This retrospective cohort study was conducted between January 2018 and September 2022 at the Neurological Institute of Thailand, a tertiary care and referral center for neurological disorders.

The participants in this study were individuals who had experienced their first-ever transient ischemic attack or acute ischemic stroke and asymptomatic atherosclerotic carotid artery stenosis, having at least 1 year of follow-up, were included in this study. A vascular neurologist (T. T.), and a geriatrician (C.P.) evaluated the medical records of these patients. Transient ischemic attack or ischemic stroke patients were adjudicated by consensus between the two investigators, and any discrepancies were excluded. Only patients whose eligibility was confirmed by both investigators were included in this study.

Patients were excluded from this study if they (1) had carotid artery disease from other mechanisms such as radiation-related carotid stenosis/occlusion, Takayasu disease, fibromuscular dysplasia; (2) received vitamin K oral antagonist or direct oral anticoagulant; (3) had underwent carotid endarterectomy or carotid artery stenting for asymptomatic carotid artery stenosis; (4) had moderate or severe intracranial atherosclerosis; (5) had cardiac arrhythmia or congestive heart failure.

Study participants were categorized into two groups: (1) patients who received cilostazol-based dual antiplatelet therapy and (2) those who received single antiplatelet therapy (Figure 1).

The patients’ baseline characteristics included sex, age, baseline National Institutes of Health Stroke Scale (NIHSS), baseline ABCD² score (the risk of stroke on the basis of age, blood pressure, clinical features, duration of transient ischemic attack, and presence or absence of diabetes), antiplatelet agent type, treatment duration, underlying disease, smoking, low-density lipoprotein cholesterol level (LDL-C), HbA1c level, radiographic data of carotid artery disease, medication non-adherence, and the Fazekas scale. We excluded patients with incomplete or incorrect data for the following variables: age, NIHSS, ABCD², HbA1C level, LDL-C level, clopidogrel loading dose, and time to dual antiplatelet therapy.

Cilostazol-based dual antiplatelet therapy was defined as a combination of 200 mg/day of cilostazol and either aspirin 81–100 mg per day or clopidogrel (75 mg/day).

Single antiplatelet therapy was defined as aspirin 81–325 mg per day or clopidogrel 75 mg/day.

Medication adherence was monitored through electronic prescription refills, with non-adherence defined as the proportion of patients with a refill lag >1 month during follow-up over 1 year.

Achieved target blood pressure was defined as the proportion of patients with hypertension whose systolic blood pressure measured at each visit was <140 mmHg (<130 mmHg if diabetic) for >80% of the follow-up visits within 1 year.

Achieved target LDL-C level was defined as the proportion of patients with hypercholesterolemia with LDL-C levels measured at each visit <1.8 mmol/L for >80% of the follow-up visits within 1 year.

Achieved target HbA1c was defined as the proportion of patients with diabetes mellitus with HbA1c levels measured at each visit of <53 mmol/mol for >80% of the follow-up visits within 1 year.

Smoking cessation was defined as the proportion of smokers who discontinued tobacco smoking within 6 months of the onset of ischemic stroke/transient ischemic attack.

Asymptomatic carotid artery stenosis refers to stenosis in first-ever transient ischemic attack or acute ischemic stroke patients without neurological symptoms referable to the carotid arteries. Asymptomatic carotid artery stenosis was defined as the presence of atherosclerotic narrowing of the proximal internal carotid artery by ≥50% at the level of bifurcation.

Ischemic events were classified as recurrent ischemic stroke or transient ischemic attacks. Recurrent ischemic stroke was defined as the first episode of neurological deficit persisting for over 24 h, localized to previous asymptomatic carotid artery stenosis. Recurrent transient ischemic attack was defined as a focal and localizable (such as hemispheric neurological deficit) transient ischemic attack or monocular blindness persisting for less than 24 h, localized to a previous asymptomatic carotid artery stenosis.

Carotid artery stenosis can be diagnosed using either gadolinium-enhanced magnetic resonance angiography or contrast-enhanced computed tomographic angiography and measured using the North American Symptomatic Carotid Endarterectomy Trial (NASCET) (5) criteria.

Hemorrhagic complications were classified as major or minor. Major hemorrhage was defined as (1) life-threatening hemorrhage with or without any blood component transfusion, (2) hemorrhage requiring any blood component transfusion, and (3) hemorrhage in visceral/vital organs, such as intra-orbital hemorrhage, intracranial hemorrhage, or intraspinal hemorrhage. Minor hemorrhage was defined as any hemorrhagic event not meeting the criteria for major hemorrhage.

Death was defined as vascular-related death, such as myocardial infarction or stroke-related death.

Number of new ischemic lesions, which were defined as any new ischemic lesions apart from the index lesions on follow-up fluid attenuation inversion recovery using slice-to-slice comparison with the baseline diffusion-weighted imaging and fluid attenuation inversion recovery.

The primary efficacy outcome of this study was the first episode of composite recurrent ischemic events and vascular-related death. The secondary efficacy outcomes included the first occurrence of ischemic event recurrence, vascular-related death, and number of new ischemic lesions.

The primary safety outcome of this study was the occurrence of hemorrhagic complications such as intracranial hemorrhages or extracranial hemorrhages. Other secondary safety outcome was the occurrence of adverse events.

Propensity scores were estimated using a logistic regression model based on the study participants’ baseline characteristics. We matched the dual antiplatelet treatment group with the single antiplatelet treatment group in a 1:1 ratio using the nearest-neighbor matching method.

We calculated that a sample size of 516 patients would provide 80% power and thereby avoid a type 2 error to detect a 64% risk reduction in the dual antiplatelet treatment group, assuming an 11% event rate of the composite endpoint in the single antiplatelet group (6–8). This study’s sample size calculation formula was derived from a textbook (9). Categorical variables were reported as numbers (%), while continuous variables were reported as mean ± SD or median and interquartile range (IQR) as appropriate. Survival analysis for composite outcomes was estimated using Kaplan–Meier survival curves and compared using Cox regression analysis. Hazard ratios with 95% confidence intervals (CI) are reported. If multiple events of similar type occurred, the time to the first event was used in the model. A value of p less than 0.05 was considered significant. Statistical analyses were performed using SPSS for Windows (version 22.0; IBM Corp., Armonk, NY).

Between January 2018 and September 2022, 4,362 transient ischemic attack or acute ischemic stroke patients were admitted to the stroke unit. 927 patients who had experienced their first-ever transient ischemic attack or acute ischemic stroke and asymptomatic atherosclerotic carotid artery disease were enrolled. This study excluded 64 (6.9%) patients who had moderate or severe intracranial atherosclerosis, 60 (6.5%) patients who had no antiplatelet treatment or received combination of aspirin plus clopidogrel, 43 (4.6%) patients who had cardio-embolic stroke, 25 (2.7%) patients who had indication for anticoagulants, 48 (5.2%) patients who had underwent either carotid endarterectomy or stenting, 120 (12.9%) patients who had follow up less than 1 year, and 38 (4.1%) patients who had congestive heart failure or cardiac arrhythmia. Nevertheless, none of the continuous variables were absent in the database. However, 13 patients were excluded due to the absence of radiographic data (Figure 1).

This single-center, tertiary care setting included 516 patients (Figure 1) with asymptomatic carotid artery stenosis (308 men and 208 women), with a median age of 64 years (Table 1). The baseline characteristics of the study participants are summarized in Table 1. Before propensity score matching, the proportion of patients with coronary artery disease was higher in the dual antiplatelet group. After propensity score matching, all imbalanced baseline characteristics between the study groups were well-balanced, eliminating significant differences.

Table 2 shows the types of antiplatelet treatments used by study participants. The median duration of the dual antiplatelet therapy was 6 months. In this study, 97(56.4%) patients received cilostazol plus clopidogrel, and 75(43.6%) received cilostazol plus aspirin.

Table 3 shows the 6-month outcomes of dual antiplatelet therapy in the propensity score-matched cohort. Composite events occurred in six (3.8%) patients in the dual antiplatelet group compared with six (3.8%) patients in the single antiplatelet group (HR, 1.02; 95% CI, 0.94–1.11; p = 0.343). Recurrent ischemic events occurred in four (2.5%) patients in the dual antiplatelet group and three (1.9%) patients in the single antiplatelet group (HR, 1.28; 95% CI, 0.99–1.47; p = 0.149). Vascular-related death occurred in two (1.3%) patients in the dual antiplatelet group and three (1.9%) patients in the single antiplatelet group (HR, 0.76; 95% CI, 0.51–1.03; p = 0.094).

Table 3 shows the 1-year outcomes of the dual antiplatelet therapy in the propensity score-matched cohort. Composite events occurred in 10 (6.3%) patients in the dual antiplatelet group compared with 12 (7.6%) in the single antiplatelet group (HR, 0.74; 95% CI, 0.61–0.90; p = 0.024). Recurrent ischemic events occurred in six (3.8%) patients in the dual antiplatelet group compared with seven (4.5%) in the single antiplatelet group (HR, 0.88; 95% CI, 0.71–1.05; p = 0.263). Vascular-related death occurred in four (2.5%) patients in the dual antiplatelet group and five (3.2%) in the single antiplatelet group (HR, 0.85; 95% CI, 0.69–1.02; p = 0.118). The number of new ischemic lesions was significantly lower in the dual antiplatelet group (HR, 0.88; 95% CI, 0.77–0.98; p = 0.032).

Extracranial hemorrhage occurred in 12 (7.6%) patients in the dual antiplatelet group compared to nine (5.7%) in the single antiplatelet group (HR, 1.35; 95% CI, 1.13–1.48; p = 0.017). No intracranial hemorrhages were observed in this cohort.

In the subgroup analyses, we compared the main outcomes between the dual and single antiplatelet groups according to sex, age, hypertension, diabetes mellitus, hypercholesterolemia, chronic kidney disease, coronary artery disease, smoking, and degree of carotid artery stenosis >70% (Figure 2). A reduced risk of composite events was observed in the presence of coronary artery disease, and the degree of stenosis was >70%. Figure 3 shows the survival analysis of the study participants based on the composite events.