According to current guidelines, acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) should receive dual antiplatelet therapy (DAPT) for a minimum of 12 months, with a preference for potent P2Y₁₂ receptor inhibitors [1, 2, 3]. These agents are key for thrombosis prevention and reducing cardiovascular risk. However, the protection that DAPT provides against thrombotic events comes at the cost of an elevated bleeding risk. Therefore, risk stratification and personalized DAPT strategies for patients undergoing PCI will help maximize net clinical benefit [4]. With the continuous development of precision medicine, related research has increasingly focused on methods for assessing ischemic and bleeding risks in ACS patients [4, 5, 6, 7] to help the identify ACS patients with high-risk features as well as to formulate precise DAPT strategies. In order to stratify the high risk, multiple guidelines and study have defined high-risk populations for ischemia or bleeding: the definition of high-risk in the 2023 European Society of Cardiology (ESC) guidelines, the Academic Research Consortium for High Bleeding Risk (ARC-HBR) criteria, and the derivation and validation of the predicting bleeding complications in patients undergoing stent implantation and subsequent dual antiplatelet therapy (PRECISE-DAPT) score, etc. [5]. Potent P2Y₁₂ receptor inhibitors or extended duration of DAPT may be a therapeutic consideration for patients with high risk ischemic features, whereas clopidogrel or shortened DAPT duration may be appropriate for patients with high bleeding risk. However, for patients with dual high-risks, determining the optimal DAPT strategy based on risk assessment alone is not straightforward because there is a greater need to balance ischemic and bleeding risk in these patients. Currently, the optimal DAPT strategy within 12 months after PCI for dual high-risk ACS patients has not been firmly established.

Despite advancements in defining antiplatelet strategies for the chronic phase beyond one year post-PCI, a critical evidence gap remains regarding the optimal antiplatelet regimen during the first year following PCI, specifically in patients at dual high-risk. While clinical trials, such as the OPT-BIRISK (optimal antiplatelet therapy for high bleeding and ischemic risk) trial has focused on determining the strategy after the standard DAPT period [5], there is a distinct lack of randomized or large-scale data guiding the initial strategy within this first year. This gap is particularly relevant for dual high-risk patients, in whom the balance between preventing thrombotic events and mitigating bleeding complications is most delicate.

Platelet function testing (PFT) can individualize the responses to platelet activation and aggregation capacity, ensuring that patients with ACS receive adequate platelet inhibition during long-term treatment. Recognizing that PFT serves as a predictor for ischemic and bleeding events in post-PCI patients, researchers have used PFT to adjust antiplatelet therapy. The 2020 ESC guidelines for non-ST-segment elevation ACS (NSTE-ACS) state that de-escalation is presented as a viable alternative in patients with ACS who are unsuitable for intensive therapy. This de-escalation may be based on clinical judgment or guided by PFT or genetic testing, depending on the risk profiles of patients and the feasibility of testing, although it is only a class IIb recommendation [3]. For patients requiring DAPT escalation, platelet function may be oversuppressed, thereby requiring adjustment under guidance. The platelet function monitoring to adjust antiplatelet therapy in elderly patients stented for an acute coronary syndrome (ANTARCTIC) trial, which adopted a mixed strategy of adjusting therapy (either escalation or de-escalation) based on PFT results in 877 ACS patients aged 75 and above after PCI. However, this trial failed to demonstrate that the PFT-guided strategy significantly reduced the net adverse clinical events [8]. This negative outcome suggests that the utility of a PFT-guided strategy remains uncertain. Consequently, there is currently no clear consensus regarding the precise implementation of PFT in clinical care. Key questions include whether it holds greater value in guiding de-escalation rather than escalation, or in selected high-risk subgroups. A meta-analysis showed that PFT-guided medication adjustment, compared to empirical medication adjustment, could reduce the risks of cardiac death, recurrent myocardial infarction, in-stent thrombosis, stroke, and minor bleeding; however, no differences in all-cause mortality and major bleeding were found [9]. The current studies have not identified the optimal population for PFT. Therefore, the reason for this study which was the investigation and outcomes of PFT in dual high risk patients because even in other populations with different risk profiles prove its efficacy and safety.

This was a real-world, single-centre cohort study that retrospectively analysed 1816 ACS patients at a dual high risk who underwent PCI. The conclusions are as follows. (1) A significant proportion of ACS patients undergoing PCI exhibit the dual high-risk features, accounting for approximately 55.09% (1822/3307). (2) The PFT-guided DAPT scheme selection is recommended for patients with dual high-risk ACS who have undergone PCI. Compared to DAPT regimens subjectively chosen by clinicians based on experience, this approach can significantly benefit from NACE (a composite endpoint of MACCE and BARC bleeding (type 3 or greater)) and MACCE.

For ACS patients undergoing PCI, current guidelines recommend using a 12-month combination of aspirin and potent P2Y₁₂ receptor inhibitors for DAPT. Although intensified or prolonged DAPT treatment can reduce the risk of ischemia, it can increase bleeding events, which is a predictive factor for poor prognosis. The risk of ischemia in patients with ACS is time-dependent and gradually decreases over time. Therefore, in clinical practice, efforts are being made to balance bleeding and ischemia risks through unguided de-escalation strategies, in order to achieve personalized treatment [10]. For patients at a dual high risk for ischemia and bleeding, there is an even greater need to balance ischemic and bleeding risks. In this study, the prevalence of dual high-risk ACS patients was approximately 60%, notably higher than the 32% reported using the “evaluating the performance of the can rapid risk stratification of unstable angina patients suppress adverse outcomes with early implementation of the ACC/AHA guidelines (CRUSADE)”-“global registry of acute coronary events (GRACE)” risk combinations [11]. This result differs significantly from our findings. A likely explanation for this discrepancy is the divergent methodological approaches used to define dual high-risk status. Additionally, while the aforementioned study focused on ACS patients, our study exclusively included ACS patients who underwent PCI. This suggests that the coronary artery disease severity in our cohort may be greater, potentially explaining the higher proportion of dual high-risk patients. Similarly, a study applying the OPT-BIRISK criteria reported a comparable dual high-risk prevalence of 58.8% (4146/7049) in ACS patients who underwent PCI, which is closely aligned with our findings [12]. However, current evidence offers little guidance on DAPT regimens for dual high-risk patients. In 2020, the ESC guidelines proposed a preliminary antiplatelet drug transition model based on ischemic and bleeding risk. Bleeding risk was assessed in NSTE-ACS patients who underwent PCI. For high bleeding risk patients, de-escalation to aspirin monotherapy is recommended at the 3-month post-PCI. For remarkably high bleeding risk patients, de-escalation to clopidogrel monotherapy is suggested at the 1-month post-PCI. For low bleeding risk patients, further assessment of high ischemic risk is required to develop a more precise antiplatelet strategy [3]. However, this model lacks discussion on antiplatelet regimens for dual high-risk patients, highlighting the gap in evidence in the guidelines. For dual high-risk patients, an additional tool beyond the current risk scoring systems is required to assist clinicians in selecting DAPT regimens. However, ischemic and bleeding events in ACS patients undergoing PCI result from the synergistic effects of multiple factors, including age and comorbidities such as diabetes, hypertension, atrial fibrillation, heart failure, complex CAD, procedural factors, and anticoagulants or nonsteroidal anti-inflammatory drugs [3, 5, 13, 14, 15]. In recent years, studies on PFT-guided DAPT for patients with ACS have not resulted in definitive guidelines [3, 8, 9]. PFT can individually reflect platelet activation and aggregation capacity, ensuring adequate platelet inhibition during the long-term treatment of patients with ACS. Previous studies identified high platelet reactivity as an independent risk factor for MACCE within 12 months after PCI. Conversely, it was negatively correlated with bleeding events [16, 17]. In the ANTARCTIC study, adjustments were made for DAPT escalation or de-escalation based on PFT [8, 18]. Compared to medication adjustments based on experience, PFT-guided medication adjustments can reduce the risks of cardiac death, myocardial infarction, in-stent thrombosis, and stroke, as well as minor bleeding risks [9]. However, other studies suggested that PFT-guided DAPT does not reduce the occurrence of ischemic and bleeding events [19, 20]. A potential explanation is that PFT alone has a limited role in guiding DAPT. In contrast, risk-scoring systems for patients with ACS encompass various high-risk factors beyond PFT. Therefore, it is important to determine how PFT can be combined with risk scores to guide the selection of DAPT regimens selection. In other diseases, combining scoring systems with biomarkers to guide diagnosis and treatment is common, such as combining the results of the Wells and Geneva scores with D-dimer levels to assist in the identification of pulmonary embolism [21].

A study has shown that the association between low platelet reactivity and bleeding events is weaker than the association between high platelet reactivity and thrombotic complications [22]. This may be because the optimal cutoff values for platelet reactivity related to high bleeding and ischemic risks are not yet clearly defined [23, 24]. However, because the ischemic risk in ACS patients gradually decreases after PCI while the bleeding risk increases. Consequently, the bleeding risk surpasses the ischemic risk at one month post-ACS onset, after which both risks tend to stabilize [25]. Since bleeding and ischemic risks vary at different stages following PCI, the optimal therapeutic window for platelet reactivity may differ. The most convenient approach is to perform PFT to guide the DAPT scheme selection when a patient’s ischemic and bleeding risks begin to stabilize, which is also the optimal time for medication transition. In this study, PFT was conducted at 3 months after PCI to guide the DAPT strategy selection. Most patients in this study underwent outpatient follow-up at 3 months after PCI; however, evidence confirms that potent P2Y₁₂ inhibitors maintain a critical advantage in preventing early-phase ischemic events within the first month of ACS [26]. This suggests that although the bleeding risk begins to exceed the ischemic risk at 1 month after PCI, the ischemic risk remains relatively high, and transitioning medications at this stage may increase the occurrence of ischemic events, particularly when de-escalating antiplatelet drugs are used. Despite the continuing increase in the risk of in-stent thrombosis within six months post-PCI with newer-generation drug-eluting stents, in-stent thrombosis has been shown not to significantly differ between 3 and 6 months after PCI [27]. Therefore, in our study, we chose to adjust antiplatelet therapy and perform PFT at 3 months after PCI. In addition, because the distribution of cytochrome P450 family 2 subfamily C member 19 (CYP2C19) alleles varies among African, European, and East Asian populations and these alleles can influence platelet reactivity [28]. There is a need to identify the optimal window for platelet reactivity across ethnic groups, especially considering the ‘East Asian paradox’. Owing to the inclusion of East Asian populations in this study, there may be certain limitations in the generalizability of the results.

In real-world practice, the choice of P2Y₁₂ receptor inhibitors for post-PCI patients typically considers three aspects: the assessment results of the ischemia and bleeding risks, the complexity of lesions during PCI, and whether the patient has respiratory distress and gout caused by ticagrelor. Given that the population included in this study were all at double high risk, and the complexity of lesions was also included in the assessment of ischemic risk, the use of ticagrelor in this study was based on the subjective habits and experience of different clinical doctors. An analysis was performed to assess the potential confounding effect of ticagrelor use at discharge, which revealed no significant difference between the two groups (p = 0.200). De-escalation strategies for DAPT include switching to a less potent P2Y₁₂ receptor inhibitor, dosage reduction, and shortening the duration of DAPT. Clearly, De-escalation ticagrelor from the standard dose (90 mg BID) to a lower dose (60 mg BID) represents one of these regimens. Previous pharmacodynamic and pharmacokinetic study have demonstrated that in patients with a history of myocardial infarction, the antiplatelet effect of low-dose ticagrelor is comparable to that of the 90 mg twice daily regimen [3]. Thus, reducing ticagrelor from the standard dose to the lower dose. Its essence is a “response-guided de-escalation”. Rationale for reducing platelet related from 90 mg to 60 mg is a continuation of strong platelet inhibition. And it is applicable to patients who still have significant ischemic risk (such as complex lesions, diabetes, previous myocardial infarction), but cannot tolerate the risk of bleeding at a dose of 90 mg. The strategy of switching from ticagrelor 90 mg to clopidogrel 75 mg is primarily suitable for patients with bleeding risk outweighing ischemic risk, those intolerant to ticagrelor, and those who prefer or require clopidogrel due to personal preference or economic considerations.

The results of this study indicate that PFT-guided DAPT strategy selection can benefit patients in terms of NACE, MACCE, cardiac death, and stroke without increasing the risk of BARC bleeding (type 3 or greater). The results in this dual high-risk ACS population are corroborated by other studies of PFT-guided DAPT [20, 29]. The “Guided de-escalation of antiplatelet treatment in patients with acute coronary syndrome undergoing percutaneous coronary intervention (TROPICAL-ACS)” study analysis showed that for acute myocardial infarction patients post-PCI, after 7 days of prasugrel and clopidogrel treatment, those with low platelet reactivity,who de-escalated to clopidogrel had a lower incidence of the primary endpoints (cardiac death, myocardial infarction, stroke, and BARC $\ge$2 bleeding) at 1 year compared to those who continued prasugrel (7.3% vs. 9.0%, p 0.001, HR: 0.81, 95% CI: 0.62–1.06), with increased clinical benefit and no inferiority in ischemic events such as in-stent restenosis, all-cause death, and urgent revascularization [20]. A pre-specified analysis showed that guided de-escalation to clopidogrel based on low platelet reactivity at one month post-PCI reduced both ischemic and bleeding events at one year, resulting in a net clinical benefit [29]. In contrast to the timing of platelet inhibition after acute coronary syndrome (TOPIC) trial, our analysis failed to identify guided DAPT as an independent predictor of major bleeding events. The limited sample size resulted in a low number of BARC bleeding (type 3 or greater) events and a potential reduction in statistical power. However, the PFT method used in this study was LTA, which is considered the “gold standard” [22], but lacks a clear cutoff value for low platelet reactivity and is influenced by thrombocytopenia and thrombocytosis. Although this study excluded patients with thrombocytopenia and thrombocytosis, the cutoff value for low platelet reactivity in this study was set at MAR(ADP) $\le$30%, which may require further study.

Although the prognostic impact of guided DAPT in dual high-risk ACS patients has not been established, similar study have been conducted [8]. The ANTARCTIC study was a randomized controlled trial (RCT) conducted across 35 centres in France. This trial enrolled 877 elderly (age $\ge$75) patients with ACS after stent implantation and randomly assigned them to either a monitored group or a conventional group. In the monitored group, adjustments were made based on the results of VerifyNow. The conventional group received a fixed dose of prasugrel (5 mg/day) without any adjustments or PFT. No significant differences were observed between the two groups in the MACE within 12 months post-PCI [8]. The study population comprised elderly patients, and according to the OPT-BIRISK trial definition of dual high-risk patients, any patient aged $\ge$75 years was considered to have a dual high risk without further assessment of other risk factors for ischemia or bleeding. Relying solely on age to determine whether a patient carries a dual high risk is inaccurate. Therefore, although the population in this study was similar to that in the ANTARCTIC study, there were certain differences that may explain the inconsistent conclusions between the two studies. The relevant consensus suggests that when clinical judgment indicates a balance between ischemic and bleeding risks, PFT-guided DAPT can demonstrate certain advantages [22]. This balance typically includes two scenarios—namely, low ischemic risk with low bleeding risk and high ischemic risk with high bleeding risk. The latter scenario has a lower tolerance to inappropriate DAPT regimens than the former, necessitating individualised treatment. This innovative aspect of this study addresses clinical challenges in real-world practice. The results of this study show that the main difference between antiplatelet agents across the groups is represented by the number of patients on ticagrelor 60 mg (5.9% vs. 2.3%), which may explain the lower incidence of major bleeding and stroke according to the “prevention of cardiovascular events in patients with prior heart attack using ticagrelor compared to placebo on a background of aspirin (PEGASUS)” trial [30]. Therefore, we would stress that, patients with dual high-risk may more likely benefit from such approach rather than standard DAPT regimens, as supported by previous pharmacodynamic data [31]. On the other hand, due to the low number of plaques on ticagrelor 60 mg in this study, and the fact that 218 (30.6%) patients completed the conversion at 3 months after PCI, the guided selection of antiplatelet regulation is more likely to have been the one ultimate leading to the results.

Cox regression analysis revealed that in addition to guided DAPT being a protective factor for NACE, MACCE, cardiac death, and stroke, cerebrovascular disease, age, and number of stents were identified as risk factors for ischemic events. Primary PCI is a risk factor for bleeding. These findings are consistent with those of multiple studies and ischemic or bleeding risk scoring systems [4, 5, 7, 32, 33, 34, 35]. These factors directly increase the risk of NACE. The ACS guidelines, developed by the ESC in 2023, propose criteria for high ischemic risk, including complex CAD [32]. The OPT-CAD, patterns of non-adherence to antiplatelet regimens in stented patients-coronary artery thrombosis event (PARIS-CTE), and DAPT scoring systems also include multiple risk factors, such as smoking [4, 5]. This study adopted the risk evaluation system from the OPT-BIRISK trial, which is more suitable for the Chinese ACS population. Compared with other scoring systems, it incorporates PCI-related factors. This approach provides a comprehensive risk profile by simultaneously evaluating both ischemic and bleeding in the ACS patients undergoing PCI [7]. Since the population of the OPT-BIRISK trial was Chinese, it was more appropriate to evaluate the Chinese population in this study. The risk assessments in this study were conducted during patient hospitalization, and no dynamic assessment was implemented at 3 months after PCI. However, the OPT-BIRISK trial included indicators such as GFR and creatinine level, which can be improved with standardized treatment. Improvements in these indicators might lead to changes in the dual high-risk assessment results for ischemia and bleeding at 3 months after PCI. In this study, the decision not to perform dynamic assessments was primarily based on the low proportion of patients with eGFR 60 mL/min/1.73 m² at baseline, which had a minimal impact on the final assessment results, while the likelihood of improvement in other indicators in the scoring system was low. However, these factors can impair the response to clopidogrel. Acute clinical symptoms, diabetes, advanced age, BMI, and chronic kidney disease have been described by previous studies as clinical characteristics associated with impaired clopidogrel responsiveness [33, 34]. The “age, body mass index, chronic kidney disease, diabetes mellitus, and genotyping (ABCD-GENE)” score largely encompasses these factors and has high accuracy in predicting high platelet reactivity [35]. Despite the known influence of multiple factors on platelet reactivity, their impact on assessments of ischemic and bleeding risk remains uncertain.

(1) This was a cohort study, and physicians subjectively determined whether to use PFT to guide the selection of DAPT protocol samples. In addition, we began conducting PFT in October 2020. The enrollment times of the patients in the two groups were not entirely synchronised, resulting in a selection bias in the study population. Moreover, owing to the limitation of not conducting random grouping in the cohort study, there were certain confounding factors in this research. To address potential confounding, baseline characteristics were thoroughly analyzed, and a Cox regression model was employed to control for their influence on the outcomes. (2) Currently, there are advantages and disadvantages to the assessment systems for the risk of ischemia and bleeding. This study adopted the definition of dual high risk established in the OPT-BIRISK trial. Although it is the most suitable risk assessment system for this study, it has the inherent limitation of not comprehensively assessing risks. The OPT-BIRISK criteria are trial-specific and their generalisability is questionable. (3) The current analysis was performed on East-Asian patients, a population with distinct ischemic and bleeding risk profiles compared to other ethnic groups. (4) LTA was used in this study for PFT. However, the cutoff values for high and low platelet reactivity obtained using different PFT methods are inconsistent, and the conversion of platelet reactivity between different testing methods is currently unclear. Therefore, further research is needed to explore whether other PFT methods could benefit ACS patients at a dual high risk for ischaemia and bleeding. (5) Since this was a real-world study, patients in the control group received various DAPT regimens. Future studies should compare PFT-guided DAPT regimens with de-escalation, escalation, extension, and shortening of DAPT to provide more evidence for PFT-guided DAPT and to refine antiplatelet therapy strategies. (6) At present, there is no recognized clinical cut-off value for the treatment of platelet dysfunction worldwide. So each laboratory should develop a cutoff value related to clinical outcomes based on their own treatment (medication) situation, testing methods, and clinical practice. The normal range of ADP for platelet function testing in our center is 52–84%, and the safe range for ADP treatment is 30–50%. At the same time, drawing on relevant research [22, 36], we have set the following standards: When the MAR(ADP) $>$50% cut-off, escalation should be considered. When The MAR(ADP) $\le$30% cut-off, de-escalation should be considered.

The primary recommendation for patients with ACS with dual high risk among the East-Asian population is to use PFT to guide DAPT within 12 months after PCI, as it can reduce the incidence of NACE, primarily by lowering MACCE. However, the conclusions of this study need to be further verified in RCTs with a larger sample size.

All data generated or analyzed during this study are included in this published article [and its supplementary information files].

ZX: Formulation or evolution of overarching research goals and aims; ML: Development or design of methodology; ML, YL and JW: Application of statistical or analysis of study data; ML, XS, CL, XW and ZZ: Data curation; ML: Writing the initial draft; ZX and ZZ: Critical review. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

The studies involving human participants were reviewed and approved by the Ethics Committee of Clinical Investigation, Langfang People’s Hospital (2025-YXLW-002). Based on the retrospective study design of this study, the ethics committee believes that informed consent can be exempted. This study was conducted in accordance with the Declaration of Helsinki.

Not applicable.

This study was supported by the Medical Science Research Project of Hebei (no. 20232053).

The authors declare no conflict of interest.

Supplementary material associated with this article can be found, in the online version, at https://doi.org/10.31083/RCM41544.