Ticagrelor versus Placebo for Prevention of Cerebral Ischemia in Low‑Grade Aneurysmal Subarachnoid Hemorrhage (WFNS 1‑3) Within 72 h – Randomized Double‑Blind Trial

Primary objective: To assess, in patients with low‑grade aneurysmal subarachnoid hemorrhage (WFNS 1‑3) presenting within 72 hours, the impact of a 14‑day oral ticagrelor regimen (180 mg loading dose followed by 90 mg twice daily) initiated at the start of endovascular aneurysm treatment on the incidence of ischemic complications, defined as peri‑procedural symptomatic or asymptomatic thromboembolic events and delayed cerebral ischemia occurring within 14 days post‑procedure. This evaluation addresses a key determinant of neurological outcome after endovascular management of ruptured aneurysms.

Secondary objectives:

• Incidence of peri‑procedural symptomatic and asymptomatic thromboembolic events within 24 hours of aneurysm treatment.
• Occurrence of neurological deterioration and asymptomatic MRI lesions attributable to delayed cerebral ischemia within 14 days.
• Total number of ischemic events per patient.
• Requirement for rescue therapy during embolisation or for delayed cerebral ischemia.
• Quality of aneurysm occlusion assessed at procedure completion, 24 hours, and 3 months by MRI/MRA.
• Clinical outcome at 3 months.
• Safety profile, including hemorrhagic and other adverse events.

The trial enrolled adults aged 18 to 80 years of both sexes diagnosed with low‑grade aneurysmal subarachnoid hemorrhage (World Federation of Neurological Surgeons grade 1–3) whose aneurysm treatment was planned to be completed within 72 hours of rupture. The sponsor did not provide the total number of participants. Eligible subjects were required to have a saccular aneurysm ≥ 4 mm amenable to endovascular coiling (stents or flow diverters were excluded) and to be affiliated with a social‑security scheme. All participants provided free, informed written consent prior to any study‑related procedures. Lifestyle factors such as diet, physical activity, or smoking were not specified as selection criteria.

The study is a multicenter, double‑blind, randomized, placebo‑controlled trial evaluating a 14‑day course of ticagrelor (180 mg loading dose followed by 90 mg twice daily) versus matching placebo in patients with low‑grade aneurysmal subarachnoid hemorrhage (WFNS 1–3) treated endovascularly within 72 hours of rupture. After eligibility screening, participants who provide informed consent undergo a baseline visit on the day of aneurysm treatment during which the study drug is initiated. Subsequent visits occur on days 3, 7, 14 (end of treatment), and day 15 for assessment of peri‑procedural and delayed ischemic events, followed by a follow‑up visit at 3 months for clinical outcome, imaging, and safety evaluation. The total involvement for each participant is approximately 15 days of active treatment plus the 3‑month follow‑up. Early termination may occur if a participant experiences a major adverse event (e.g., intracranial hemorrhage, aneurysm re‑rupture, severe bleeding), requires rescue therapy, withdraws consent, or deviates significantly from the protocol. Recruitment is planned to start in June 2026 and conclude in September 2029.

The investigational product is Brilique 90 mg film‑coated tablets containing the active substance ticagrelor. The medication is administered orally. A loading dose of 180 mg is given at the start of the endovascular aneurysm treatment, followed by a maintenance dose of 90 mg taken twice daily for a total duration of 14 days.

The control arm receives a matching placebo, identified as Placebo du Brilique. The placebo tablets are identical in appearance to the active drug and are taken orally with the same schedule as the investigational product.

Dosing is performed under direct clinical supervision at the time of the endovascular procedure, after which patients self‑administer the twice‑daily doses. Compliance is monitored by pill count at each study visit and by patient diary entries documenting administration times. Any missed or delayed doses are recorded and reported according to the protocol.

Efficacy will be evaluated primarily by the incidence of symptomatic and asymptomatic peri‑procedural thromboembolic events occurring within the first 24 hours after endovascular treatment. These events are identified through (i) angiographic detection of clot formation near the aneurysm neck or in distal branches, (ii) clinical assessment of neurological worsening of ≥2 points on the NIHSS compared with baseline, and (iii) imaging confirmation of acute infarcts on a 24‑hour MRI diffusion‑weighted imaging (≥5 hyperintense DWI lesions or a single lesion >10 mm). Angiography is performed during the procedure, NIHSS scores are recorded at baseline and at 24 hours, and the MRI is obtained at the 24‑hour timepoint for central review.

Secondary efficacy assessments comprise multiple components: occurrence of peri‑procedural angiographic, clinical, or imaging thromboembolic events within 24 hours; neurological deterioration and asymptomatic MRI lesions attributable to delayed cerebral ischemia (DCI); combined incidence of all ischemic events per patient at day 15; rate of rescue therapy during angiography or for DCI; aneurysm occlusion evaluated by the Raymond Roy classification at procedure completion, at 24 hours, and on MRI‑MRA at 3 months; and clinical outcomes at 3 months measured by the modified Rankin Scale (mRS < 3), Glasgow Outcome Scale‑Extended (GOSE > 5), health‑related quality of life using the EQ‑5D, cognitive status via the MoCA (≤ 25 indicating deterioration), and mortality. Adverse events, including aneurysmal rupture, intracranial and other major bleedings, minor bleedings, and ticagrelor‑related non‑hemorrhagic events (dyspnea, bradyarrhythmia, uric acid and creatinine levels) are recorded at baseline, day 7, and day 15. All assessments follow a predefined schedule aligned with the study timeline and are analyzed according to the trial’s statistical analysis plan.