Contrast‐enhanced sonothrombolysis in acute ischemic stroke patients without intracranial large‐vessel occlusion

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Acute ischemic stroke therapy has traditionally targeted recanalization through intravenous (iv) clot lysis and thrombectomy. Recent studies have shown that thrombectomy is highly effective in ischemic stroke patients with intracranial large‐vessel occlusion (LVO).1 However, few treatment options are available for an impaired microcirculation in the absence of LVO. The majority of acute ischemic stroke patients have no LVO on hospital admission.3 A number of these patients display an impaired microcirculation due to occlusion of cerebral vessels, which are too small for visualization on CT angiography (CTA). The microcirculation is also highly relevant in patients with LVO. A large proportion of these patients fail to achieve clinical improvement despite recanalization.4 The lack of improvement may be caused by a microvascular “no‐reflow phenomenon” caused by fibrin deposits and cell detritus leading to ischemia.5 The ischemic microcirculation thus constitutes a new battleground in acute stroke treatment.
Sonothrombolysis disaggregates fibrin fibers, promote microstreaming, and increase the thrombolytic effect of tissue plasminogen activator (tPA).7 Studies have shown that sonothrombolysis leads to a more efficient large‐vessel recanalization than treatment with iv thrombolysis alone.9 The effect of sonothrombolysis may be further augmented through the addition of intravenous gas‐filled contrast agents originally developed for diagnostic purposes. These microbubbles increase thrombus dissolution through stable cavitation and mechanical stress.7 Treatment of acute ischemic stroke with sonothrombolysis in combination with microbubbles, that is, contrast‐enhanced sonothrombolysis (CEST), has been associated with improved rates of recanalization in patients with LVO.12 Animal studies have also shown promising results with CEST in rats with impaired microperfusion following recanalization of LVO, suggesting a beneficial effect of CEST on the ischemic microcirculation.14 The exact mechanisms behind this effect are not known. No studies have so far investigated the treatment effect of CEST in acute ischemic stroke without LVO.
NOR‐SASS was a phase III trial of CEST in a general stroke population.15 In this study, we aimed to assess safety and efficacy of CEST in acute ischemic stroke patients without LVO on admission.

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