ABCD-GENE Score Stratifying Risk-Benefit Profile of Clopidogrel-Aspirin Therapy in Ischemic Stroke Within 24–72 Hours

Article information

J Stroke. 2026;28(2):316-320

Publication date (electronic) : 2026 May 28

doi : https://doi.org/10.5853/jos.2025.05092

Yun Chen^1,*, Lingling Jiang^1,2,*, Ying Gao^1,2, Weiqi Chen^1,2, Hongyi Yan^1,2, Tingting Wang^1,2, Yingying Yang^1,2, Yuesong Pan^,1,2, Yilong Wang^{,1,2,3,4,5,6,7}

¹Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China

²China National Clinical Research Centre for Neurological Diseases, Beijing, China

³Chinese Institute for Brain Research, Beijing, China

⁴National Centre for Neurological Diseases, Beijing, China

⁵Advanced Innovation Centre for Human Brain Protection, Capital Medical University, Beijing, China

⁶Beijing Laboratory of Oral Health, Capital Medical University, Beijing, China

⁷Laboratory for Clinical Medicine, Capital Medical University, Beijing, China

Correspondence: Yilong Wang Beijing Tiantan Hospital, Capital Medical University, No. 119, South 4th Ring West Road, Fengtai District, Beijing 100070, China Tel: +86-010-59975029 E-mail: yilong528@aliyun.com

Correspondence: Yuesong Pan Beijing Tiantan Hospital, Capital Medical University, No. 119, South 4th Ring West Road, Fengtai District, Beijing 100070, China Tel: +86-010-59975029 E-mail: yuesongpan@aliyun.com

*These authors contributed equally as first author.

Received 2025 October 9; Revised 2026 February 28; Accepted 2026 March 11.

Dear Sir:

For secondary prevention after acute minor ischemic stroke or transient ischemic attack (TIA), dual antiplatelet therapy with clopidogrel-aspirin is recommended to reduce the high risk of recurrence [1]. However, the efficacy of clopidogrel varies considerably due to the influence of both CYP2C19 polymorphisms and clinical factors [2], leading to high platelet reactivity (HPR) and subsequent treatment failure [3,4]. The ABCD-GENE score—comprising age, body mass index (BMI), chronic kidney disease (CKD), and diabetes combined with CYP2C19 genetic status—was originally developed to identify clopidogrel non-responders in myocardial infraction [5,6]. It was later extended to apply to patients with minor ischemic stroke or TIA (within 24 h of symptom onset), with a higher score predicting diminished clopidogrel efficacy [7]. Given that the treatment window for initiating dual antiplatelet therapy extends to 72 hours, as evidenced by the Intensive Statin and Antiplatelet for Acute High-Risk Intracranial or Extracranial Atherosclerosis (INSPIRES) trial [8], this study aimed to explore whether the ABCD-GENE score could help stratify the risk-benefit profile of clopidogrel-aspirin therapy initiated 24–72 hours after symptom onset in the INSPIRES trial.

The INSPIRES trial (ClinicalTrials.gov number, NCT03635749) was a multicenter, double-blind, randomized, 2-by-2 factorial trial conducted in China from September 17, 2018, to October 15, 2022, evaluating clopidogrel-aspirin versus aspirin alone, initiated within 72 hours of minor stroke or TIA onset [9]. This analysis specifically evaluated outcomes stratified by the ABCD-GENE score among patients who initiated therapy within 24–72 hours, following CONSORT (Consolidated Standards of Reporting Trials) guidelines. The ABCD-GENE score was calculated using baseline data (age, BMI, CKD, diabetes) and genotyping for CYP2C19 (*2, *3) (Supplementary Table 1) [7]. ABCD-GENE score was categorized into two groups (<10 and ≥10; as a cutoff value of 10 achieves optimal sensitivity and specificity) [6] and further stratified into three groups to estimate clopidogrel efficacy; scores of 0–5 (generally characterized by no more than one clinical risk factor), scores of 6–24 (defined by multiple clinical risk factors, or one CYP2C19 loss-of-function allele with at least one clinical factor, or those with two CYP2C19 loss-of-function alleles but no clinical risk factor), scores >24 (corresponding to the presence of at least one clinical risk factor together with two CYP2C19 loss-of-function alleles) [7]. The gradient of stroke risk and ABCD-GENE score was shown in Supplementary Figure 1, and HRs were estimated with the reference value set at the median ABCD-GENE score (ABCD-GENE score of 6). The efficacy outcomes included new stroke, composite vascular events, ischemic stroke, recurrent stroke within 90 days, and poor functional out-come at day 90. Safety outcomes included moderate-to-severe bleeding, death from any cause, and any bleeding. The definitions of efficacy and safety outcomes were the same as in the INSPIRES study [8]. Poor functional outcomes included modified Rankin Scale scores of 2–6 at the 90-day follow-up. The efficacy and safety analyses adhered to the intention-to-treat principle. Cumulative risks were estimated using Kaplan-Meier curves. Between-group differences were assessed using generalized linear models for poor functional outcomes and Cox proportional hazards models for other clinical outcomes, as well as interaction tests between treatment and ABCD-GENE score subgroups. Statistical significance was defined as a two-sided P-value of <0.05.

In the INSPIRES trial, 5,317 patients were assigned within 24– 72 hours after stroke onset. In this study, 4,693 patients were included, among which 2,320 (49.4%) were assigned to the clopidogrel-aspirin group and 2,373 were assigned to the aspirin group. The flowchart was presented in Supplementary Figure 2. Baseline characteristics stratified by treatment assignment were shown in Supplementary Table 2. Baseline characteristics across subgroups stratified by ABCD-GENE score stratified by two categories of <10 and ≥10 were detailed in Supplementary Table 3 and three categories of 0–5, 6–24, and >24 were shown in Table 1. Among the 4,693 patients included in this study, those who received clopidogrel-aspirin therapy demonstrated a reduced risk of new stroke compared with aspirin monotherapy (hazard ratio [HR], 0.80 [95% confidence interval, CI, 0.65–0.99]). The efficacy and safety outcomes in this population were detailed in Supplementary Table 4. Patients with ABCD-GENE score <10 presented a reduced risk of new stroke in clopidogrel-aspirin therapy group compared with aspirin monotherapy group (HR, 0.77 [95% CI, 0.61–0.98]), while no significant difference between clopidogrel-aspirin and aspirin group was found in patients with ABCD-GENE score ≥10 (HR, 0.93 [95% CI, 0.58–1.50]) (P_interaction=0.48) (Supplementary Table 5 and Supplementary Figure 3). Similar results were observed for the secondary efficacy outcomes. In the analyses stratified by the ABCD-GENE score (0–5, 6–24, and >24), the efficacy and safety outcomes were shown in Table 2 and Figure 1. The effect of clopidogrel-aspirin compared with aspirin alone in reducing new stroke was the most obvious in patients with ABCD-GENE score of 0–5 (HR, 0.62 [95% CI, 0.44–0.86], P<0.01), while no significant difference was observed in patients with ABCD-GENE score of 6–24 (HR, 0.89 [95% CI, 0.67–1.18], P=0.41) and patients with ABCD-GENE score of >24 (HR, 1.98 [95% CI, 0.83–4.71], P=0.12) (P_interaction=0.03). Similar results were observed for composite vascular events, ischemic stroke, and recurrent stroke. Because the number of patients in the >24 group was very small, no patient in this group had a moderate-to-severe bleeding event; therefore, the effect of treatment on the primary safety outcome was not estimated, nor were the secondary safety outcomes. No interaction was found between treatment and ABCD-GENE scores for safety outcomes.

Table 1.

Baseline characteristics among individuals stratified by ABCD-GENE score (0–5, 6–24, >24)

Table 2.

Effect of clopidogrel-aspirin compared with aspirin on clinical outcome stratified by ABCD-GENE scores of 0–5, 6–24, >24

Figure 1.

Cumulative probability of new stroke stratified by ABCD-GENE score (0–5, 6–24, and >24). (A) Cumulative probability of new stroke stratified by treatment assignment in patients with ABCD-GENE score <6. (B) Cumulative probability of new stroke stratified by treatment assignment in patients with ABCD-GENE score 6–24. (C) Cumulative probability of new stroke stratified by treatment assignment in patients with ABCD-GENE score >24. HR, hazard ratio; CI, confidence interval.

This study demonstrated that the ABCD-GENE score (category of 0–5, 6–24 and >24) could help stratify the risk-benefit profile of clopidogrel-aspirin therapy initiated 24–72 hours after atherosclerosis-derived minor stroke or TIA. Specifically, patients with a score >24 faced an increased trend of recurrent stroke in clopidogrel-aspirin group, whereas those with a score <6 benefited most from the dual treatment. In our previous analysis of the INSPIRES genetic subgroup (randomized 24 to 72 h postonset), poor metabolizers of clopidogrel cannot benefit from the clopidogrel-aspirin therapy (HR for recurrent stroke, 1.23 [95% CI, 0.61–2.47]) [10]. When clinical risk factors were incorporated, minor stroke or TIA patients with an ABCD-GENE score >24 represented a group with higher platelet reactivity, who faced an elevated risk of recurrent stroke (HR, 3.12 [95% CI, 0.99–9.81]) when receiving clopidogrel-aspirin therapy, suggesting those patients might be unsuitable for this regimen. Although the population of poor metabolizers was relatively small, and the differences in clopidogrel efficacy outcomes among patients with an ABCD-GENE score >24 did not reach statistical significance, yet the trend toward potential risk of stroke with dual antiplatelet therapy was noted in this subgroup. The markedly elevated HR observed in this subgroup, which was associated with wide CIs, likely arises because the group concentrates both genetic poor metabolizers (two LOF alleles) and clinically higher-risk patients (with older age, diabetes, CKD); thus, residual confounding and small-sample instability may partly account for the apparent excess risk. Meanwhile, we found that the ABCD-GENE score did not effectively identify patients at risk of poor functional outcomes. Across subgroups stratified by the score, those with higher scores in the clopidogrel-aspirin group had not exhibit worse functional outcomes. Thus, the ABCD-GENE score may help identify patients with minor stroke or TIA with a higher probability of stroke recurrence. Additionally, the low number of bleeding events precluded the detection of any significant differences in bleeding risk across strata.

In conclusion, our study supported the utility of the ABCDGENE score in risk-benefit stratification for clopidogrel-aspirin therapy initiated within 24–72 hours of minor stroke or TIA onset, and patients with higher ABCD-GENE score may be unsuitable for clopidogrel-aspirin treatment.