Early Prophylactic Aspirin for Aneurysmal Subarachnoid Hemorrhage

Aneurysmal subarachnoid hemorrhage (aSAH) is a life-threatening neurological emergency associated with high rates of morbidity and mortality. Delayed cerebral ischemia (DCI) and subsequent cerebral infarction are major contributors to poor functional outcomes in survivors. Antiplatelet agents such as aspirin have been hypothesized to reduce the risk of microthrombosis and DCI, but evidence for their early prophylactic use in aSAH remains limited and controversial. This trial aims to investigate the efficacy and safety of early aspirin administration in improving long-term functional outcomes in aSAH patients. Eligible patients will be randomized into two groups: the intervention group will receive 100 mg of oral aspirin daily for not less than 10 days and not more than 14 consecutive days, while the control group will receive an identical placebo. All patients in both groups will receive standardized aSAH management according to current clinical guidelines, including nimodipine, blood pressure control, and supportive care. The primary endpoint is the functional outcome measured by the modified Rankin Scale (mRS) at 3 months. Secondary endpoints include incidence of clinical DCI at discharge, percentage of imaging DCI detected on CT/MRI at discharge, all-cause mortality at 3 months, and safety outcomes including major bleeding events.

Inclusion criteria

• Age ≥ 18 years and ≤ 80 years.
• Spontaneous subarachnoid hemorrhage (SAH) confirmed by non-contrast head CT.
• Diagnosis of ruptured intracranial aneurysm confirmed, and successfully treated by either surgical clipping or endovascular coiling within 48 hours of ictus.
• Hunt-Hess grade ≤ 4 or WFNS grade ≤ 4 (assessed within 48 hours of SAH onset).
• Fisher grade 2-4 or modified Fisher grade 1-4.
• No significant focal neurological deficit after aneurysm intervention, defined as NIHSS scores ≤ 1 in the following items: 5a (left arm motor), 5b (right arm motor), 6a (left leg motor), 6b (right leg motor), and 9 (language).
• Pre-morbid modified Rankin Scale (mRS) score ≤ 1 prior to SAH onset.

Exclusion criteria

• Hunt-Hess grade 5 or WFNS grade 5 (assessed within 48 hours of SAH onset).
• Patients requiring any intracranial stent or non-embolic intrasaccular device during aneurysm embolization, with post-procedural need for antiplatelet therapy.
• Angiogram-negative SAH.
• Note: Prior history of ruptured intracranial aneurysm or re-rupture of previously treated aneurysm is not excluded.
• Moderate-to-severe vasospasm demonstrated on pre-operative or intra-operative CTA/DSA in the emergency setting.
• SAH caused by non-saccular aneurysms, including mycotic, blood-blister, fusiform, or dissecting aneurysms, or cases without basal cistern subarachnoid hemorrhage.
• Significant pre-existing intracranial pathology at the time of enrollment, including but not limited to: traumatic brain injury, moyamoya disease, high suspicion or documented CNS vasculitis, severe fibromuscular dysplasia, arteriovenous malformation, arteriovenous fistula, significant cervical or intracranial atherosclerotic stenosis (≥70%), or malignant brain tumor.
• Medical conditions requiring chronic use of antiplatelet agents (aspirin, clopidogrel, or ticagrelor), such as transient ischemic attack, myocardial infarction, atrial fibrillation, prosthetic heart valve, arteriovenous fistula, unstable angina, or other conditions requiring thromboprophylaxis.
• Thrombocytopenia (platelet count <20,000/μL, excluding aggregation artifacts), active disseminated intravascular coagulation (DIC) at enrollment, or documented history of coagulopathy or bleeding diathesis.
• History of gastrointestinal bleeding or major systemic hemorrhage within 30 days, hemoglobin <8 g/dL at admission, INR ≥1.5, or severe hepatic impairment defined as AST, ALT, alkaline phosphatase (AP), or GGT >2 times the upper limit of normal.
• Creatinine clearance <30 mL/min.
• Severe comorbidities that may confound study outcomes, including but not limited to: multiple sclerosis, dementia, major depression, immunosuppressed state or during intensive immunosuppressive therapy, cancer with expected survival <1 year, multi-organ failure, or any other condition potentially causing cognitive impairment.
• Contraindications to aspirin therapy, including:

• Hypersensitivity to aspirin, other salicylates, or any excipients in the formulation;
• History of asthma induced by salicylates or NSAIDs;
• Active peptic ulcer disease;
• Bleeding diathesis;
• Hepatic or renal failure;
• Uncontrolled severe heart failure;
• Concomitant use with methotrexate at doses ≥15 mg/week.
• Pregnancy or positive HCG test.
• Incomplete repair of the responsible aneurysm as judged by the treating physician, with high risk of early re-bleeding.
• History of head trauma within 3 months prior to SAH onset.
• Recent cerebral disease within 3 months prior to SAH onset, such as tumor, stroke, epilepsy, vasculitis, AVM, or hydrocephalus.
• History of psychiatric illness or seizure disorder.
• Breastfeeding women.
• Expected survival <1 year prior to SAH onset.
• Participation in another randomized clinical trial that may confound the evaluation of this study.