Abstract 158: Persisting Arterial Occlusion And Risk Of Symptomatic Intracranial Hemorrhage In Systemic Thrombolysis: A Pooled Analysis Of Randomized Sonothrombolysis Studies

Abstract

Background & Purpose: Recent observational data showed that delayed (>6 hours) recanalization in acute ischemic stroke (AIS) patients treated with systemic thrombolysis may be associated with a higher risk of symptomatic intracranial hemorrhage (sICH). We sought to investigate the relationship of persisting occlusion during the first two hours of iv-tPA and the likelihood of sICH using pooled data from three randomized sonothrombolysis studies. Subjects & Methods: We evaluated the risk of sICH among AIS patients randomized in the Combined Lysis of Thrombus in Brain Ischemia (CLOTBUST), Transcranial Ultrasound in Clinical Sonothrombolysis (TUCSON) and a pilot randomized clinical safety study of sonothrombolysis augmentation with ultrasound-activated perflutren-lipid microspheres (Definity study). Acute proximal arterial occlusions were identified in all patients at baseline using Trancranial Doppler (TCD). Patients underwent continuous or intermitted TCD-monitoring for a two-hour period following tPA-bolus. Persisting occlusion was defined as absence of improvement of baseline TIBI flow grade at the end of TCD-monitoring. sICH was defined using ECASS-2 definition as imaging evidence of ICH with clinical worsening (NIHSS≥4) within 72 hours from stroke onset. Results: A total of 176 AIS patients (mean age 68±14years, 57% men, median baseline NIHSS-score 16 points, interquartile range 11-20) were randomized in CLOTBUST (n=126), DEFINITY (n=15) and TUCSON (n=35). A total of 75 (43%) and 101 (57%) individuals were randomized to systemic thrombolysis and sonothrombolysis respectively. Persisting occlusion was identified at the end of TCD-monitoring in 65 patients (37%). Patients with persisting occlusion tended to have higher sICH rates compared to individuals with partial or complete recanalization (9.2% vs. 2.7%; p=0.078 by Fisher’s exact test). After adjusting for demographic characteristics, onset-to-treatment time, baseline stroke severity, baseline TIBI flow grade and treatment (sonothrombolysis vs. systemic thrombolysis) persisting occlusion was independently associated with a higher likelihood of sICH (OR:6.29, 95%CI:1.28-30.85; p=0.024). Conclusions: Failure to recanalize during the first two hours following tPA-bolus appears to increase sICH risk among AIS treated with standard systemic thrombolysis and sonothrombolysis. Possible mechanisms (elevated blood pressure with persistent occlusion and late, potentially harmful recanalization causing reperfusion injury to infracted brain tissue) are now subject of a prospective multicenter study (CLOTBUST-PRO).