Randomized Controlled Contrast-Enhanced Sonothrombolysis in an Unselected Acute Ischemic Stroke Population

The only proven effective acute ischemic stroke treatment to achieve recanalization, reduce stroke severity, and improve outcome is intravenous thrombolysis with recombinant tPA (tissue-type plasminogen activator) given within 41⁄2 hours from symptom onset. Partial-to-complete recanalization of larger occluded vessels is achieved in only 1 out of 3 patients who undergo thrombolysis. Many stroke patients, therefore, face severe brain damage, disability, and death. An improved acute treatment is urgently needed. Contrast-enhanced sonothrombolysis (CEST), encompassing a thrombolytic drug, ultrasound, and microbubbles, may be the next step in acute ischemic stroke treatment. Transcranial ultrasound weakens fibrin cross-links; promotes motion of blood around the clot; increases uptake, penetration, and concentration of tPA within the thrombus; and thus augments clot lysis. Intravenous alteplase therapy with transcranial ultrasound is safe and may induce higher rates of arterial recanalization, as compared with placebo. Adding intravenous contrast (microbubbles) induces further acceleration of ultrasound-enhanced thrombolysis, leading to a more complete recanalization and to a trend toward better shortand long-term outcome. Previous sonothrombolysis studies, with or without microbubbles, were performed in patients with visible occlusions Background and Purpose—The NOR-SASS (Norwegian Sonothrombolysis in Acute Stroke Study) aimed to assess effect and safety of contrast-enhanced ultrasound treatment in an unselected acute ischemic stroke population. Methods—Patients treated with intravenous thrombolysis within 4.5 hours after symptom onset were randomized 1:1 to either contrast-enhanced sonothrombolysis (CEST) or sham CEST. A visible arterial occlusion on baseline computed tomography angiography was not a prerequisite for inclusion. Pulse-wave 2 MHz ultrasound was given for 1 hour and contrast (SonoVue) as an infusion for ≈30 minutes. Magnetic resonance imaging and angiography were performed after 24 to 36 hours. Primary study end points were neurological improvement at 24 hours defined as National Institutes of Health Stroke Scale score 0 or reduction of ≥4 National Institutes of Health Stroke Scale points compared with baseline National Institutes of Health Stroke Scale and favorable functional outcome at 90 days defined as modified Rankin scale score 0 to 1. Results—A total of 183 patients were randomly assigned to either CEST (93 patient) or sham CEST (90 patients). The rates of symptomatic intracerebral hemorrhage, asymptomatic intracerebral hemorrhage, or mortality were not increased in the CEST group. Neurological improvement at 24 hours and functional outcome at 90 days was similar in the 2 groups both in the intention-to-treat analysis and in the per-protocol analysis. Conclusions—CEST is safe among unselected ischemic stroke patients with or without a visible occlusion on computed tomography angiography and with varying grades of clinical severity. There was, however, statistically no significant clinical effect of sonothrombolysis in this prematurely stopped trial. Clinical Trial Registration—URL: http://www.clinicaltrials. gov. Unique identifier: NCT01949961. (Stroke. 2017;48:335-341. DOI: 10.1161/STROKEAHA.116.014644.)