Efficacy and Safety of Indobufen, Aspirin, Cilostazol and Clopidogrel in the Treatment of Ischemic Stroke

Stroke is the second leading cause of death and the third leading cause of disability worldwide, with a 5%-10% one-year recurrence rate after acute ischemic stroke (AIS), making effective secondary prevention critical. Indobufen, aspirin, clopidogrel, and cilostazol-as monotherapy or in combination-constitute the main antiplatelet strategies for secondary prevention of ischemic stroke. Guidelines recommend early clopidogrel-aspirin dual therapy for mild stroke or TIA, while aspirin remains standard for moderate-to-severe cases, though it carries gastrointestinal and bleeding risks. Clopidogrel may be resistant due to CYP2C19 loss-of-function alleles in Asian populations. Cilostazol may be suitable for patients with CYP2C19-deficiency but has an uncertain intracranial bleeding risk. Indobufen, a reversible COX inhibitor, offers lower bleeding risk and fewer gastrointestinal adverse effects, yet lacks large-scale head-to-head trials against the other agents. Thus, real-world evidence to guide optimal antiplatelet selection for diverse ischemic stroke patients is lacking. This study aims to compare the effectiveness and safety of these four agents (monotherapy or guideline-recommended dual therapy) for secondary prevention of ischemic stroke, providing hypothesis-generating evidence for future prospective research.

• indubufen, aspirin, clopidogrel, cilostazol (Drug): Dosage, Frequency: Indobufen (200 mg twice daily); Aspirin (100 mg once daily); Cilostazol (100 mg twice daily); Clopidogrel (75 mg once daily). Dual antiplatelet therapy (DAPT) with two of these agents was permitted if clinically indicated, as per the treating physician's judgment.

Primary outcomes

• Incidence of composite events, including any new stroke or bleeding events [Within 1 year of treatment]: Stroke includes any ischemic/hemorrhagic stroke. Bleeding events were defined in accordance with the Global Utilization Of Streptokinase And TPA For Occluded Arteries (GUSTO) definition for bleeding.

Secondary outcomes

• Incidence of new cardiovascular events and death [Within 1 year]: any stroke/ myocardial infarction/ cardiovascular death
• GUSTO-defined bleeding events of all grades [Within 1 year]: GUSTO-defined bleeding events include intracranial hemorrhage, clinically significant gastrointestinal bleeding, and other specified types of bleeding.
• National Institutes of Health Stroke Scale (NHISS) score [Within 1 year of treatment]: The NIHSS score is commonly used to assess the degree of neurological impairment in patients with acute stroke. The NIHSS consists of 11 items, with a total score ranging from 0 to 42. Each item has different scoring criteria, typically ranging from 0 (normal) to 4 (most severe)
• Modified Rankin Scale ( mRS ) score [Within 1 year of treatment]: The MRS score is primarily used to measure the degree of disability and daily living ability of patients. The MRS score ranges from 0 to 6, with a total of 7 levels. The higher the score, the more severe the disability and the worse the prognosis.
• Barthel Index [Within 1 year of treatment]: The Barthel Index is a standardized scale widely used to assess patients' activities of daily living (ADL), covering ten basic functional items including feeding, bathing, dressing, toileting, bowel and bladder control, bed-to-chair transfer, walking, and stair climbing. Total scores range from 0 to 100, with higher scores indicating greater independence and better self-care ability. In stroke research, the Barthel Index is commonly used to evaluate neurological recovery and long-term functional outcomes.
• Drug-related adverse events [Within 1 year of treatment]: Drug-related adverse events include gastrointestinal discomfort, rash, abnormal liver function, etc.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Age ≥ 18 years;
2. Diagnosed with acute ischemic stroke (AIS) patients according to the Chinese Guidelines for the Diagnosis and Treatment of Acute Ischemic Stroke 2018 ;
3. Hospitalized in the Department of Neurology, Nanfang Hospital, Southern Medical University, between January 2020 and December 2025;
4. Received one of the following as a secondary prevention regimen within 7 days after discharge: indobufen, aspirin, clopidogrel, or cilostazol, either as monotherapy or as dual therapy;
5. Have follow-up records at 1 year after treatment initiation.

Exclusion Criteria:

1. Already having long-term anticoagulant therapy at baseline;
2. History of hemorrhagic stroke or active bleeding;
3. Severe hepatic or renal dysfunction (defined as AST/ALT > 3 times the upper limit of normal, or estimated glomerular filtration rate < 30 mL/min/1.73m²), end-stage disease, intracranial tumor, or intracranial infection.