Dear Sir:

For patients with non-cardioembolic ischemic stroke, antiplatelet agents are recommended to reduce the risk of recurrent stroke and cardiovascular events, and dual antiplatelet therapy is advised during the acute and early phases of ischemic stroke for at least 3 weeks to 3 months [1]. However, long-term use of dual antiplatelet therapy is not recommended because of the increased risk of bleeding [2], and an appropriate single antiplatelet agent should be used for long-term maintenance therapy. However, there is limited evidence regarding the comparative effectiveness of aspirin and clopidogrel as maintenance therapies in patients with ischemic stroke. Recent findings suggest that clopidogrel is more effective than aspirin as a long-term maintenance therapy in reducing ischemic and bleeding events in patients with cardiovascular disease [3]. In this study, we sought to compare the efficacy and safety of aspirin and clopidogrel in long-term maintenance therapy after dual antiplatelet therapy in patients with non-cardioembolic acute ischemic stroke.

This retrospective cohort study used a prospective registry supplemented with detailed electronic medical records from the rSMART system (Medical Data Utilization Platform Server, NFEC-2023-03-286318) of consecutive patients admitted to a government-initiated comprehensive stroke center. A total of 494 patients hospitalized for ischemic stroke between 2011 and 2022 were enrolled, all of whom received dual antiplatelet therapy for at least 3 weeks to 3 months before switching to aspirin or clopidogrel monotherapy. The primary outcome was the incidence of net adverse clinical and cerebral events (NACCE) over a period of 3 years after switching. The secondary outcomes included major adverse cardiovascular events (MACE), components, major bleeding, and all-cause death. NACCE were defined as a composite of MACE, major bleeding, and death from other causes. Kaplan-Meier analysis and Cox proportional hazards regression modeling were used to compare clinical outcome risks according to the antiplatelet agent administered. Cox proportional hazards models were adjusted for sex, age, established risk factors, and variables that exhibited a P-value ≤0.05 in univariate analysis. Subgroup analysis based on the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification (large vessel atherosclerosis [LAA] vs. non-LAA) and sensitivity analyses were performed to evaluate the consistency of the main findings. The baseline characteristics according to antiplatelet agents are presented in (Supplementary Table 1. Of the 494 patients, 89 (18.0%) received aspirin and 405 (82.0%) received clopidogrel as maintenance therapy (Supplementary Figure 1). Detailed methodological descriptions and supporting analyses are available in Supplementary Methods and Supplementary Results.

The annual incidences of NACCE were 4.86% and 9.47% in the clopidogrel and aspirin groups, respectively. Kaplan-Meier analysis demonstrated a lower risk of NACCE in the clopidogrel group than in the aspirin group (log-rank P=0.033) (Figure 1). Multivariate Cox regression analysis confirmed this result; the clopidogrel group exhibited a lower risk of NACCE after adjusting for confounders (hazard ratio [HR]=0.467, 95% confidence interval [CI]=0.230-0.945, P=0.034) (Table 1). Regarding secondary outcomes, the clopidogrel cohort showed a lower risk of MACE (HR=0.404, 95% CI=0.174-0.938, P=0.035) and death (HR=0.160, 95% CI=0.033-0.788, P=0.024) than the aspirin group. Although the difference in acute coronary syndrome did not reach statistical significance (P=0.059), a trend toward a lower risk in the clopidogrel group was observed. No significant differences were observed between the two groups in terms of recurrent ischemic stroke, intracranial bleeding, or major bleeding events (Table 1).

In the sensitivity analysis, TOAST classification (P<0.1, univariate analysis) and current smoking status (a clinically relevant risk factor) were additionally adjusted. The results remained consistent for NACCE (HR=0.481, 95% CI=0.232-0.995, P=0.048) and mortality (HR=0.147, 95% CI=0.024-0.890, P=0.037) (Supplementary Table 2). In subgroup analysis, patients with LAA demonstrated a lower mortality rate in the clopidogrel group than in the aspirin group, as supported by Kaplan-Meier analysis (log-rank P=0.024) and multivariate Cox regression (P=0.022) (Supplementary Figure 2 and Supplementary Table 3). In addition, the incidence of NACCE tended to be lower in the clopidogrel group (P=0.056). No outcome events showed significant differences in the non-LAA group (Supplementary Table 4).

Our study is the first to demonstrate the efficacy and safety of clopidogrel as maintenance monotherapy after a guideline-recommended dual therapy of 3 weeks to 3 months, with implications for real-world practice. Previous studies have reported superior efficacy of clopidogrel over aspirin in patients with ischemic stroke [4-6]. Considering recent evidence from atherosclerotic cardiovascular disease reaearch [3], clopidogrel may provide superior benefits over aspirin as maintenance monotherapy in patients with cerebrovascular disease, particularly those with non-cardioembolic ischemic stroke of atherosclerotic etiology. Patients with a history of ischemic stroke have an increased risk of cardiovascular events and vascular death [7]. Therefore, coronary artery disease prevention is as essential as recurrent stroke prevention in this population. Although it did not significantly reduce the risk of acute coronary syndrome in our analysis, the observed reductions in NACCE, MACE, and mortality may be attributed to the predominance of risk reduction of cardiovascular events. A similar pattern was observed in the LAA subgroup, suggesting that atherosclerosis-related mechanisms may mediate the therapeutic effects of clopidogrel. In addition to its antiplatelet effects, clopidogrel has been shown to exert anti-inflammatory and anti-atherosclerotic effects [8], suggesting that it may be an optimal monotherapy for the prevention of atherosclerotic vascular events. Additionally, some studies have reported a lower risk of bleeding with clopidogrel than with aspirin, which may have implications for mortality outcomes [4,5,9]. Our findings provide further evidence supporting the clinical effectiveness of clopidogrel over aspirin as a maintenance monotherapy in patients with non-cardioembolic ischemic stroke.

This study had several limitations. First, the data were subject to potential residual bias because this was not a randomized study, and the prospectively registered cohort study involved a retrospective analysis, although all patients were enrolled consecutively. Additionally, patient characteristics, such as socioeconomic status, lifestyle, stress, and regular health management, may have differed between groups. Second, CYP2C19 genotyping and clopidogrel resistance testing, which may have influenced the study results by reducing antiplatelet efficacy, were not routinely performed or included in the analysis [10]. Third, although this study was drawn from an extensive registry containing 11,058 patients, the sample size was relatively small after selection. Therefore, extensive multicenter studies are warranted.

These findings suggest that clopidogrel is more effective than aspirin in reducing the risk of NACCE, MACE, and mortality when used as maintenance therapy after dual antiplatelet therapy in patients with non-cardioembolic ischemic stroke. Clopidogrel may represent a superior long-term strategy for reducing vascular events, supporting antiplatelet selection for maintenance therapy in non-cardioembolic stroke, especially LAA stroke.