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IV tPA in LVO is Associated With Increased Perfusion Through Venous Outflow
The utility of intravenous tPA (tissue type plasminogen activator) as bridging therapy before endovascular thrombectomy (EVT) remains controversial in treatment of large vessel occlusion (LVO). Recent data from three randomized control trials conducted in Asia showed that EVT alone was noninferior to IV tPA plus EVT in functional outcome, while MR CLEAN-NO IV showed that EVT alone was neither superior nor inferior to IV tPA plus EVT. 1-3 More recently, DIRECT-SAFE and SWIFT-DIRECT demonstrated that EVT alone was not noninferior to IV tPA plus EVT. 4,5 Concurrently, investigators have also explored the pathophysiology of large vessel occlusion and determined that arterial collaterals and venous outflow (VO) serve as key mechanisms of tissue perfusion in regions of ischemic beds distal to a large vessel occlusion. 6 It was reported in 2021 that venous outflow can be implemented as a neuroimaging parameter that correlates strongly with tissue perfusion and the status of collateral supply during a stroke.7
This study by Faizy et al. published in Stroke is unique from prior retrospective analyses and recent RCTs in that it not only measured the functional outcome at 90 days, but also provided a radiographic evaluation of perfusion through the stroke tissue as determined by venous outflow during the hyperacute phase of an LVO. To do so, they performed a retrospective cohort study of 717 subjects presenting to Stanford University and University Medical Center Hamburg-Eppendorf for acute ischemic stroke that underwent EVT. Patients were included if they had a suspected anterior circulation large vessel occlusion from acute ischemic stroke within 16 hours of last known normal and were treated with IV tPA, EVT, or both, and had undergone CT, CTA, and CT perfusion before EVT. Venous outflow was graded in a scale called COVES, which ranges from 0 to 6 with 2 points assigned to each opacification of three major cortical veins seen on a single-phase CTA.6 A favorable venous outflow profile was assigned to COVES score of 3-6. Notably, the venous outflow was always determined before EVT, and there was no difference in the time from symptom onset to imaging across the two groups.
Among the included patients, 365 (51%) of patients had IV tPA plus EVT, and 352 (49%) received EVT alone. The study demonstrated that favorable venous outflow was achieved in 51% of patients with IV tPA plus EVT compared to 28% of patients with EVT alone. The median COVES for tPA plus EVT was 3 [IQR, 1-3], while median COVES for EVT alone was 1 [IQR, 1-3] (P<0001). A multivariable binary logistic regression analysis further verified that tPA bridging therapy prior to EVT was independently associated with favorable venous outflow. The functional outcome, as measured by modified Rankin Scale score, was also more favorable in the tPA plus EVT group with median score of 3 [IQR, 1-5] compared to the EVT only group with median score of 4 [IQR, 2-6] (P<0.001).
This observation suggests that IV tPA before EVT in large vessel occlusion stroke leads to better functional outcome, and that this effect can be visualized radiographically in the hyperacute setting as increased perfusion through the venous outflow. It implies a pathophysiological underpinning that could explain tPA’s beneficial effect observed in the recent RCTs, as tPA may facilitate venous outflow by reducing microvascular thrombosis distal to a large vessel occlusion.
Limitations of this study include retrospective design, the use of single-phase CTA for venous analysis, and the subjectivity involved in radiographical evaluation of partial and full filling of a cortical vein. Furthermore, the results would only apply to patients that present to a comprehensive stroke center and not primary stroke centers without access to EVT. A meta-analysis of randomized control trials including MR CLEAN-NO IV, DIRECT-SAFE, and SWIFT-DIRECT may shed further light into this fascinating phenomenon.
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