Original and Modified Graeb Score Correlation With Intraventricular Hemorrhage and Clinical Outcome Prediction in Hyperacute Intracranial Hemorrhage.

Background and Purpose- The Graeb score is a visual rating scale of intraventricular hemorrhage (IVH) on noncontrast head CT. Little data exist in the hyperacute (<6 hour) period for reliability and predictive value of the modified Graeb Score (mGS) or the original Graeb Score (oGS) for clinical outcomes or their correlation with quantitative IVH volumes. Methods- A retrospective analysis of multicenter prospective intracranial hemorrhage study was performed. oGS and mGS inter-observer agreement and IVH volume correlation on the baseline noncontrast head CT were calculated by intraclass correlation coefficient and Pearson coefficient respectively. Predictors of poor outcome (modified Rankin Scale scores ≥4) at 3 months were identified using a backward stepwise selection multivariable analysis. oGS and mGS performance for modified Rankin Scale scores ≥4 was determined by receiver operating characteristic analysis. Results- One hundred forty-one patients (65±12 years) with median (interquartile range) time to CT of 82.5 (70.3-157.5) minutes were included. IVH was observed in 43 (30%) patients. Inter-observer agreement was excellent for both oGS (intraclass correlation coefficient, 0.90 [95% CI, 0.80-0.95]) and mGS (intraclass correlation coefficient, 0.97 [95% CI, 0.84-0.99]). mGS (R=0.79; P<0.01) correlated better than oGS (R=0.71; P<0.01) with IVH volumes (P=0.02). Models of thresholded oGS and mGS were not different from a model of planimetric baseline intracranial hemorrhage and IVH volume for poor outcome prediction. Area under the curves were 0.70, 0.73, and 0.72, respectively. Conclusions- Excellent correlation for oGS and mGS with IVH volume was seen. Thresholded oGS and mGS are reasonable surrogates for planimetric IVH volume for hyperacute intracranial hemorrhage studies.

Effect of Recombinant Activated Coagulation Factor VII on Hemorrhage Expansion Among Patients With Spot Sign-Positive Acute Intracerebral Hemorrhage: The SPOTLIGHT and STOP-IT Randomized Clinical Trials.

Importance: Intracerebral hemorrhage (ICH) is a devastating stroke type that lacks effective treatments. An imaging biomarker of ICH expansion-the computed tomography (CT) angiography spot sign-may identify a subgroup that could benefit from hemostatic therapy. Objective: To investigate whether recombinant activated coagulation factor VII (rFVIIa) reduces hemorrhage expansion among patients with spot sign-positive ICH. Design, Setting, and Participants: In parallel investigator-initiated, multicenter, double-blind, placebo-controlled randomized clinical trials in Canada ("Spot Sign" Selection of Intracerebral Hemorrhage to Guide Hemostatic Therapy [SPOTLIGHT]) and the United States (The Spot Sign for Predicting and Treating ICH Growth Study [STOP-IT]) with harmonized protocols and a preplanned individual patient-level pooled analysis, patients presenting to the emergency department with an acute primary spontaneous ICH and a spot sign on CT angiography were recruited. Data were collected from November 2010 to May 2016. Data were analyzed from November 2016 to May 2017. Interventions: Eligible patients were randomly assigned 80 µg/kg of intravenous rFVIIa or placebo as soon as possible within 6.5 hours of stroke onset. Main Outcomes and Measures: Head CT at 24 hours assessed parenchymal ICH volume expansion from baseline (primary outcome) and total (ie, parenchymal plus intraventricular) hemorrhage volume expansion (secondary outcome). The pooled analysis compared hemorrhage expansion between groups by analyzing 24-hour volumes in a linear regression model adjusted for baseline volumes, time from stroke onset to treatment, and trial. Results: Of the 69 included patients, 35 (51%) were male, and the median (interquartile range [IQR]) age was 70 (59-80) years. Baseline median (IQR) ICH volumes were 16.3 (9.6-39.2) mL in the rFVIIa group and 20.4 (8.6-32.6) mL in the placebo group. Median (IQR) time from CT to treatment was 71 (57-96) minutes, and the median (IQR) time from stroke onset to treatment was 178 (138-197) minutes. The median (IQR) increase in ICH volume from baseline to 24 hours was small in both the rFVIIa group (2.5 [0-10.2] mL) and placebo group (2.6 [0-6.6] mL). After adjustment, there was no difference between groups on measures of ICH or total hemorrhage expansion. At 90 days, 9 of 30 patients in the rFVIIa group and 13 of 34 in the placebo group had died or were severely disabled (P = .60). Conclusions and Relevance: Among patients with spot sign-positive ICH treated a median of about 3 hours from stroke onset, rFVIIa did not significantly improve radiographic or clinical outcomes. Trial Registration: ClinicalTrials.gov identifier: NCT01359202 and NCT00810888.

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 .).

Observed Cost and Variations in Short Term Cost-Effectiveness of Therapy for Ischemic Stroke in Interventional Management of Stroke (IMS) III.

BACKGROUND: Examination of linked data on patient outcomes and cost of care may help identify areas where stroke care can be improved. We report on the association between variations in stroke severity, patient outcomes, cost, and treatment patterns observed over the acute hospital stay and through the 12-month follow-up for subjects receiving endovascular therapy compared to intravenous tissue plasminogen activator alone in the IMS (Interventional Management of Stroke) III Trial. METHODS AND RESULTS: Prospective data collected for a prespecified economic analysis of the trial were used. Data included hospital billing records for the initial stroke admission and subsequent detailed resource use after the acute hospitalization collected at 3, 6, 9, and 12 months. Cost of follow-up care varied 6-fold for patients in the lowest (0-1) and highest (20+) National Institutes of Health Stroke Scale category at 5 days, and by modified Rankin Scale at 3 months. The kind of resources used postdischarge also varied between treatment groups. Incremental short-term cost-effectiveness ratios varied greatly when treatments were compared for patient subgroups. Patient subgroups predefined by stroke severity had incremental cost-effectiveness ratios of $97 303/quality-adjusted life year (severe stroke) and $3 187 805/quality-adjusted life year (moderately severe stroke). CONCLUSIONS: Detailed economic and resource utilization data from IMS III provide powerful evidence for the large effect that patient outcome has on the economic value of medical and endovascular reperfusion therapies. These data can be used to inform process improvements for stroke care and to estimate the cost-effectiveness of endovascular therapy in the US health system for stroke intervention trials. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Registration number: NCT00359424.

Endovascular Therapy Is Effective and Safe for Patients With Severe Ischemic Stroke: Pooled Analysis of Interventional Management of Stroke III and Multicenter Randomized Clinical Trial of Endovascular Therapy for Acute Ischemic Stroke in the Netherlands Data.

BACKGROUND AND PURPOSE: We assessed the effect of endovascular treatment in acute ischemic stroke patients with severe neurological deficit (National Institutes of Health Stroke Scale score, ≥20) after a prespecified analysis plan. METHODS: The pooled analysis of the Interventional Management of Stroke III (IMS III) and Multicenter Randomized Clinical Trial of Endovascular Therapy for Acute Ischemic Stroke in the Netherlands (MR CLEAN) trials included participants with an National Institutes of Health Stroke Scale score of ≥20 before intravenous tissue-type plasminogen activator (tPA) treatment (IMS III) or randomization (MR CLEAN) who were treated with intravenous tPA ≤3 hours of stroke onset. Our hypothesis was that participants with severe stroke randomized to endovascular therapy after intravenous tPA would have improved 90-day outcome (distribution of modified Rankin Scale scores), when compared with those who received intravenous tPA alone. RESULTS: Among 342 participants in the pooled analysis (194 from IMS III and 148 from MR CLEAN), an ordinal logistic regression model showed that the endovascular group had superior 90-day outcome compared with the intravenous tPA group (adjusted odds ratio, 1.78; 95% confidence interval, 1.20-2.66). In the logistic regression model of the dichotomous outcome (modified Rankin Scale score, 0-2, or functional independence), the endovascular group had superior outcomes (adjusted odds ratio, 1.97; 95% confidence interval, 1.09-3.56). Functional independence (modified Rankin Scale score, ≤2) at 90 days was 25% in the endovascular group when compared with 14% in the intravenous tPA group. CONCLUSIONS: Endovascular therapy after intravenous tPA within 3 hours of symptom onset improves functional outcome at 90 days after severe ischemic stroke. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00359424 (IMS III) and ISRCTN10888758 (MR CLEAN).

Twelve-Month Clinical and Quality-of-Life Outcomes in the Interventional Management of Stroke III Trial.

BACKGROUND AND PURPOSE: Randomized trials have indicated a benefit for endovascular therapy in appropriately selected stroke patients at 3 months, but data regarding outcomes at 12 months are currently lacking. METHODS: We compared functional and quality-of-life outcomes at 12 months overall and by stroke severity in stroke patients treated with intravenous tissue-type plasminogen activator followed by endovascular treatment as compared with intravenous tissue-type plasminogen activator alone in the Interventional Management of Stroke III Trial. The key outcome measures were a modified Rankin Scale score ≤2 (functional independence) and the Euro-QoL EQ-5D, a health-related quality-of-life measure. RESULTS: 656 subjects with moderate-to-severe stroke (National Institutes of Health Stroke Scale ≥8) were enrolled at 58 centers in the United States (41 sites), Canada (7), Australia (4), and Europe (6). There was an interaction between treatment group and stroke severity in the repeated measures analysis of modified Rankin Scale ≤2 outcome (P=0.039). In the 204 participants with severe stroke (National Institutes of Health Stroke Scale ≥20), a greater proportion of the endovascular group had a modified Rankin Scale ≤2 (32.5%) at 12 months as compared with the intravenous tissue-type plasminogen activator group (18.6%, P=0.037); no difference was seen for the 452 participants with moderately severe strokes (55.6% versus 57.7%). In participants with severe stroke, the endovascular group had 35.2 (95% confidence interval: 2.1, 73.3) more quality-adjusted-days over 12 months as compared with intravenous tissue-type plasminogen activator alone. CONCLUSIONS: Endovascular therapy improves functional outcome and health-related quality-of-life at 12 months after severe ischemic stroke. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00359424.

Endovascular revascularization results in IMS III: intracranial ICA and M1 occlusions.

BACKGROUND: Interventional Management of Stroke III did not show that combining IV recombinant tissue plasminogen activator (rt-PA) with endovascular therapies (EVTs) is better than IV rt-PA alone. OBJECTIVE: To report efficacy and safety results for EVT of intracranial internal carotid artery (ICA) and middle cerebral artery trunk (M1) occlusion. METHODS: Five revascularization methods for persistent occlusions after IV rt-PA treatment were evaluated for prespecified primary and secondary endpoints, after accounting for differences in key baselines variables using propensity scores. Revascularization was scored using the arterial occlusive lesion (AOL) and the modified Thrombolysis in Cerebral Ischemia (mTICI) scores. RESULTS: EVT of 200 subjects with intracranial ICA or M1 occlusion resulted in 81.5% AOL 2-3 recanalization, in addition to 76% mTICI 2-3 and 42.5% mTICI 2b-3 reperfusion. Adverse events included symptomatic intracranial hemorrhage (SICH) (8.0%), vessel perforations (1.5%), and new emboli (14.9%). EVT techniques used were standard microcatheter n=51; EKOS n=14; Merci n=77; Penumbra n=39; Solitaire n=4; multiple n=15. Good clinical outcome was associated with both TICI 2-3 and TICI 2b-3 reperfusion. Neither modified Rankin scale (mRS) 0-2 (28.5%), nor 90-day mortality (28.5%), nor asymptomatic ICH (36.0%) differed among revascularization methods after propensity score adjustment for subjects with intracranial ICA or M1 occlusion. CONCLUSIONS: Good clinical outcome was associated with good reperfusion for ICA and M1 occlusion. No significant differences in efficacy or safety among revascularization methods were demonstrated after adjustment. Lack of high-quality reperfusion, adverse events, and prolonged time to treatment contributed to lower-than-expected mRS 0-2 outcomes and study futility compared with IV rt-PA. TRIAL REGISTRATION NUMBER: NCT00359424.

Evolution of practice during the Interventional Management of Stroke III Trial and implications for ongoing trials.

BACKGROUND AND PURPOSE: We explored changes in the patient population and practice of endovascular therapy during the course of the Interventional Management of Stroke (IMS) III Trial. METHODS: Changes in baseline characteristics, use of baseline CT angiography, treatment times and specifics, and outcomes were compared between the first 4 protocols and the fifth and final protocol. RESULTS: Compared with subjects treated in the first 4 protocol versions (n=610), subjects treated in fifth and final protocol (n=46) were older (75 versus 68 years, P<0.0002) and less likely to have a pretreatment Rankin of 0 (76% versus 89%, P=0.01), were more likely to have a pretreatment CT angiography (65% versus 45%, P=0.009), had quicker median times in the endovascular arm from onset to start of intra-arterial therapy (209 versus 250 minutes, P=0.002) and to reperfusion (269 versus 344 minutes, P<0.0001), had a higher mean dose of total tissue-type plasminogen activator in the endovascular arm (74.0 versus 63.7 mg, P<0.0001), and were less likely to receive intra-arterial tissue-type plasminogen activator as part of the endovascular procedure (16% versus 44%, P=0.015). There were no significant differences in functional and safety outcomes between subjects treated in the 2 treatments arms in either the first 4 protocols or fifth protocol although the small sample size in the fifth protocol provided limited power. CONCLUSIONS: Endovascular technology and diagnostic approaches to acute stroke patients changed substantially during the IMS III Trial. Efforts to decrease the time to delivery of endovascular therapy were successful.

Recanalization and clinical outcome of occlusion sites at baseline CT angiography in the Interventional Management of Stroke III trial.

PURPOSE: To use baseline computed tomographic (CT) angiography to analyze imaging and clinical end points in an Interventional Management of Stroke III cohort to identify patients who would benefit from endovascular stroke therapy. MATERIALS AND METHODS: The primary clinical end point was 90-day dichotomized modified Rankin Scale (mRS) score. Secondary end points were 90-day mRS score distribution and 24-hour recanalization. Prespecified subgroup was baseline proximal occlusions (internal carotid, M1, or basilar arteries). Exploratory analyses were subsets with any occlusion and specific sites of occlusion (two-sided α = .01). RESULTS: Of 656 subjects, 306 (47%) underwent baseline CT angiography or magnetic resonance angiography. Of 306, 282 (92%) had arterial occlusions. At baseline CT angiography, proximal occlusions (n = 220) demonstrated no difference in primary outcome (41.3% [62 of 150] endovascular vs 38% [27 of 70] intravenous [IV] tissue-plasminogen activator [tPA]; relative risk, 1.07 [99% confidence interval: 0.67, 1.70]; P = .70); however, 24-hour recanalization rate was higher for endovascular treatment (n = 167; 84.3% [97 of 115] endovascular vs 56% [29 of 52] IV tPA; P < .001). Exploratory subgroup analysis for any occlusion at baseline CT angiography did not demonstrate significant differences between endovascular and IV tPA arms for primary outcome (44.7% [85 of 190] vs 38% [35 of 92], P = .29), although ordinal shift analysis of full mRS distribution demonstrated a trend toward more favorable outcome (P = .011). Carotid T- or L-type occlusion (terminal internal carotid artery [ICA] with M1 middle cerebral artery and/or A1 anterior cerebral artery involvement) or tandem (extracranial or intracranial) ICA and M1 occlusion subgroup also showed a trend favoring endovascular treatment over IV tPA alone for primary outcome (26% [12 of 46] vs 4% [one of 23], P = .047). CONCLUSION: Significant differences were identified between treatment arms for 24-hour recanalization in proximal occlusions; carotid T- or L-type and tandem ICA and M1 occlusions showed greater recanalization and a trend toward better outcome with endovascular treatment. Vascular imaging should be mandated in future endovascular trials to identify such occlusions. Online supplemental material is available for this article.

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.

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.

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.).

Is intra-arterial thrombolysis beneficial for M2 occlusions? Subgroup analysis of the PROACT-II trial.

BACKGROUND AND PURPOSE: The role of endovascular therapy for acute M2 trunk occlusions is debatable. Through a subgroup analysis of Prolyse in Acute Cerebral Thromboembolism-II, we compared outcomes of M2 occlusions in treatment and control arms. METHODS: Solitary M2 occlusions were identified from the Prolyse in Acute Cerebral Thromboembolism-II database. Primary endpoints were successful angiographic reperfusion (TICI 2-3) at 120 minutes and functional independence (mRS 0-2) at 90 days. RESULTS: Forty-four patients with solitary M2 occlusions, 30 in the treatment arm and 14 in the control arm, were identified. Successful reperfusion (TICI 2-3) was achieved in 53.6% and 16.7% of patients in the treatment and control arms, respectively (P=0.04). A favorable clinical outcome (mRS 0-2) was observed in 53.3% and 28.6%, respectively (P=0.19). Baseline characteristics were similar between the 2 groups. CONCLUSIONS: Intra-arterial thrombolysis may lead to a 3-fold increase in the rate of early reperfusion of solitary M2 occlusions and could potentially double the chance of a favorable functional outcome at 90 days. Clinical Trial Registration- This trial was not registered because enrollment began before July 1, 2005.

Parenchymal hematoma and total lesion volume in combined IV/IA revascularization stroke therapy.

BACKGROUND AND PURPOSE: A positive correlation between large parenchymal hematoma (PH) volume and large CT lesion volume in subjects treated with intravenous (IV) recombinant tissue plasminogen activator (rtPA) as well as placebo controls was identified in the European Cooperative Acute Stroke Study II (ECASS II). A study was undertaken to examine the relationship between PH volume and total lesion volume (including both cerebral infarction and hemorrhage) in subjects with symptomatic parenchymal hematoma (sPH) treated with combined IV and intra-arterial (IA) rtPA in the Interventional Management of Stroke (IMS) studies. METHODS: Hematoma and lesion volumes were measured planimetrically and by the ABC/2 method in 105 subjects from IMS studies I and II following combined IV and IA rtPA treatment. PH type 1 or 2 was determined by dichotomizing at >30% of lesion volume. Hematoma and lesion volumes for both symptomatic PH1 (sPH1) and PH2 (sPH2) types were compared using both measurement methods. Both sPH types were compared for baseline NIH Stroke Score, baseline Alberta Stroke Program Early CT score and treatment revascularization score based on the planimetric volume method. RESULTS: The volume of sPH1 and sPH2 did not differ by either method of measurement. Subjects with sPH2 had a lower lesion volume compared with all PH1 (p=0.004) and sPH1 (p=0.02) by both methods. The ABC/2 method overestimated PH volume by 55±33% and lesion volume by 34±22% for sPH compared with the planimetric method. CONCLUSIONS: In IMS I and II, hemorrhages in subjects with sPH2 were similar in volume to those in subjects with sPH1 and were associated with a smaller rather than a larger total lesion volume compared with other PH in the setting of combined IV/IA therapy. The use of PH2 as a sole surrogate for sPH in studies of stroke treatment may underestimate the incidence of clinically significant hemorrhage.

Intra-arterial iodinated radiographic contrast material injection administration in a rat middle cerebral artery occlusion and reperfusion model: possible effects on intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Observations in human interventional stroke treatment led us to hypothesize that iodinated radiographic contrast material use may contribute to intracerebral hemorrhage. Effects of intra-arterial iodinated radiographic contrast material on hemorrhagic transformation after middle cerebral artery occlusion and reperfusion were studied in a placebo-controlled, blinded preclinical study in rats. METHODS: Four groups of male Sprague-Dawley rats were studied: saline group (n=8), contrast group (n=12), heparin group (n=9), and contrast+heparin group (n=9). The middle cerebral artery was occluded for 5 hours using suture placement. Heparin was infused before suture removal and reperfusion. Saline and/or contrast were infused immediately during reperfusion. Incidence, location, and size of hemorrhage were determined by brain necropsy inspection at 24 hours. RESULTS: There was a significant increase in incidence of cortical hemorrhage from control (37.5%), contrast (75.0%), heparin (77.8%) to contrast+heparin (100%; Cochran-Mantel-Haenszel correlation, P<0.01). Both pooled contrast groups (85.7%) and pooled heparin groups (88.9%) had higher rates of cortical intracerebral hemorrhage compared with the control group (P<0.05). Similar trends for increased cortical intracerebral hemorrhage were seen in the contrast-only (P=0.18) and heparin-only (P=0.18) groups. There was a trend for decreased infarct edema in rats receiving contrast versus those without (P=0.06). CONCLUSIONS: Intraarterial iodinated radiographic contrast material may increase cortical intracerebral hemorrhage, similar to heparin. Iodinated radiographic contrast material effect may be additive to heparin effect on the incidence of cortical intracerebral hemorrhage.

Microcatheter contrast injections during intra-arterial thrombolysis increase intracranial hemorrhage risk.

BACKGROUND AND PURPOSE: Combined analysis of the Interventional Management of Stroke I and II trials demonstrated a significant association between microcatheter contrast injections and both intracranial hemorrhage (ICH) and contrast extravasation following combined intravenous (IV) and intra-arterial (IA) thrombolysis. The reliability of these observations was tested in our local registry of IA cases. DESIGN/METHODS: Treatment angiograms and post-procedure CTs of patients treated with combined IV/IA or IA only recombinant tissue plasminogen activator for ICA-T, M1 or M2 occlusions (n=77) were reviewed. The number of microcatheter injections (MCIs) within/distal to the target occlusion was assigned for every case. The association of MCIs to total ICH, total parenchymal hematoma (PH1+PH2) and PH2 after adjusting for significant covariates was tested. RESULTS: MCIs were used in 21 (27%) cases (range MCI 0-6). Any ICH occurred in 38 (49%) cases, including eight (10%) PH1s and eight (10%) PH2s. The use of MCIs was associated with increased PH (p=0.04), PH2 (p=0.07) and total ICH (p=0.03). MCIs were associated with increased contrast extravasation (CEx) (p=0.02). ICH was observed in all CEx cases (n=5, 100% vs 46% non-CEx; p=0.03), and four (80%) CEx cases developed PH2s (p<0.01). MCIs remained associated with total ICH after adjustment for significant covariates of Thromolysis in Cerebral Infarction score, glucose level and presence of atrial fibrillation (OR 3.60; 95% CI 1.12 to 11.49, p=0.03). MCI use was the only significantly associated covariate for total PHs. CONCLUSIONS: MCI use was associated with ICH and with clinically significant PHs in this cohort, providing further evidence that MCIs be reduced during IA thrombolysis.

Microcatheter contrast injections during intra-arterial thrombolysis may increase intracranial hemorrhage risk.

BACKGROUND AND PURPOSE: During intra-arterial revascularization, either guide catheter injections of contrast in the neck or microcatheter contrast injections (MCIs) at or beyond the site of an occlusion, can be used to visualize intracranial vasculature. Neurointerventionalists vary widely in their use of MCIs for a given circumstance. We tested the hypothesis that MCIs are a risk factor for intracranial hemorrhage (ICH) in the Interventional Management of Stroke (IMS) I and II trials of combined intravenous/IA recombinant tissue plasminogen activator therapy. METHODS: All arteriograms with M1, M2, and ICA terminus occlusions were reanalyzed (n=98). The number of MCIs within or distal to the target occlusion was assigned. Postprocedure CTs were reviewed for contrast extravasation and ICH. Contrast extravasation was defined as a hyperdensity suggestive of contrast (Hounsfield unit >90) seen at 24 hours or present before 24 hours and persisting or replaced by ICH at 24 hours. RESULTS: In this IMS subset, the rate of any ICH was 58% (57 of 98). More MCIs were seen in the ICH group (median=2 versus 1; P=0.04). Increased MCIs were associated with higher ICH rates (P=0.03). MCIs remained associated with ICH in multivariable analysis (P=0.01) as did baseline CT edema/mass effect, atrial fibrillation, time to intravenous recombinant tissue plasminogen activator initiation, and Thrombolysis in Cerebral Infarction reperfusion score. MCIs were also associated with contrast extravasation in unadjusted and adjusted analyses. CONCLUSIONS: MCIs may risk ICH in the setting of combined intravenous/intra-arterial recombinant tissue plasminogen activator therapy, possibly due to contrast toxicity or pressure transmission by injections. MCIs should be minimized whenever possible. These findings will be tested prospectively in the IMS III trial.

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>or=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>or=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 ( approximately 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 5 h 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.

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.