Safety of intravenous thrombolysis in stroke of unknown time of onset: A systematic review and meta-analysis

The safety of intravenous tissue plasminogen activator (IV-tPA) in patients with stroke of unknown time of onset (SUTO) was unclear and mostly concerned. We sought to investigate the safety in terms of symptomatic intracranial hemorrhage (sICH) and death in SUTO patients treated with IV-tPA. We searched PubMed and EMBASE from inception to 2 December 2020 for eligible studies reporting IV-tPA in SUTO patients compared to conservative medical therapy, or to stroke of known onset time (SKOT) treated with IV-tPA within standard time window. We pooled relative risk (RR) with 95% confidence interval (95%CI) with random-effects model. Twenty-four studies were included, enrolling 77,398 patients. SUTO patients with IV-tPA had higher incidence of sICH than that in SUTO patients without IV-tPA (3.8% versus 0.96%; RR = 3.75, 95%CI: 2.69-5.22) but comparable to that in SKOT patients with IV-tPA (3.8% versus 4.1%; RR = 1.16, 95%CI: 0.94-1.44). There was no significant difference in death risk in SUTO patients with IV-tPA versus SUTO patients without IV-tPA (RR = 1.34, 95%CI: 0.60-3.01) and versus SKOT patients with IV-tPA (RR = 1.19, 95%CI: 0.95-1.50). Compared with SUTO patients without IV-tPA, SUTO patients with IV-tPA had higher likelihood of favorable functional outcome (adjusted RR = 1.28, 95%CI: 1.03-1.60) and functional independence (adjusted RR = 1.95, 95%CI: 1.24-3.06), comparable to that in SKOT patients with IV-tPA in favorable functional outcome (adjusted RR = 0.67, 95%CI: 0.38-1.20) and functional independence (adjusted RR = 0.84, 95%CI: 0.59-1.18). SUTO patients could be treated safely and effectively with IV-tPA under the guidance of imaging evaluation.