke Scale (NIHSS ≥ 10) strokes, and with a similar safety profile. Aims The primary objective of this NIH-funded, Phase III, randomized, multicenter, open-label clinical trial is to determine whether a combined i.v./i.a. approach to recanalization is superior to standard i.v. rt-PA alone when initiated within 3 h of acute ischemic stroke onset. The IMS III trial will develop and maintain a network of interventional centers to test the safety, feasibility, and potential efficacy of new FDA-approved catheter devices as part of a combined i.v./i.a. approach to recanalization as the IMS III study progresses. A secondary objective of the IMS III trial is to determine the cost-effectiveness of the combined i.v./i.a. approach as compared with standard i.v. rt-PA. Trial enrollment began in July of 2006. Design A projected 900 subjects with moderate-to-large (NIHSS ≥ 10) ischemic strokes between ages 18 and 80 will be enrolled over the next 5 years at 40-plus centers in the United States and Canada. Patients must have i.v. treatment initiated within 3 h of stroke onset in both arms. Subjects will be randomized in a 2: 1 ratio with more subjects enrolled in the combined i.v./i.a. group. The i.v. rt-PA alone group will receive the standard full dose [0·9 mg/kg, 90 mg maximum (10% as bolus)] of rt-PA intravenously over an hour. The combined i.v./i.a. group will receive a lower dose of i.v. rt-PA (~0·6 mg/kg, 60 mg maximum) over 40 min, followed by immediate angiography. If a treatable thrombus is not demonstrated, no i.a. therapy will be administered. If an appropriate thrombus is identified, treatment will continue with either the Concentric Merci® thrombus-removal device, infusion of rt-PA and delivery of low-intensity ultrasound at the site of the occlusion via the EKOS® Micro-Infusion Catheter, or infusion of rt-PA via a standard microcatheter. If i.a. rt-Pa therapy is the chosen strategy, a maximum of 22 mg of i.a. rt-PA may be given. The choice of i.a. strategy will be made by the treating neurointerventionalist. The i.a. treatment must begin within 5 h and be completed within 7 h of stroke onset. Study outcomes The primary outcome measure is a favorable clinical outcome, defined as a modified Rankin Scale Score of 0–2 at 3 months. The primary safety measure is mortality at 3 months and symptomatic ICH within the 24 h of randomization.

Gene expression in blood changes rapidly in neutrophils and monocytes after ischemic stroke in humans: a microarray study.

Ischemic brain and peripheral white blood cells release cytokines, chemokines and other molecules that activate the peripheral white blood cells after stroke. To assess gene expression in these peripheral white blood cells, whole blood was examined using oligonucleotide microarrays in 15 patients at 2.4 ± 0.5, 5 and 24 h after onset of ischemic stroke and compared with control blood samples. The 2.4 h blood samples were drawn before patients were treated either with tissue-type plasminogen activator (tPA) alone or with tPA plus Eptifibatide (the Combination approach to Lysis utilizing Eptifibatide And Recombinant tPA trial). Most genes induced in whole blood at 2 to 3 h were also induced at 5 and 24 h. Separate studies showed that the genes induced at 2 to 24 h after stroke were expressed mainly by polymorphonuclear leukocytes and to a lesser degree by monocytes. These genes included: matrix metalloproteinase 9; S100 calcium-binding proteins P, A12 and A9; coagulation factor V; arginase I; carbonic anhydrase IV; lymphocyte antigen 96 (cluster of differentiation (CD)96); monocarboxylic acid transporter (6); ets-2 (erythroblastosis virus E26 oncogene homolog 2); homeobox gene Hox 1.11; cytoskeleton-associated protein 4; N-formylpeptide receptor; ribonuclease-2; N-acetylneuraminate pyruvate lyase; BCL6; glycogen phosphorylase. The fold change of these genes varied from 1.6 to 6.8 and these 18 genes correctly classified 10/15 patients at 2.4 h, 13/15 patients at 5h and 15/15 patients at 24 h after stroke. These data provide insights into the inflammatory responses after stroke in humans, and should be helpful in diagnosis, understanding etiology and pathogenesis, and guiding acute treatment and development of new treatments for stroke.

Subarachnoid Hemorrhage A Preventable Disease With a Heritable Component

Background and Purpose— Subarachnoid hemorrhage (SAH) caused by ruptured intracranial aneurysm affects approximately 16 000 Americans annually, and almost 40% of affected patients die within 30 days despite the best current therapy. Prevention of SAH is therefore of paramount importance. We present a preliminary analysis of risk factors for SAH from our population-based, case-control study. Methods— Cases were prospectively collected and matched 2:1 by age, race, and gender to controls using random digit dialing. Personal risk factor history, family history, neuroimaging data, and genetic samples were obtained. Univariate and bivariate analyses were performed and population-attributable risks estimated. Multivariable analysis was performed using conditional logistic regression. Results— Between June 1997 and February 2000, 107 cases and 197 controls were enrolled. In bivariate analyses, a large proportion of population-attributable risk for SAH could be explained by modifiable risk factors: smoking, hypertension, and heavy alcohol use. In multivariable analysis, current cigarette smoking, history of hypertension, frequent alcohol use, lower body mass index, and a family history of a relative with SAH or intracranial aneurysm were found to be significant, independent risk factors for SAH. Conclusion— Our data confirm previous reports that SAH clusters within some families independent of environmental risk factors, suggesting that SAH has a significant genetic component. Yet, even among families at increased risk of SAH, smoking cessation, treatment of hypertension, and reduced alcohol intake may substantially decrease SAH risk. The independent associations with heavy alcohol use and low body mass index with SAH may be confounded by smoking and require further study.

Revascularization End Points in Stroke Interventional Trials Recanalization Versus Reperfusion in IMS-I

Background and Purpose— The acute stroke literature lacks a standard convention regarding the critical end point of revascularization. Two distinct parameters may be clinically important: (1) recanalization of the primary arterial occlusive lesion (AOL) and (2) global reperfusion of the distal vascular bed. We sought to determine their relationship in the Interventional Management of Stroke (IMS) Phase I trial of combined intravenous (IV) and intraarterial (IA) recombinant tissue plasminogen activator. Methods— Sixty-one angiograms were reanalyzed using recanalization and reperfusion scores. The AOL Score was defined as: 0=no recanalization of the primary occlusion, I=incomplete or partial recanalization of the primary occlusion with no distal flow, II=incomplete or partial recanalization of the primary occlusion with distal flow, or III=complete recanalization of the primary occlusion with distal flow. The Thrombolysis in Myocardial Infarction (TIMI) Score was defined as: 0=no perfusion, 1=perfusion past the initial occlusion but no distal branch filling, 2=perfusion and incomplete or slow distal branch filling, or 3=full perfusion with filling of all distal branches. We compared the 2 scores with one another and with good clinical outcome (modified Rankin Score zero to 2). Results— AOL and TIMI scores showed modest agreement (kappa, 0.30; confidence interval, 0.16 to 0.44). Good clinical outcome was seen in 49% of patients with AOL II/III scores (P=0.055) and 54% with TIMI 2/3 scores (P=0.019). The 2 methods did not significantly differ in predicting outcome (P=0.13). Conclusions— AOL recanalization and TIMI reperfusion scores comparably predict clinical outcome in this treatment paradigm. Other modalities may show different relationships between these 2 revascularization end points. Future studies should distinguish between these parameters semantically and methodologically.

Combined Intravenous and Intra-Arterial Recombinant Tissue Plasminogen Activator in Acute Ischemic Stroke

Background and Purpose A retrospective analysis was performed on 20 consecutive patients who presented with severe acute ischemic stroke and were evaluated for a combined intravenous (IV) and local intra-arterial (IA) recombinant tissue plasminogen activator (rtPA) thrombolytic approach within 3 hours of onset. Methods Twenty consecutive patients with carotid artery distribution strokes were evaluated and treated using a combined IV and IA rtPA approach over a 14-month period (September 1998 to October 1999). rtPA (0.6 mg/kg) was given intravenously (maximum dose 60 mg); 15% of the IV dose was given as bolus, followed by a continuous infusion over 30 minutes. A maximal IA dose, up to 0.3 mg/kg or 24 mg, whichever was less, was given over a maximum of 2 hours. IV treatment was initiated within 3 hours in 19 of 20 patients. All 20 patients underwent angiography, and 16 of 20 patients received local IA rtPA. Results The median baseline National Institutes of Health Stroke Scale (NIHSS) score for the 20 patients was 21 (range 11 to 31). The median time from stroke onset to IV treatment was 2 hours and 2 minutes, and median time to initiation of IA treatment was 3 hours and 30 minutes. Ten patients (50%) recovered to a modified Rankin Scale (mRS) of 0 or 1; 3 patients (15%), to an mRS of 2; and 5 patients (25%), to an mRS of 4 or 5. One patient (5%) developed a symptomatic intracerebral hemorrhage and eventually died. One other patient (5%) expired because of complications from the stroke. Conclusions We believe that the greater-than-expected proportion of favorable outcomes in these patients with severe ischemic stroke reflects the short time to initiation of both IV and IA thrombolysis.

Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion Imaging

Background Thrombectomy is currently recommended for eligible patients with stroke who are treated within 6 hours after the onset of symptoms. Methods We conducted a multicenter, randomized, open‐label trial, with blinded outcome assessment, of thrombectomy in patients 6 to 16 hours after they were last known to be well and who had remaining ischemic brain tissue that was not yet infarcted. Patients with proximal middle‐cerebral‐artery or internal‐carotid‐artery occlusion, an initial infarct size of less than 70 ml, and a ratio of the volume of ischemic tissue on perfusion imaging to infarct volume of 1.8 or more were randomly assigned to endovascular therapy (thrombectomy) plus standard medical therapy (endovascular‐therapy group) or standard medical therapy alone (medical‐therapy group). The primary outcome was the ordinal score on the modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability) at day 90. Results The trial was conducted at 38 U.S. centers and terminated early for efficacy after 182 patients had undergone randomization (92 to the endovascular‐therapy group and 90 to the medical‐therapy group). Endovascular therapy plus medical therapy, as compared with medical therapy alone, was associated with a favorable shift in the distribution of functional outcomes on the modified Rankin scale at 90 days (odds ratio, 2.77; P<0.001) and a higher percentage of patients who were functionally independent, defined as a score on the modified Rankin scale of 0 to 2 (45% vs. 17%, P<0.001). The 90‐day mortality rate was 14% in the endovascular‐therapy group and 26% in the medical‐therapy group (P=0.05), and there was no significant between‐group difference in the frequency of symptomatic intracranial hemorrhage (7% and 4%, respectively; P=0.75) or of serious adverse events (43% and 53%, respectively; P=0.18). Conclusions Endovascular thrombectomy for ischemic stroke 6 to 16 hours after a patient was last known to be well plus standard medical therapy resulted in better functional outcomes than standard medical therapy alone among patients with proximal middle‐cerebral‐artery or internal‐carotid‐artery occlusion and a region of tissue that was ischemic but not yet infarcted. (Funded by the National Institute of Neurological Disorders and Stroke; DEFUSE 3 ClinicalTrials.gov number, NCT02586415.)

Collaterals at Angiography and Outcomes in the Interventional Management of Stroke (IMS) III Trial

Background and Purpose— Endovascular strategies provide unique opportunity to correlate angiographic measures of collateral circulation at the time of endovascular therapy. We conducted systematic analyses of collaterals at conventional angiography on recanalization, reperfusion, and clinical outcomes in the endovascular treatment arm of the Interventional Management of Stroke (IMS) III trial. Methods— Prospective evaluation of angiographic collaterals was conducted via central review of subjects treated with endovascular therapy in IMS III (n=331). Collateral grade before endovascular therapy was assessed with the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology scale, blinded to all other data. Statistical analyses investigated the association between collaterals with baseline clinical variables, angiographic measures of recanalization, reperfusion and clinical outcomes. Results— Adequate views of collateral circulation to the ischemic territory were available in 276 of 331 (83%) subjects. Collateral grade was strongly related to both recanalization of the occluded arterial segment (P=0.0016) and downstream reperfusion (P<0.0001). Multivariable analyses confirmed that robust angiographic collateral grade was a significant predictor of good clinical outcome (modified Rankin Scale score ⩽2) at 90 days (P=0.0353), adjusted for age, history of diabetes mellitus, National Institutes of Health Stroke Scale strata, and Alberta Stroke Program Early CT Score. The relationship between collateral flow and clinical outcome may depend on the degree of reperfusion. Conclusions— More robust collateral grade was associated with better recanalization, reperfusion, and subsequent better clinical outcomes. These data, from the largest endovascular trial to date, suggest that collaterals are an important consideration in future trial design. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00359424.