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Introduction
According to current guidelines, reperfusion therapies are recommended as effective treatment strategies for patients with acute ischemic stroke [1,2]. However, a significant subset of patients cannot receive reperfusion therapies due to the strict therapeutic window as well as the lack of access to endovascular care; such patients are instead recommended to receive antiplatelet therapy. For patients with minor stroke or high-risk transient ischemic attack, the Clopidogrel With Aspirin in Acute Minor Stroke or Transient Ischemic Attack (CHANCE) [3] and Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) [4] trials both found that dual antiplatelet therapy with clopidogrel and aspirin initiated within 24 hours of stroke onset significantly reduced the risk of recurrent stroke compared with aspirin alone. Recently, the Intensive Statin and Antiplatelet Therapy for Acute High-Risk Intracranial or Extracranial Atherosclerosis (INSPIRES) trial further identified that the above population with presumed atherosclerotic causes showed a greater benefit from dual antiplatelet therapy initiated within 72 hours after stroke onset than from monotherapy [5]. However, the guideline still recommends monotherapy with aspirin alone for patients with acute mild-to-moderate ischemic stroke [1], who are at high risk of early neurological deterioration (END), which is associated with poor prognosis [6].
The Antiplatelet Therapy in Acute Mild to Moderate Ischemic Stroke (ATAMIS) trial was the first randomized clinical trial with a large sample size to demonstrate that dual antiplatelet therapy with clopidogrel and aspirin could significantly reduce the risk of END at 7 days compared with aspirin alone in patients with acute mild-to-moderate ischemic stroke within 48 hours of stroke onset [7]. A prior meta-analysis also showed that dual antiplatelet therapy immediately following the index stroke was more effective than monotherapy for secondary stroke prevention [8]. However, the effect of time from stroke onset to antiplatelet therapy (OTT) on preventing END in acute mild-to-moderate stroke remains unclear.
In this context, we performed a pre-specified post hoc analysis of the ATAMIS trial to determine whether earlier dual antiplatelet therapy initiation was associated with a lower risk of END in patients with acute mild-to-moderate ischemic stroke who were not considered candidates for reperfusion therapies.
Methods
All data supporting the findings of this study are available from the corresponding author upon reasonable request.
Study design and participants
Details on the design, protocol, and statistical analysis plan of the ATAMIS trial have been previously published [7,9]. In brief, the ATAMIS trial was a multicenter, open-label, blinded-endpoint, randomized clinical trial enrolling 3,000 patients between December 20, 2016, and August 9, 2022, which aimed to assess the effect of clopidogrel plus aspirin in patients with acute mild-to-moderate ischemic stroke. The eligibility criteria included an age of 18 years or older, functioning independently before stroke (modified Rankin Scale [mRS] scores, 0–1; range, 0 [no symptoms] to 6 [death]), and diagnosis with acute mild-to-moderate ischemic stroke (baseline National Institute of Health Stroke Scale [NIHSS] scores, 4–10; range, 0–42, with higher scores indicating greater stroke severity) within 48 hours after stroke onset. The exclusion criteria were patients who met the eligibility criteria for intravenous thrombolysis or endovascular therapy and had a clear indication for anticoagulation or history of intracerebral hemorrhage. All study procedures were reviewed and approved by the Ethics Committee of the General Hospital of Northern Theater Command (Approval Number: k [2016] 6-1). Written informed consents were obtained from either the patients or their legally authorized representatives. This study was registered at ClinicalTrials.gov (NCT02869009). All patients from the modified intention-to-treat analysis set were included in the post hoc analysis. If patients were diagnosed with atrial fibrillation following randomization, they received anticoagulation therapy after antiplatelet therapy, in accordance with the national guidelines, and were included in the full analysis set based on the intention-to-treat principle. The detailed screening of patients for the analysis has been previously reported [7]. The current analysis followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline (Appendix 1).
Procedures
In the ATAMIS trial, patients were randomly assigned to receive either dual antiplatelet therapy with clopidogrel plus aspirin or monotherapy with aspirin alone. Further details of antiplatelet therapy have been described in a previous report [7]. In this post hoc analysis, according to OTT using 24 hours as a cutoff in which dual antiplatelet therapy was recommended for minor stroke by guideline [1], eligible patients were divided into two subgroups based on treatment time: 0–24 hours group (OTT <24 h) and 24–48 hours group (OTT ≥24 h). Neurological status, measured with NIHSS score, was evaluated at admission, and at 7 and 14 days after randomization. Follow-up data, including the assessment of clinical prognosis, recurrent events, and safety events, were collected 90 days after randomization.
Outcomes
In this post hoc analysis, all the outcomes paralleled the ATAMIS trial [7]. The primary outcome was occurrence of END at 7 days, defined as an increase in NIHSS of greater than 2 points compared with baseline (excluding cerebral hemorrhage) [10]. The secondary outcomes were excellent functional outcome at 90 days, defined as an mRS score of 0 to 1; a shift in the distribution of the ordinal mRS score at 90 days; a change in the NIHSS score compared with baseline at 14 days; time from randomization to occurrence of new stroke [11] within 90 days; and time from randomization to the occurrence of other vascular events (pulmonary embolism, peripheral vessel or cardiovascular event) or all-cause death within 90 days. Safety outcomes included the occurrence of any bleeding events or intracranial hemorrhage during the trial, given that these were directly associated with antiplatelet therapy. Detailed information for the outcome assessment is shown in the Supplementary Methods.
Statistical analysis
Considering the potentially imbalanced characteristics between the groups in the post hoc analysis, the primary analysis was adjusted. Continuous variables are summarized as median (interquartile range [IQR]) and categorical variables as frequencies (percentages). The baseline characteristics between groups were compared using the Mann–Whitney U test or chi-square test. For the treatment effect of outcomes, we estimated the absolute number of events, as well as the risk difference (RD), odds ratio (OR), geometric mean ratio (GMR), or hazard ratio (HR) with their 95% confidence intervals (CIs).
First, as a continuous variable, restricted cubic spline analysis with three knots at the 10th, 50th, and 90th percentile [12] was applied to explore the nonlinear association between OTT, as well as the probability of the primary outcome compared with antiplatelet therapies. The probability was calculated using binary logistic regression analysis, and the best-fit line was drawn according to probability and OTT. As a categorical variable, the primary outcome was analyzed for each subgroup.
Second, both unadjusted and adjusted generalized linear models and Cox regression analyses were performed to evaluate the effect of antiplatelet therapies on outcomes according to OTT, and in each time subgroup. The primary adjusted model included any imbalanced baseline variables (P<0.1), as well as pre-specified covariates (age, sex, history of diabetes, history of hypertension, NIHSS score at randomization, and presumed stroke cause based on the Trial of Org 10172 in Acute Stroke Treatment [TOAST] classification [13]) in the ATAMIS trial. Adjusted interactions between the OTT and the effect of antiplatelet therapy on outcomes were assessed by including imbalanced variables between time subgroups.
Third, a subgroup analysis of primary outcome was conducted according to six pre-specified factors (age [<65 yrs or ≥65 yrs], sex [female or male], history of diabetes [yes or no], history of hypertension [yes or no], NIHSS score at randomization [<7 or ≥7], and presumed stroke cause), in order to investigate the characteristics of patients benefiting from dual antiplatelet therapy in each time subgroup.
In addition, per-protocol analysis was restricted to patients who received the completed intervention, as specified in the protocol [9], while propensity score matching analysis for all outcomes was performed as a sensitivity analysis. Propensity score matching was performed to generate a new cohort with a balanced sample size between the time subgroups to control for sample-size bias. Furthermore, patients were analyzed by grouping with different OTT cutoff values, such as 12 hours or 18 hours.
Detailed information regarding the adjusted models, propensity score matching, and statistical analysis is presented in the Supplementary Methods. All analyses were exploratory, and all P values were nominal. Two-sided P values <0.05 were considered significant. All statistical analyses were performed using the SPSS software (version 26.0; IBM Corp., Armonk, NY, USA) and R software (version 4.1.0; R Foundation for Statistical Computing, Vienna, Austria).
Results
Patient characteristics
A total of 2,915 patients from the ATAMIS trial were enrolled in this post hoc analysis, including 1,757 patients in the 0–24 hours group (OTT: median [IQR], 9.0 h [5.4 to 14.5 h]) and 1,158 patients in the 24–48 hours group (OTT: median [IQR], 28.6 h [25.1 to 41.2 h]). The median (IQR) age was 66 (59–73) years, and 1,020 (35.0%) patients were women. In total, 902 patients were assigned to receive clopidogrel plus aspirin, and 855 patients were assigned to receive aspirin alone in the 0–24 hours group, whereas 600 and 558 patients were assigned to receive these treatments in the 24–48 hours group, respectively (Figure 1).
Table 1 shows the baseline characteristics of patients assigned to different antiplatelet therapies in each time subgroup. In the 0–24 hours group, a higher proportion of patients with diabetes was assigned to the clopidogrel plus aspirin group. In the 24–48 hours group, a higher proportion of patients with a history of transient ischemic attack were assigned to receive aspirin alone. We identified differences in age, sex, current smoking, current drinking, NIHSS score at admission, OTT, presumed stroke cause, and location of the responsible vessel between the 0–24 hours and 24–48 hours groups.
Association between continuous OTT and outcomes
As a natural continuous characteristic of OTT, the probability of END at 7 days was compared between the clopidogrel plus aspirin and aspirin alone groups according to OTT, which revealed that the probability decreased with a longer OTT (Figure 2A and B). Compared with aspirin alone, the analysis revealed a significantly decreased risk of END after receiving clopidogrel plus aspirin therapy (4.8% vs. 6.7%; adjusted RD, -1.9%; 95% CI, -3.6% to -0.2%; P=0.03) (Table 2). However, no significant interactions were observed (adjusted P=0.13). As such, we explored the nonlinear association between continuous OTT and the primary outcome using restricted cubic spline analysis. Although no significant nonlinear association was found (P for nonlinear=0.06) (Figure 2C and D), the odds ratio for END at 7 days, as well as that for antiplatelet therapy, decreased with longer OTT and plateaued at 48 hours.
The distribution of mRS scores at 90 days between the clopidogrel plus aspirin and aspirin alone groups is presented in Figure 3A. None of the secondary or safety outcomes were significantly different between clopidogrel plus aspirin and aspirin alone across the continuous OTT, and no significant interactions were found (Table 2).
Association between categorical OTT and outcomes
Compared with aspirin alone, the analysis revealed significantly decreased odds in END following clopidogrel plus aspirin treatment in the 0–24 hours group (5.7% vs. 9.2%; adjusted RD, -3.7%; 95% CI, -5.5% to -2.0%; P<0.01) (Table 3), while no significant difference was found in the 24–48 hours group (3.5% vs. 2.9%; adjusted RD, 0.6%; 95% CI, -0.8% to 2.0%; P=0.40) (Table 3). Significant interactions between the time subgroups and the effect of antiplatelet therapy on the primary outcome were observed (adjusted P=0.03).
The distribution of mRS scores at 90 days between the clopidogrel plus aspirin and aspirin alone groups in each time subgroup is presented in Figure 3B and C. None of the secondary or safety outcomes showed significant differences between the clopidogrel plus aspirin and aspirin alone in each time subgroup, and no significant interactions were found (Table 3).
Subgroup analysis
To explore the characteristics of patients who benefited from early dual antiplatelet therapy, we further investigated the association between OTT, as well as the effect of antiplatelet therapy on the primary outcome in relation to age, sex, history of hypertension, history of diabetes, stroke severity, and presumed stroke cause (Figure 4). In each characteristic subgroup, clopidogrel plus aspirin showed a lower risk of END at 7 days than aspirin alone in the 0–24 hours group compared with the 24–48 hours group, which was similar to the result observed in the primary analysis. Notably, significant interactions between the OTT subgroup and the effect of antiplatelet therapy on the primary outcome were identified in patients with NIHSS scores of 4 to 7 at admission (P=0.046) and an undetermined stroke etiology (P=0.01).
Sensitivity analysis
All outcomes analyzed in patients with propensity score matching and from the per-protocol analysis set were similar to those in patients from the modified intention-to-treat analysis set. As the number of OTT groups increased, the results also indicated that patients benefited more from earlier dual antiplatelet therapy. The results of the sensitivity analysis are presented in the Supplementary Results.
Discussion
In this post hoc analysis of the ATAMIS trial, we found that the risk of END 7 days after receiving antiplatelet therapy decreased as the OTT increased. Furthermore, we divided patients with acute mild-to-moderate ischemic stroke within 48 hours of symptom onset into the 0–24 hours and 24–48 hours groups according to the OTT, using 24 hours as a cutoff, with the aim of exploring the relationship between OTT and the effect of antiplatelet therapies on clinical outcomes after stroke. The results showed that, compared with patients receiving aspirin alone, the risk of END at 7 days was significantly lower in patients receiving clopidogrel plus aspirin within 24 hours of symptom onset, particularly in patients with NIHSS scores of 4 to 7 at admission, or an undetermined cause of stroke. Collectively, these findings indicated that the earlier dual antiplatelet treatment is started, the lower the risk of END in this population.
END is a common and important complication of acute ischemic stroke [14,15]. OTT is a critical characteristic of patients with ischemic stroke routinely used to select the appropriate treatment strategy in current guidelines [1], and is strongly associated with patient prognosis [16,17]. The current analysis found that the risk of END decreased with OTT, regardless of the antiplatelet strategy. This finding was similar to that reported in a prospective multicenter observational study from China [14], focusing on the worsening of patients with acute ischemic stroke receiving conventional treatment rather than reperfusion treatment, which shared a similar targeted population as the ATAMIS trial. Overall, these results may be attributed to the greater expansion and progression of existing infarct lesions in the early stage [18], which was the primary reason for ischemic END [19]. Although the risk was higher in the early stage of acute ischemic stroke, regardless of the antiplatelet treatments received (Figure 2C), a greater reduction in the risk of END after receiving dual antiplatelet therapy compared with antiplatelet monotherapy (Figure 2D) was observed, which was beneficial for functional outcome that was associated with END [15]. Collectively, these findings indicated a higher risk of END at 7 days in patients with shorter OTT than those with longer OTT, and the importance of intensive antiplatelet therapy in the early stage after stroke onset.
In the secondary analysis of the POINT trial, the benefit of dual antiplatelet therapy in acute minor ischemic stroke or transient ischemic attack with high-risk factors was greatest when dual antiplatelet therapy was initiated within 12 hours of symptom onset and persisted until 72 hours [20]. Similarly, the effect of dual antiplatelet therapy in acute mild-to-moderate ischemic stroke on preventing the occurrence of END at 7 days was also found higher within 0–24 hours of symptom onset than 24–48 hours in the current analysis. On the one hand, the higher occurrence of END in patients with shorter OTT partially contributed to the larger benefit of dual antiplatelet therapy at this stage, given that it provided the opportunity to find a significant risk difference. On the other hand, as patients with shorter OTT had a greater risk of experiencing expansion and progression of infarct lesions [18], antiplatelet therapy may play a more important role in preventing END in the early stage of stroke given stroke progression due to clot propagation [21,22]. The benefit of early antiplatelet therapy was further proven in patients receiving intravenous thrombolysis to reduce reocclusion and to improve neurological function at 7 days [23,24], which further supported our findings indicating the better benefit of early antiplatelet therapy in preventing END. Collectively, the current findings suggest that dual antiplatelet therapy should be initiated as early as possible after stroke onset to reduce the risk of END, considering its stronger antithrombotic effect than that of monotherapy.
In our subgroup analysis, we found that the interaction between the OTT and the effect of dual antiplatelet therapy was significantly associated with the NIHSS score at admission, or the presumed stroke cause. Patients with NIHSS scores of 4 to 7 at admission were found to achieve a greater benefit from early dual antiplatelet therapy than those with NIHSS scores of 8 to 10, which was in good agreement with the benefit of early dual antiplatelet therapy in patients with minor stroke observed in a previous study [20]. Interestingly, patients with an undetermined cause of stroke etiology were found to benefit significantly from early dual antiplatelet therapy. However, in the ATAMIS trial, most patients diagnosed with undetermined-cause stroke had a lower proportion of complete etiology examinations. Given the unclear and potential heterogeneous causes of stroke of undetermined cause, the association between OTT and the effect of dual antiplatelet therapy in specific stroke etiologies needs further investigation.
Overall, our study had several limitations. First, although relatively large populations of 1,757 and 1,158 patients were included in each time subgroup in this post hoc analysis, an imbalanced sample size between the treatment groups may have rendered our study underpowered. However, we conducted a propensity score matching analysis to test the robustness of the findings. Second, owing to the lack of sufficient etiological examinations, a large proportion of patients were classified as having an undetermined cause of stroke. The interactions between stroke etiology, OTT, and antiplatelet treatment efficacy in the current study should therefore be interpreted with caution. The specific causes of stroke in patients benefiting from early dual antiplatelet therapy should be explored in the future. Third, the lack of an association with functional outcomes may contradict the clinical relevance of this finding, which can be attributed to the fact that a decrease in the occurrence of END may not result in a significantly good prognosis at 90 days. Additionally, the neutral finding in preventing stroke recurrence may be due to a lack of statistical power triggered by an insufficient sample size. Fourth, the generalizability of the results must be validated in other cohorts, particularly non-Chinese populations. Fifth, as the ATAMIS trial excluded patients who received intravenous thrombolysis or endovascular therapy, our findings cannot be generalized to patients who tended to receive reperfusion treatment. Finally, we interpreted our findings with caution because of the exploratory nature of the post hoc analysis. However, these findings warrant further investigation.
Conclusions
In conclusion, this post hoc analysis of the ATAMIS trial indicates that adults with acute mild-to-moderate ischemic stroke who are not considered candidates for reperfusion treatments may benefit more from early clopidogrel plus aspirin treatment started within 24 hours of symptom onset compared with 24–48 hours of onset with respect to the prevention of END at 7 days. These findings should be confirmed in future studies.
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