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...
A 49-year-old woman with a history of chronic headaches had worsening head pain over the preceding 3 days. The noncontrast CT scan showed a 2.8 ϫ 2.6 cm round lesion in the left mesial temporal region. Transcranial contrast-enhanced ultrasound visualized a partially thrombosed aneurysm with an outer diameter of 2.8 ϫ 3.0 cm and a perfused lumen of 1.1 ϫ 1.2 cm (figure, B). CT-Angio 3-D reconstruction (figure, A) proved the lesion to be an aneurysm. Digital subtraction angiography outlined a lumen of 1.3 ϫ 1.3 ϫ 1.1 cm, the aneurysm arising from the supraclinoidal segment of the left internal carotid artery. Using a phase inversion imaging technique, the flow dynamics of the aneurysm could be assessed in real time (video). 1,2
Background Effective acute interventions for ischemic and hemorrhagic stroke are time-critical, making rapid brain imaging an important component of high quality stroke care. National guideline recommendations are that initial brain imaging be performed within 25 minutes of ED arrival. Direct EMS routing of acute stroke patients to certified Stroke Centers has the potential to increase the proportion of patients receiving high quality care, including more rapid post arrival brain imaging. Methods Data collected in the ongoing, region-wide NIH FAST-MAG trial permitted analysis of the impact of EMS implementation of a stroke center routing policy on door to imaging (DTI) times. FAST-MAG is an NIH, multicenter trial of prehospital initiation of neuroprotective therapy conducted in 228 ambulances transporting patients to 51 adult receiving hospitals in Los Angeles County. In November 2009, the LA EMS Agency instituted a policy of preferentially routing acute stroke patients to Approved Stroke Centers that had been certified by the Joint Commission. Data on patients from all sites was analyzed from 2005-2010. Results Among the first 1000 patients enrolled, mean age was 70 (SD 14), 41%were female, median NIHSS was 9 (IQR 3, 17) and onset to door time was 71 (SD 55) minutes. Throughout the 5 year period analyzed, patients cared for at hospitals that would become Approved Stroke Centers (ASCs) had shorter door to imaging times than patients cared for at non-ASCs. Comparing the 9 inaugural ASCs with the 42 others, 34.4 vs 42.3 minutes (0.001). Comparing the 23 eventual ASCs with the 28 non-ASCs, 35.5 vs 46.5 minutes (<0.0001). Preferential EMS routing of patients to ASCs resulted in a reduction of DTI times among the entire cohort: enrollments across all sites before vs after implementation of the routing policy: 44.9 vs 32.0 minutes (<0.0001). With implementation of the routing system, the proportion of patients meeting the 25 minute DTI goal increased from 25% vs 47%, p<0.0001. Conclusions Direct EMS routing to certified Stroke Centers reduced times from ED arrival to initial brain imaging, and more than doubled frequency of achievement of the national DTI target. These results support wide national dissemination of regionally organized stroke critical care systems.
Background and Objectives: Early neurological improvement (ENI) at 2-hours post thrombolysis has recently been proposed to most accurately predict recanalization when repeat vascular imaging is not available. However, these studies analyzed recanalization at a delayed time point (≥24 hours). The Argatroban tPA Stroke Study (ARTSS-1), is a recently completed NIH sponsored, Phase IIa, prospective, open-label, safety and activity study of Argatroban and rtPA in patients with ischemic stroke ( NCT00268762 ). We hypothesized 2-hour recanalization correlates with ENI (NIHSS improvement of 20% or greater from baseline). Methods: A total of 65 patients with intracranial large vessel occlusive disease were given standard dose (0.9mg/kg) tPA and a 100 μg/kg bolus of argatroban followed by infusion of 1 μg/kg per minute for 48 hours adjusted to a PTT of 1.75 times baseline. Pre-tPA vessel imaging using TCD or CTA confirmed intracranial occlusions. A multivariate logistic regression tested whether recanalization at 2 hours was associated with ENI after controlling for age, NIHSS, clot location (ICA, MCA or vertebrobasilar). We analyzed whether patients with ENI had statistically significant greater odds of an excellent mRS (0 or 1) at day 7. Results: Recanalization data was available for 47 patients at 2-hours. ENI occurred at 2-hours in 46% patients. Patients with any recanalization (complete or partial) at 2-hours were more likely to experience ENI (OR 3.4; 95% CI 0.71-16.6, p=0.124). This association strengthened when 2-hour complete recanalization was analyzed (OR 5.4; 95% CI 0.98-29.2, p=0.053). In an unadjusted analysis, patients with ENI at 2-hours were five times more likely to have excellent mRS outcomes at day 7 (OR 4.7; 95% CI 1.4-15.6, p=0.01). In the adjusted model, the association remained significant (OR 3.8; 95%CI 1.1-13.4, p=0.041). Conclusion: Two-hour recanalization is predictive of early neurological improvement and better early clinical outcomes in patients treated with combination Argatroban and tPA. A randomized, controlled clinical trial of this promising adjunctive therapy is warranted and ongoing (ARTSS-2 trial, NCT01464788 ).
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