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 the 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 prior to endovascular therapy was assessed with the ASITN/SIR 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 276/331 (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 (mRS≤2) at 90 days (p=0.0353), adjusted for age, history of diabetes, NIHSS strata, and ASPECTS. 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.

Background and Purpose-Ultrasound transiently expands perflutren-lipid microspheres (S), transmitting energy momentum to surrounding fluids. We report a pilot safety/feasibility study of ultrasound-activated S with systemic tissue plasminogen activator (tPA). Methods-Stroke subjects treated within 3 hours had abnormal Thrombolysis in Brain Ischemia (TIBI) residual flow grades 0 to 3 before tPA on transcranial Doppler (TCD). Randomization included Controls (tPAϩTCD) or Target (tPAϩTCDϩ2.8 mL S). The primary safety end point was symptomatic intracranial hemorrhage (sICH) with worsening by Ն4 NIHSS points within 72 hours. Results-Fifteen subjects were randomized 3:1 to Target, nϭ12 or Control, nϭ3. After treatment, asymptomatic ICH occurred in 3 Target and 1 Control, and sICH was not seen in any study subject. S reached MCA occlusions in all Target subjects at velocities higher than surrounding residual red blood cell flow: 39.8Ϯ11.3 vs 28.8Ϯ13.8 cm/s, PϽ0.001. In 75% of subjects, S permeated to areas with no pretreatment residual flow, and in 83% residual flow velocity improved at a median of 30 minutes from start of S infusion (range 30 s to 120 minutes) by a median of 17 cm/s (118% above pretreatment values). To provide perspective, current study recanalization rates were compared with the tPA control arm of the CLOTBUST trial: complete recanalization 50% versus 18%, partial 33% versus 33%, none 17% versus 49%, Pϭ0.028. At 2 hours, sustained complete recanalization was 42% versus 13%, Pϭ0.003, and NIHSS scores 0 to 3 were reached by 17% versus 8%, Pϭ0.456. Conclusions-Perflutren S reached and permeated beyond intracranial occlusions with no increase in sICH after systemic thrombolysis suggesting feasibility of further S dose-escalation studies and development of drug delivery to tissues with compromised perfusion. (Stroke. 2008;39:1464-1469.)Key Words: microspheres Ⅲ thrombolysis Ⅲ stroke Ⅲ occlusion Ⅲ transcranial Doppler I ntravenous tissue plasminogen activator (tPA) remains the only approved therapy for acute ischemic stroke. 1 Successful thrombolysis depends on tPA delivery to the thrombus via residual flow around acute arterial obstruction. 2 Pulsed wave transcranial Doppler (TCD) can expose the thrombus-residual flow interface to a mechanical ultrasound pressure wave, and TCD monitoring can safely facilitate early recanalization in stroke subjects treated with systemic tPA. 3 In the CLOTBUST (Combined Lysis of Thrombus with 2 MHz transcranial Ultrasound and Systemic TPA) trial, TCD monitoring for 2 hours after tPA bolus with 1 hour tPA infusion tripled the chance of complete and sustained recanalization. 3 This early augmentation of reperfusion resulted in a trend toward favorable clinical recovery. Based on this trend, a pivotal trial to confirm efficacy of sonothrombolysis would require an estimated 600 subjects. 3 Because this is a large sample for an acute stroke trial, CLOTBUST investigators started to explore further ways to augment early reperfusion that could reduce the sample size of the pivotal ...

Background and Purpose-Argatroban is a direct thrombin inhibitor that safely augments recanalization achieved by tissue-type plasminogen activator (tPA) in animal stroke models. The Argatroban tPA Stroke Study was an open-label, pilot safety study of tPA plus Argatroban in patients with ischemic stroke due to proximal intracranial occlusion. Methods-During standard-dose intravenous tPA, a 100-g/kg bolus of Argatroban and infusion for 48 hours was adjusted to a target partial thromboplastin time of 1.75ϫ baseline. The primary outcome was incidence of significant intracerebral hemorrhage defined as either symptomatic intracerebral hemorrhage or Parenchymal Hematoma Type 2. Recanalization was measured at 2 and 24 hours by transcranial Doppler or CT angiography. Results-Sixty-five patients were enrolled (45% men, mean age 63Ϯ14 years, median National Institutes of Health Stroke Scaleϭ13). The median (interquartile range) time tPA to Argatroban bolus was 51 (38 -60) minutes. Target anticoagulation was reached at a median (interquartile range) of 3 (2-7) hours. Significant intracerebral hemorrhage occurred in 4 patients (6.2%; 95% CI, 1.7-15.0). Of these, 3 were symptomatic (4.6%; 95% CI, 0.9 -12.9). Seven patients (10%) died in the first 7 days. Within the 2-hour monitoring period, transcranial Doppler recanalization (nϭ47) occurred in 29 (61%) patients: complete in 19 (40%) and partial in another 10 (21%). Conclusions-The combination of Argatroban and intravenous tPA is potentially safe in patients with moderate neurological deficits due to proximal intracranial arterial occlusions and may produce more complete recanalization than tPA alone. T he thrombin inhibitor Argatroban (GlaxoSmithKline, Philadelphia, PA) selectively inhibits free and clotassociated thrombin. 1,2 Safety has been demonstrated with and without thrombolytics or with aspirin in patients with acute myocardial infarction. [3][4][5] In a randomized trial of Argatroban versus heparin in combination with intravenous thrombolysis for acute myocardial infarction, complete coronary reperfusion was significantly more frequent with Argatroban compared with heparin. 3 In animal stroke models, Argatroban safely augments the benefit of recombinant tissue-type plasminogen activator (tPA) by improving microcirculatory flow, increasing speed and completeness of recanalization, and preventing reocclusion. 6 -10 Argatroban monotherapy (in a double-blind, randomized Phase II trial) in 60 patients with stroke within 48 hours of onset improved The benefit of tPA in acute stroke is linked to the speed and degree of clot lysis and artery recanalization. 16 -18 However, only 20% to 30% of patients will have complete recanalization on transcranial Doppler imaging (TCD) within 2 hours of intravenous tPA therapy, 60% will have only partial recanalization, and 34% of those with any recanalization will experience reocclusion. 19,20 Because of its short half-life, allowing careful titration of the anticoagulant effect, we hypothesized that Argatroban might be safely added to...

Background and Purpose General anesthesia (GA) for endovascular therapy (EVT) of acute ischemic stroke (AIS) may be associated with worse outcomes. Methods The IMS III trial randomized patients within 3hrs of AIS onset to IV t-PA±EVT. GA use within 7hrs of stroke onset was recorded per protocol. Good outcome was defined as 90day mRS≤2. A multivariable analysis adjusting for dichotomized NIHSS (8-19 versus ≥20), age, and time from onset to groin puncture was performed. Results Four hundred thirty-four patients were randomized to EVT, 269(62%) were treated under local anesthesia and 147(33.9%) under GA; 18(4%) were undetermined. The two groups were comparable except for median baseline NIHSS (16 local anesthesia versus 18 [GA], p<0.0001). The GA group was less likely to achieve a good outcome (adjusted-RR 0.68, CI 0.52-0.90; p=0.0056) and had increased in-hospital mortality (adjusted-RR 2.84, CI 1.65-4.91; p=0.0002). Those with medically indicated GA had worse outcomes (adjusted RR 0.49, CI 0.30-0.81, p=0.005) and increased mortality (RR 3.93, CI 2.18-7.10; p<0.0001) with a trend for higher mortality with routine GA. There was no significant difference in the adjusted risks of SAH (p=0.32) or symptomatic ICH (p=0.37). Conclusions GA was associated with worse neurological outcomes and increased mortality in the EVT arm; this was primarily true among patients with medical indications for GA. Relative risk estimates, though not statistically significant, suggest reduced risk for SAH and sICH under local anesthesia. Although the reasons for these associations are not clear, these data support the use of local anesthesia when possible during EVT.