Introduction
Dual antiplatelet therapy (DAPT) with aspirin and clopidogrel is often recommended as a cornerstone in the secondary prevention of stroke in patients with ischemic stroke or transient ischemic attack (TIA) [1-3]. The combination of aspirin and ticagrelor, a potent direct oral P2Y12 receptor antagonist, has been demonstrated to be effective in reducing the risk of recurrent stroke and other major ischemic events, particularly in patients carrying CYP2C19 loss-of-function (LOF) alleles [4]. Notably, our previous subgroup analysis suggested that the additional benefit of ticagrelor plus aspirin in reducing stroke recurrence was confined to patients without intracranial arterial stenosis (ICAS) [5]. Similar findings have been reported in other antiplatelet therapy studies, which have revealed differential treatment benefits between patients with and without ICAS. However, despite the use of DAPT, new ischemic events continue to occur in patients without ICAS.
Evidence from the CHANCE (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events), CHANCE-2 (Ticagrelor or Clopidogrel with Aspirin in High-Risk Patients with Acute Nondisabling Cerebrovascular Events-II), POINT (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke), and THALES (The Acute Stroke or Transient Ischaemic Attack Treated with Ticagrelor and ASA for Prevention of Stroke and Death) trials has highlighted that a 21-day duration of DAPT strikes the optimal balance between efficacy and safety [6-10]. Extending antiplatelet therapy beyond this period has not shown additional clinical benefit and may, instead, increase the risk of bleeding complications. It is noteworthy that an exploratory analysis of the Acute Stroke or Transient Ischemic Attack Treated with Aspirin or Ticagrelor and Patient Outcomes (SOCRATES) trial suggested that the use of aspirin within 7 days prior to randomization might result in a residual effect, potentially influencing the outcomes of subsequent treatment [11]. Additionally, antiplatelet agents have been shown to impair renal function, which could alter drug metabolism and efficacy [12-14]. Based on these findings, we speculated that the residual effect of previous antiplatelet therapy, not limited to aspirin, may persist for several days and potentially influence the observed efficacy and safety of DAPT. However, this hypothesis remains unproven and requires further investigation.
DAPT efficacy varies between patients with and without ICAS, likely because of differences in the inflammatory burden and individual responses to treatment [15,16]. Previous antiplatelet therapy plausibly influences these factors. For instance, discontinuation of antiplatelet therapy shortly before trial enrollment might trigger a rebound effect, heightening platelet reactivity [17,18]. Antiplatelet agents modulate systemic inflammation by suppressing platelet activation and aggregation, thereby reducing the inflammatory burden [19,20].
Therefore, we aimed to explore the relationship between previous antiplatelet therapy and the efficacy and safety of DAPT regimens in patients with and without ICAS using data from the CHANCE-2 trial.
Methods
Data availability
Data are available to researchers upon request by directly contacting the corresponding author to reproduce the results or replicate the procedure.
Study design and participants
This study was a post-hoc analysis of the CHANCE-2 trial. The detailed rationale, design, and methods of the CHANCE-2 trial have been previously described [21]. CHANCE-2 was a randomized, double-blind, double-dummy, controlled, multicenter clinical trial performed at 202 centers in China. Patients were enrolled if they met the following criteria: (1) aged 40 years or older; (2) had an acute non-disabling ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] score ≤3) or a high-risk TIA (defined by a ABCD2 [age, blood pressure, clinical features, duration of TIA, and the presence or absence of diabetes mellitus] score ≥4); (3) were CYP2C19 LOF allele carriers; (4) could receive the study drug within 24 hours of symptom onset; and (5) signed informed consent. From September 23, 2019, to March 22, 2021, 6,412 patients were recruited and randomized in a 1:1 ratio to receive ticagrelor (placebo clopidogrel plus a 180 mg loading dose of ticagrelor on day 1, followed by 90 mg twice daily for days 2-90) or clopidogrel (placebo ticagrelor plus a 300 mg loading dose of clopidogrel on day 1, followed by 75 mg daily for days 2-90). All patients received aspirin (75-300 mg loading dose, followed by 75 mg daily for 21 days).
The trial protocol was approved by the Ethics Committee of Beijing Tiantan Hospital (institutional review board approval number: KY2019-035-02) and all participating centers. All participants or their representatives provided written informed consent prior to enrollment. The trial was registered at Clinical-Trials.gov (Registration URL: http://www.clinicaltrials.gov) under the unique identifier NCT04078737.
Data collection and imaging assessment
Baseline information, including demographics, medical history, physical examination findings, previous medications, and pre-stroke modified Rankin Scale (mRS), NIHSS, and ABCD2 scores, was collected through face-to-face interviews by trained research neurologists at each center, following a standard data collection protocol established by the steering committee. Previous antiplatelet therapy was defined as the use of antiplatelet drugs, including aspirin, clopidogrel, and ticagrelor, within 1 month before the onset of the qualifying event.
In the CHANCE-2 trial, the enrolled patients underwent standard imaging examinations of brain tissue and intracranial arteries using magnetic resonance imaging with diffusion-weighted imaging sequences and intracranial vascular imaging (magnetic resonance angiography, computed tomography angiography, or digital subtraction angiography) at each center. All imaging data collected by each center were saved in the DICOM (Digital Imaging and Communications in Medicine) format and delivered to Beijing Tiantan Hospital for centralized reading. The intracranial arteries, including the distal internal carotid, middle cerebral (M1 and M2), anterior cerebral, posterior cerebral, and basilar arteries, and the intracranial portion of the vertebra (V4), were independently assessed by two experienced neurologists. If there was a discrepancy, a third independent reviewer made the adjudication [5]. ICAS was determined by the presence of at least 50% stenosis of the ipsilateral or contralateral intracranial major artery according to the Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trial criteria [22]. All reviewers were unaware of the patients’ baseline and outcome information.
Efficacy and safety outcomes
The primary efficacy outcome was new stroke (ischemic or hemorrhagic) within 90 days. Secondary efficacy outcomes encompassed new stroke within 30 days, composite vascular events (stroke, TIA, myocardial infarction, and vascular death), ischemic stroke, and disabling stroke (defined as an mRS score of ≥2) within 90 days. The primary safety outcome was severe or moderate bleeding within 90 days according to the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries criteria (GUSTO) [23]. The secondary safety outcome was any bleeding within 90 days. All efficacy and safety outcomes at 1-year follow-up were assessed in this study.
Statistical analysis
Patients included in the current subanalysis of the CHANCE-2 trial were divided into two subgroups (ICAS and non-ICAS) based on the presence or absence of ICAS. In each subgroup, the baseline characteristics were compared according to previous antiplatelet therapy status (yes/no). Continuous variables are presented as medians with interquartile ranges (IQRs) and compared using the non-parametric Wilcoxon test due to a skewed distribution. Categorical variables are presented as frequencies with percentages and were tested using the χ2 or Fisher’s exact test.
The interactions between previous antiplatelet therapy and randomized antiplatelet treatment regimens with respect to efficacy and safety outcomes were assessed using crude and multivariable Cox proportional hazards models, with the study centers set as a random effect. Cox proportional hazards regression was also performed to analyze the differences in the rates of efficacy and safety outcomes between the ticagrelor-aspirin and clopidogrel-aspirin groups. In the multivariate model, age, sex, Han ethnicity, body mass index (BMI, calculated as weight in kilograms divided by the square of height in meters), current smoking status, medical history of hypertension, diabetes, dyslipidemia, myocardial infarction, ischemic stroke, TIA, and previous lipid-lowering therapy were adjusted. Crude and adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) are reported. Kaplan-Meier curves were plotted to display the cumulative incidence of the primary efficacy outcome in each subgroup and were compared using the log-rank test. A two-sided P-value of less than 0.05 was considered statistically significant. All statistical analyses were performed using the SAS statistical software (version 9.4; SAS Institute Inc., Cary, NC, USA).
Results
Baseline characteristics
Of the 6,412 patients recruited for the CHANCE-2 trial, 5,920 patients were included in the current analysis after excluding 492 patients without available intracranial arterial imaging. The baseline characteristics of the included and excluded patients were well-balanced (Supplementary Table 1).
Among the patients in the study, 701 (11.8%) had received antiplatelet therapy before enrollment, whereas 5,219 (88.2%) had not. Among the 701 patients who previously received antiplatelet therapy, 468 (66.8%) had a history of ischemic stroke (453, 64.6%) or TIA (26, 3.7%). Details of the antiplatelet drugs previously administered to the patients are presented in Supplementary Table 2. The most commonly used antiplatelet medication was aspirin (96.1%), followed by clopidogrel (3.6%), and ticagrelor (0.3%). Seven patients (1.0%) received two types of antiplatelet agents, six of whom received aspirin and clopidogrel.
The detailed characteristics of the patients with and without previous antiplatelet therapy are presented in Table 1. Patients with previous antiplatelet therapy were older; had higher BMI levels and lower high-density lipoprotein cholesterol (HDL-C) levels; more likely to be current non-smokers; had prior hypertension, diabetes, ischemic stroke, TIA, and myocardial infarction; and had previous lipid-lowering therapy compared with those without previous antiplatelet therapy. Of the 5,920 patients, 2,385 (40.3%) had ICAS, while 3,535 (59.7%) did not. The proportion of patients with a history of antiplatelet therapy was higher in the ICAS group than in the non-ICAS group (14.1% vs. 10.3%, P=0.003). In both the ICAS and non-ICAS subgroups, patients with previous antiplatelet therapy were more likely to be current nonsmokers and have a history of hypertension, diabetes, ischemic stroke, TIA, and myocardial infarction, and previous lipid-lowering therapy. Specifically, in the non-ICAS subgroup, patients who previously received antiplatelet therapy were older and had higher BMI.
Interaction of previous antiplatelet therapy with antiplatelet regimens on efficacy outcomes
The primary efficacy outcome of recurrent stroke within 90 days was observed in 404 (6.8%) patients in the current subgroup analysis. The cumulative risk of stroke recurrence according to treatment assignment and previous antiplatelet therapy is shown in Figure 1. Overall, patients without previous antiplatelet therapy and those treated with ticagrelor-aspirin after enrollment had the lowest risk of stroke recurrence (P<0.001, log-rank test). In the overall study population, patients who had previously received antiplatelet therapy had a higher rate of recurrent stroke compared to those who had not received antiplatelet therapy (7.3% vs. 6.8%, P=0.614). Although the benefit of ticagreloraspirin versus clopidogrel-aspirin for preventing recurrent stroke within 90 days was seen only in patients who had not previously received antiplatelet therapy (adjusted HR, 0.67; 95% CI, 0.54-0.82), we observed no statistically significant interaction between previous antiplatelet therapy and the two DAPT groups on recurrent stroke within 90 days (P for interaction=0.058) (Table 2).
Among the patients without ICAS, there was a significant interaction between previous antiplatelet therapy and the two DAPT groups for recurrent stroke within 90 days (Figure 2). These interactions persisted even after adjusting for other confounding factors. Ticagrelor-aspirin significantly reduced the risk of recurrent stroke (adjusted HR, 0.47; 95% CI, 0.34-0.66; P<0.001) compared with clopidogrel-aspirin in patients without previous antiplatelet therapy. However, these additional benefits of ticagrelor-aspirin have not been observed in patients with previous antiplatelet therapy. In the patients with ICAS, there was no significant difference in the effects of ticagrelor-aspirin versus clopidogrel-aspirin on the recurrent stroke, regardless of patients with or without previous antiplatelet therapy. No significant interactions were observed between previous antiplatelet therapy and the two DAPT groups for recurrent stroke (P=0.557). Similar results were observed for the secondary outcomes of stroke within 30 days, composite vascular events, ischemic stroke, and disabling stroke at 90 days of follow-up (Figure 2). The analysis of efficacy outcomes at the 1-year follow-up yielded results similar to the main analysis of outcomes at 90 days of follow-up (Supplementary Tables 3 and 4).
Interaction of previous antiplatelet therapy with antiplatelet regimens on safety outcome
The rate of severe or moderate bleeding events within 90 days (19/5,920; 0.32%) and 1 year (35/5,920; 0.59%) was low and not significantly different between patients with and without previous antiplatelet therapy, whether in the ICAS or non-ICAS group. There was no statistically significant evidence for the interaction between previous antiplatelet therapy and treatment allocation for severe or moderate bleeding events or for any bleeding, regardless of the presence of ICAS (Supplementary Table 5). Similar results were observed for the 1-year safety outcomes (Supplementary Table 6).
Discussion
In this post-hoc analysis of the CHANCE-2 trial, which included CYP2C19 LOF carriers with minor ischemic stroke or high-risk TIA, we identified the role of previous antiplatelet therapy in stratifying the efficacy of ticagrelor-aspirin and clopidogrel-aspirin DAPT only in the patients without ICAS, but not in those with ICAS. In patients without previous antiplatelet therapy, ticagrelor-aspirin therapy reduced the risk of recurrent stroke within 3 months by 33% compared to clopidogrel-aspirin therapy, without a significant increase in the risk of moderate or severe bleeding events. However, this additional benefit was not observed in patients with a history of antiplatelet therapy. These results highlight the need to reassess DAPT efficacy based on ICAS status and previous antiplatelet use to better identify patients who may benefit from ticagrelor-aspirin treatment and optimize treatment strategies.
Although no clinical trials have examined the effect of previous antiplatelet therapies on the efficacy of DAPT in patients with and without ICAS, insights from the pathophysiological features of ICAS and the pharmacological effects of antiplatelet agents offer some valuable perspectives. Inflammation plays a key role in atherosclerosis and vascular stenosis, affects the risk of stroke, and has become a focal point in cardiovascular and cerebrovascular diseases. ICAS causes local hemodynamic changes, increased wall shear stress, and damage to the vascular endothelium [24], all of which activate the inflammatory response, forming a vicious circle of inflammation and further increasing the risk of recurrent stroke. Elevated levels of inflammation have been observed in patients with ICAS and adversely affected stroke outcomes [25-27]. Furthermore, inflammation can exhibit prothrombotic effects through platelet reactivity or reduced fibrinolysis, ultimately leading to the incomplete inhibition of platelet function by antiplatelet therapy [28,29]. Previous studies have suggested that the ongoing potential inflammation may be correlated with the additional protective effect of antiplatelet therapy regimens [15,30].
In addition to platelet inhibition, antiplatelet drugs also have a potential role in modulating inflammation [31-33]. Given the elevated inflammatory burden in patients with ICAS, as well as the predominance of previous aspirin-based antiplatelet therapy, it is plausible that these factors collectively contribute to a complex and potentially synergistic confounding effect on the clinical efficacy of DAPT, likely mediated through inflammation-related pathways. However, owing to the lack of targeted and systematic assessments of local vascular inflammation, and the absence of evidence from large-scale randomized controlled trials, this hypothesis requires further investigation.
Platelet reactivity can rebound shortly after the cessation of antiplatelet therapy [17,18], especially within 1 week of clopidogrel withdrawal. Moreover, patients with previous antiplatelet therapy in this study exhibited multiple comorbidities and lower HDL-C levels, which may position them at high risk of increased platelet reactivity post-discontinuation [34]. An alternative viewpoint posits that the cessation of antiplatelet drugs will lead to the loss of the inhibitory effect on vascular inflammation and the formation of a pro-inflammatory state [35]. In the CHANCE-2 trial, patients were required to receive trial medication within 24 hours of symptom onset, and a history of antiplatelet therapy was defined as the use of antiplatelet medications within 1 month before the onset of the qualifying event. The ability to receive effective treatment shortly after stroke can significantly impact long-term prognosis [36]. Therefore, antiplatelet therapy prior to enrollment may hinder patients from experiencing the true efficacy of the trial medication.
Although there was no direct evidence supporting the notion that previous antiplatelet therapy affects the additional benefits of ticagrelor, antiplatelet therapy has been shown to impact renal function to some extent [13,37]. Furthermore, previous studies have highlighted the differences in the pharmacodynamic and pharmacokinetic profiles of ticagrelor and clopidogrel, indicating that the metabolism and clearance of clopidogrel are more reliant on renal function [38-40]. Findings of previous subgroup analysis from the CHANCE-2 trial have demonstrated that patients with impaired renal function failed to derive additional benefit from ticagrelor-aspirin [41]. Given that renal function modifies the benefits of antiplatelet drugs, it is likely that the benefits of DAPT may differ by previous antiplatelet therapy. Our study partially validates this hypothesis by finding a high prevalence of renal function impairment in patients with a history of antiplatelet therapy.
Ticagrelor, a new oral P2Y12 receptor antagonist, is superior to clopidogrel because it is associated with faster and stronger platelet inhibition. This may lead to a higher risk of bleeding in specific populations, and its safety needs to be carefully assessed. In this study, moderate or severe bleeding was similar across subgroups, but ticagrelor-aspirin increased mild and overall bleeding risks, consistent with CHANCE-2 [4]. The increased risk of bleeding was statistically significant only in patients without ICAS without previous antiplatelet therapy, possibly due to the limited sample size. Notably, we extended the study period to 12 months and obtained similar results. Although ticagrelor-aspirin demonstrated significant efficacy in patients without ICAS without prior antiplatelet use, its increased bleeding risk underscores the need for further clinical trials to refine dosing strategies and optimize the balance between therapeutic efficacy and safety risks.
Our study has several limitations. First, as this was a post-hoc analysis with limited statistical power, our findings should be regarded as hypothesis-generating and require confirmation through further studies. Second, the ICAS assessment was only conducted at baseline, and the progression of stenosis during the follow-up period may have affected the long-term outcomes. Third, we only considered the presence of ICAS without considering factors such as the location of ICAS, number of affected vessels, dominance of the affected vessel, and degree of stenosis. Moreover, we did not differentiate between symptomatic and asymptomatic ICAS, which may differ in terms of prognostic relevance. Stratification was not performed owing to the limited sample size. Fourth, 33.2% of the patients who had previously taken antiplatelet drugs had no history of ischemic stroke or TIA; however, we did not collect data on the reasons for previous antiplatelet use in these patients. Among them, 86 (36.9%) had coronary heart disease, which could provide some information. Finally, this study enrolled individuals exclusively from China, which may limit the generalizability of our findings to other populations. However, this result may inspire further research into the effects of ICAS and previous antiplatelet therapy on response variability to antiplatelet therapy, as well as its clinical application in improving the secondary prevention of recurrent stroke among high-risk patients.
Conclusions
This post-hoc subgroup analysis of the CHANCE-2 randomized clinical trial showed that in patients with minor stroke or high-risk TIA carrying CYP2C19 LOF alleles, the absence of both ICAS and previous antiplatelet therapy may predict better response to ticagrelor-aspirin therapy in reducing new stroke, compared with clopidogrel-aspirin. Further large-scale randomized controlled clinical trials are required to confirm these findings.
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