Background: Intravenous thrombolysis (IVT) for wake-up stroke (WUS) or stroke with unknown onset (SUO) has been shown to be safe and effective using advanced neuroimaging. However, many centers lack immediate access to such imaging. This study explores the feasibility and safety of non-contrast CT-based IVT for WUS/SUO.

Methods and Results: TRUST-CT is an international, multicenter registry-based study comparing WUS/SUO patients treated with non-contrast CT-based IVT to propensity-matched non-thrombolyzed controls. Among 117 IVT patients and 112 controls (median NIHSS: 10, ASPECTS: 10), symptomatic intracranial hemorrhage occurred in 3.4% of IVT patients vs. 0.9% of controls (OR 7.9, P=0.1). NIHSS improvement (≥4 points) was seen in 57.3% of IVT patients vs. 22.3% of controls (OR 5.8, P<0.001). At 90 days, 33.3% of IVT patients vs. 20.5% of controls achieved a modified Rankin Scale score of 0 or 1 (OR 1.94, P=0.05).

Conclusions: Non-contrast CT-based thrombolysis for WUS/SUO appears feasible, safe, and potentially effective, warranting further randomized trials.