Intravenous alteplase versus oral aspirin for acute central retinal artery occlusion within 4·5 h of severe vision loss (THEIA): a multicentre, double-dummy, patient-blinded and assessor-blinded, randomised, controlled, phase 3 trial

Abstract

Background: Central retinal artery occlusion (CRAO) is a subtype of ischaemic stroke that results in acute monocular vision loss. Although open-label studies and meta-analyses have suggested that early intravenous thrombolysis might improve visual acuity, no randomised controlled trials have yet confirmed this benefit. We aimed to compare the safety and efficacy of intravenous alteplase with oral aspirin in patients with CRAO treated within 4·5 h of onset of severe vision loss.

Methods: THEIA was a multicentre, double-dummy, patient-blinded, assessor-blinded, randomised, controlled, phase 3 trial conducted across 16 hospitals with stroke units in France. Adults (aged ≥18 years) presenting with sudden, severe, and persistent monocular vision loss (Snellen <20/400) due to suspected non-arteritic acute CRAO were eligible for inclusion. Participants were randomly assigned (1:1), stratified by centre, to receive either 0·9 mg/kg of bodyweight intravenous alteplase and oral placebo (alteplase group) or 300 mg oral aspirin and intravenous saline placebo (aspirin group) within 4·5 h of symptom onset. Patients, outcome assessors, and the study sponsor were masked to treatment allocation; treating nurses and neurologists were unmasked. The primary efficacy outcome was improvement in visual acuity of at least 0·3 logarithm of the minimum angle of resolution (LogMAR) from baseline to 1 month, analysed in the full analysis set, which included all patients who received the complete intervention and a visual acuity assessment at baseline. Safety outcomes included serious adverse events, particularly intracranial and extracranial bleeding, analysed in all randomly assigned participants. This study is registered at ClinicalTrials.gov (NCT03197194) and is completed.

Findings: Between June 8, 2018, and Oct 2, 2023, 70 patients (mean age 70 years [SD 9]; 25 [36%] women and 45 [64%] men) were enrolled and randomly assigned to either the alteplase group (35 [50%]) or the aspirin group (35 [50%]). In total, 65 (93%) patients received the allocated treatment: 34 (97%) in the alteplase group and 31 (89%) in the aspirin group. Mean time from symptom onset to treatment initiation was 232·4 min (SD 43·6). Among 56 patients with available data on the primary endpoint, 19 (66%) of 29 patients in the alteplase group and 13 (48%) of 27 patients in the aspirin group showed an improvement in visual acuity of at least 0·3 LogMAR at 1 month (unadjusted risk difference 17·4 [95% CI -11·8 to 46·5]; adjusted odds ratio 1·1 [95% CI 0·07 to 18·39]; p=0·95). One asymptomatic intracranial haemorrhage related to study treatment was reported in the alteplase group. 14 serious adverse events unrelated to treatment occurred in 11 patients overall (six [17%] in the aspirin group and five [14%] in the alteplase group). No symptomatic haemorrhages or major bleeding related to study treatment were reported.

Interpretation: Intravenous alteplase administered within 4·5 h of CRAO onset was not associated with a significant improvement in visual acuity compared with aspirin, despite a higher rate of improvement in the alteplase group. However, the study was likely underpowered to detect a statistical difference. Although no safety concerns related to alteplase were identified, the overall modest recovery rates underscore the need for individual patient-level data meta-analyses with forthcoming randomised controlled trials to clarify the potential benefit of thrombolysis or aspirin in patients with acute CRAO.

Funding: French Ministry of Health and Boehringer Ingelheim, France.