Antiplatelet Therapy Aims and Strategies in Asian Patients with Acute Coronary Syndrome or Stable Coronary Artery Disease

Dual antiplatelet therapy (DAPT) has been the mainstay treatment to reduce ischemic events, such as myocardial infarction or stroke, in patients with coronary artery disease (CAD). The development of potent P2Y12 inhibitors (ticagrelor and prasugrel) has helped to further reduce ischemic events, particularly among high-risk patients. Meanwhile, the evolution of newer generations of drug-eluting stents are also improving outcomes of percutaneous coronary intervention. Research studies on antiplatelet therapy in recent years have focused on balancing ischemic and bleeding risks through different strategies, which include P2Y12 inhibitor monotherapy, escalation and de-escalation, and extended DAPT. Because results from the large number of clinical studies may sometimes appear conflicting, this review aims to summarize recent advances, and demonstrate that they are aligned by a general principle, namely, strategies may be adopted based on treatment aims for specific patients at several time points. Another aim of this review is to outline the important considerations for using antiplatelet therapy in Asian patients, in whom there is a greater prevalence of CYP2C19 loss-of-function mutations, and a common increased risk of bleeding, despite high platelet reactivity (the so-called “East Asian Paradox”).


Introduction: Ischemic and Bleeding Risks
Aspirin, an irreversible cyclooxygenase (COX)-1 inhibitor, is currently the most widely used medication worldwide [1]. For decades, aspirin has been given to patients with cardiovascular (CV) and cerebrovascular conditions to reduce ischemic events, such as myocardial infarction (MI) and stroke, by diminishing platelet activity. Dual antiplatelet therapy (DAPT) was introduced in the mid-1990s, wherein aspirin is given in combination with a purinergic P2Y 12 receptor inhibitor (P2Y 12 i; e.g., ticlopidine) [2]. Together, they provide improved antithrombotic efficacy by blocking both the COX-1 and adenosine diphosphate-dependent pathways for platelet aggregation [3]. Studies have repeatedly shown that DAPT reduces both the risk of acute thrombotic events, as well as long-term ischemic recurrence from atherosclerotic plague progression [4].
Because antiplatelet therapy (APT) reduces platelet response to vascular damage, an increase in the potency, dosage, and/or duration of APT also inevitably increases the patient's risk of bleeding. This has been observed in the results of large-scale studies involving tens of thousands of patients. In other words, APT cannot reduce both ischemic and bleeding risks; rather, it poses a technological limitation that has yet to be overcome by innovations. Therefore, the balance between ischemic and bleeding risks has become the core subject of investigation in many recent trials. When prescribing APT, such a balance must be carefully and individually determined and monitored. core subject of investigation in many recent trials. When prescribing APT, such a balance must be carefully and individually determined and monitored.
In planning for an APT, besides assessing ischemic and bleeding risks, there is a wide range of factors to consider. Figure 1 illustrates the major considerations that have under gone robust research in recent years. Figure 1. Schematic representation of various important considerations in antiplatelet therapy for patients with acute coronary syndrome or stable coronary artery disease, which have been the sub jects of major clinical studies and literature discussions in recent years. Underlying these consider ations is the critical notion of balancing ischemic risk and bleeding risk.

APT Aims and Strategies
In the past decade, the introduction of newer potent P2Y12 inhibitors (e.g., ticagrelor and prasugrel) has helped to further reduce the occurrence of ischemic events in coronary artery disease (CAD) patients [5]. Meanwhile, the development of new generations o drug-eluting stents, such as biodegradable polymer stents, also appears to have lowered the thrombotic risks following a percutaneous coronary intervention (PCI), when com pared with the older bare metal stents [6]. In view of the improved APT potency and sten safety, the balance between ischemic and bleeding risks must also be managed in further detail.
Physicians working in the area may often wonder, why do results from the large number of clinical studies appear to be conflicting? For example, while some trials (e.g. PEGASUS-TIMI 54 [7]) suggest better outcomes with an extended DAPT duration, others support shortened DAPT (e.g., DAPT-STEMI [8]). Other trials suggest switching from DAPT to P2Y12i monotherapy by dropping aspirin (e.g., TWILIGHT [9]), or to a differen P2Y12i dose or agent (e.g., HOST-REDUCE POLYTECH-ACS [10] and TOPIC [11]). To an swer this question, it is essential to realize that these trials target different patient popula tions and are concerned with different research questions and objectives.
Depending on the specific aims of APT, different strategies may be adopted (Table  1). Table 1 defines short-, medium-, and long-term APT as approximately <1 month, 1-12 Figure 1. Schematic representation of various important considerations in antiplatelet therapy for patients with acute coronary syndrome or stable coronary artery disease, which have been the subjects of major clinical studies and literature discussions in recent years. Underlying these considerations is the critical notion of balancing ischemic risk and bleeding risk.

APT Aims and Strategies
In the past decade, the introduction of newer potent P2Y 12 inhibitors (e.g., ticagrelor and prasugrel) has helped to further reduce the occurrence of ischemic events in coronary artery disease (CAD) patients [5]. Meanwhile, the development of new generations of drug-eluting stents, such as biodegradable polymer stents, also appears to have lowered the thrombotic risks following a percutaneous coronary intervention (PCI), when compared with the older bare metal stents [6]. In view of the improved APT potency and stent safety, the balance between ischemic and bleeding risks must also be managed in further detail.
Physicians working in the area may often wonder, why do results from the large number of clinical studies appear to be conflicting? For example, while some trials (e.g., PEGASUS-TIMI 54 [7]) suggest better outcomes with an extended DAPT duration, others support shortened DAPT (e.g., DAPT-STEMI [8]). Other trials suggest switching from DAPT to P2Y 12 i monotherapy by dropping aspirin (e.g., TWILIGHT [9]), or to a different P2Y 12 i dose or agent (e.g., HOST-REDUCE POLYTECH-ACS [10] and TOPIC [11]). To answer this question, it is essential to realize that these trials target different patient populations and are concerned with different research questions and objectives.
Depending on the specific aims of APT, different strategies may be adopted (Table 1). Table 1 defines short-, medium-, and long-term APT as approximately <1 month, 1-12 months, and >12 months, which are arbitrary divisions that coincide with common designs of randomized controlled trials (RCTs) of APT. In practice, APT duration is often a moving target [12] that is contingent on patient factors and treatment tolerance. While, at hospital discharge, it may not be possible to determine a patient's risk over time, risk assessment should be re-evaluated regularly [13]. In addition to the differences in medication strategy, the trials were conducted in different patient groups (e.g., those with acute coronary syndrome [ACS] or stable CAD [sCAD]) and regions (e.g., U.S., Europe, or the Asia-Pacific), using various measurement criteria (e.g., Thrombolysis in Myocardial Infarction [TIMI] or Bleeding Academic Research Consortium [BARC] bleeding criteria). This review aims to categorize the recent results, and layout an important conceptual framework that underlies these studies, namely, ischemic and bleeding risks may vary for different patients at different time points.

Standard DAPT
Patients who recently had an ACS or are indicated for PCI have an elevated risk of experiencing an ischemic event (including recurrent MI), particularly in the first 30 days [14,15]. Although there are some suggestions of a decreasing trend in recurrent coronary hospitalization in recent years [16], the risk remains high, especially for patients with additional risk factors [17]. The aim of APT in these patients, by and large, is to aggressively reduce their ischemic risk, while avoiding any excessive increase in bleeding risk (Table 1).
Landmark RCTs that have established a standard DAPT duration of 12 months include CURE [18], PLATO [19], and TRITON [20], in which the ischemic benefits appeared to outweigh the bleeding risks (Tables 2 and 3). For example, in PLATO [19], where ACS patients were randomized to receive ticagrelor 90 mg twice daily (BID) versus clopidogrel 75 mg once daily (QD), the occurrences of vascular death, MI, or stroke at 12 months were 9.8% versus 11.7%, respectively (p < 0.001), and the rates of major bleeding were 11.6% versus 11.2% (non-significant [N.S.]). All-cause deaths occurred in 4.5% versus 5.9% (p < 0.001) of patients in the two arms, respectively.
Recent Asian studies of 1-year DAPT in ACS patients, such as PHILO [21], TICAKO-REA [22], and PRASFIT-Practice-II [23,24], reported somewhat lower rates of ischemic events. TICAKOREA [22] also reported significantly reduced bleeding rates for patients treated with clopidogrel versus ticagrelor. While these results might reflect the more recent and Asian clinical scenarios, these studies also had smaller sample sizes compared with the trials above. APT for Asian patients will be further discussed in Section 5.

P2Y 12 i Monotherapy
Hypothetically, P2Y 12 i monotherapy may provide two potential benefits over traditional DAPT: first, it may reduce bleeding while providing similar ischemic protection in the medium term; second, it reduces the medication burden in the longer term (e.g., when administered beyond 1 year).
In the Asian studies SMART-CHOICE [28] and STOP-DAPT2 [29], with PCI patients, switching to P2Y 12 i monotherapy also reduced bleeding without compromising ischemic event prevention. However, STOP-DAPT2-ACS [30], where ACS patients were switched from DAPT to clopidogrel monotherapy, did not achieve noninferiority, and there was a marginal increase in the major composite ischemic endpoint (2.8% vs. 1.9%, hazard ratio [HR] = 1.50, 95% confidence interval [CI]: 0.99-2.26), including a HR of 1.91 (95% CI: 1.06-3.44) for MI. One explanation could be that 1 month of DAPT was too short for ACS patients, whose conditions are more severe and unstable, and clopidogrel resistance might also have affected ischemic outcomes.

DAPT Escalation and De-Escalation, including Shortened DAPT
Another strategy is de-escalation, where DAPT continues at a reduced dose or duration, or with a less potent P2Y 12 i. Both "unguided" (by randomized allocation only) and "guided" (e.g., by platelet function test [PFT] or genotyping) de-escalation approaches have produced favorable results. A recent network meta-analysis [46] compared APT trials that shortened DAPT with those that reduced P2Y 12 i dosage or potency (total 29 trials; 50,602 patients), and found no difference in all-cause death between the two. Reducing P2Y 12 i dosage or potency was favored in terms of trial-defined net adverse CV events (NACE; risk ratio [RR] = 0.87, 95% CI: 0.70-0.94), but not with respect to bleeding (RR = 1.54, 95% CI: 1.07-2.21). However, because some of the sample sizes in the escalation and deescalation studies were relatively small, and most were open-label, adjudicator-blinded studies, there could potentially be some effects of patient selection, as well as bias in the reporting of both physician-and patient-reported clinical outcomes. More large-scale studies are required for further comparison.
It is worth noting that the time of de-escalation chosen in these trials vary in aggressiveness, from 1, 3 to 6 months after starting DAPT, i.e., when ischemic and bleeding risks remain high to becoming more stable. While these trials generally demonstrated a reduction in bleeding events without increasing ischemic events significantly, in real-life, the time chosen for de-escalation will depend on the patient's characteristics and evolving risks.

Guided Escalation and De-Escalation
Currently, two kinds of test are available for helping to select patients for the different APT strategies: PFT and genotyping. PFT measures platelet activation levels and may be performed at baseline and during APT [47]. Different laboratory techniques may be used, including light transmission, electrical impedance, and flow cytometry [47]. The RPFA-VerifyNow ® P2Y12 test is a point-of-care whole blood test for monitoring clopidogrel resistance; results are expressed as P2Y 12 reaction units (PRU) [47]. Genotyping identifies cytochrome P450 loss-of-function (LOF) mutations, which are associated with clopidogrel resistance because they reduce the liver's ability to metabolize clopidogrel into its active form [48].
In ANTARTIC [38], depending on PFT results, patients receiving DAPT could be escalated from prasugrel 5 mg QD to 10 mg QD (for those with high platelet reactivity [HPR]) or de-escalated to clopidogrel 75 mg QD (for those with low platelet reactivity). However, the trial failed to achieve superiority over DAPT with prasugrel 5 mg QD. In TROPICAL-ACS [39] and POPular Genetics [40], noninferiority was demonstrated for guided de-escalation from a potent P2Y 12 i to clopidogrel based on PFT results. PATH-PCI [42] escalated patients with high platelet maximum aggregation rate (>55%) from clopidogrel to ticagrelor, and produced a significant net clinical benefit.
TAILOR-PCI [41] enrolled 5,302 patients to receive genotype-guided or conventional DAPT. CYP2C19 carriers in the genotype-guided arm received ticagrelor, and all other patients received clopidogrel. In a primary analysis of 1,849 CYP2C19 LOF carriers, composite CV death, MI, stroke, stent thrombosis, and severe recurrent ischemia occurred in 4.0% (35/903) and 5.9% (54/946) of patients in the genotype-guided and conventional arms, respectively, but the difference did not reach statistical significance (p = 0.06). None of the 11 prespecified secondary endpoints, including major or minor bleeding, demonstrated statistical significance, except marginally for stent thrombosis (p = 0.05).
Nevertheless, an updated meta-analysis [50]  Of note, the subgroup analysis suggested that genotype-guided APT was more likely to reduce MACEs in populations that consist of more ACS or Chinese patients [50].
Because point-of-care PFT is common, and genotyping results can be produced within a few days (in POPular Genetics, the median time between blood collection and genotyping result was 4 h only [51]), guided escalation and de-escalation may be performed quite readily, even within the first 2 weeks after PCI, as in the trials. However, Angiolillo et al. [4] cautioned that patients who are de-escalated to clopidogrel could in fact have HPR, and because 7-14 days of maintenance clopidogrel is required after de-escalation to assess platelet function, they can be subject to an increased risk of thrombosis.

Long-Term DAPT
Studies on MI recurrence generally suggest that, in 30-day survivors of acute MI, mortality rates plateau at about 3 years after the first index MI [52]. To prevent long-term ischemic events, several large-scale studies have investigated the efficacy and safety of extending DAPT from 1 year to about 3 years, most notably the DAPT [43] and PEGASUS TIMI-54 [7] trials. The DAPT trial [43] reported a 1.6% absolute reduction in all-cause death, MI, or stroke after 30 versus 12 months of DAPT with prasugrel or clopidogrel, which was coupled with a 0.9% absolute increase in moderate or severe bleeding according to the GUSTO (Global Use of Streptokinase and Tissue plasminogen activator to Open occluded coronary arteries) criteria. PEGASUS [7] recruited patients who had a prior MI 1-3 years previously. Extended DAPT with ticagrelor plus aspirin achieved a 1.1% (ticagrelor 60 mg BID vs. aspirin alone, p = 0.004) or 1.2% (ticagrelor 90 mg BID vs. aspirin alone, p = 0.008) absolute reduction in CV death, MI, or stroke at 36 months, which was accompanied by a 1.2% or 1.5% absolute increase in TIMI major bleeding, for the two ticagrelor doses respectively (both p < 0.001). A post-hoc subgroup analysis of PEGASUS [53] illustrated that in patients with no bleeding risk indicators and ≥2 ischemic risk indicators (59% of 13,938 patients), ticagrelor significantly reduced the primary composite efficacy endpoint of CV death, MI, or stroke by 1.9% (p = 0.0024), and TIMI major bleeding (primary safety endpoint) only by 1.0% (p < 0.001). Given a moderate increase in bleeding, extended DAPT would likely benefit those who have elevated ischemic risks (e.g., impaired renal function, large atherosclerotic burden, multiple stents) and relatively low bleeding risks (e.g., young age; See Section 5).
THEMSIS-PCI [44] recruited patients with sCAD and diabetes mellitus, and found that, among those who underwent PCI, 3.3 years of ticagrelor (mostly at the lower 60-mg BID dose) led to a 1.3% absolute decrease in CV death, MI, or stroke, and a 0.9% increase in TIMI major bleeding. The significant ischemic benefit was not observed in patients without PCI.

Long-Term P2Y 12 i Monotherapy
Trials have also considered long-term P2Y 12 i monotherapy. GLOBAL LEADERS [31] demonstrated no significant differences between 1-month DAPT plus 23-month ticagrelor monotherapy versus 24-month DAPT, both in terms of ischemic and bleeding events, but these results were not sufficient for establishing superiority. The pre-specified subgroup analysis [54] revealed that BARC type 3 or 5 bleeding occurred in 1.95% versus 2.68% of ACS patients (p = 0.037), compared with 2.13% versus 1.62% in sCAD patients (p = 0.081), while differences in the primary endpoint of all-cause death or new Q-wave MI remained non-significant. In the ACS subgroup, there was a significant reduction in all-cause death, new Q-wave MI, and BARC type 3 or 5 bleeding when taken together (rate ratio = 0.81, p = 0.029). Although the superiority hypothesis was not sustained overall, the subgroup analysis suggests that ACS patients may still benefit from ticagrelor monotherapy following abbreviated DAPT. In the post-hoc landmark analysis of GLOBAL-LEADERS [55], which included patients who were event-free at 12 months, the second year of ticagrelor monotherapy demonstrated lower composite all-cause death, MI, or stroke compared with aspirin monotherapy (1.9% vs. 2.6%, log-rank p = 0.014, adjusted p = 0.022) that was driven by reduced MI (0.7% vs. 1.2%, p = 0.003). The authors also noted that the difference in BARC type 3 or 5 bleeding (0.5% vs. 0.3%, log-rank p = 0.051, adjusted p = 0.005) was significant only after adjustment for characteristics of patients excluded from the second-year analysis due to clinical events or nonadherence.

Long-Term Anticoagulant plus Aspirin
COMPASS [45] investigated whether low-dose rivaroxaban, alone or in combination with aspirin, would be more effective for secondary CV prevention than aspirin alone. The trial recruited 27,395 patients with sCAD and/or peripheral arterial disease, of whom 62% had previous MI and 21% had heart failure. Patients who were already using anticoagulants were excluded, including those with atrial fibrillation (AF) receiving rivaroxaban at the standard dosage.
Participants were randomized to rivaroxaban plus aspirin, rivaroxaban alone, or aspirin alone. The trial was stopped at a mean follow-up of 23 months for superiority of the rivaroxaban plus aspirin combination. Compared with aspirin alone, there was a 1.3% absolute reduction in CV death, MI, or stroke, together with a 1.2% increase in modified ISTH (International Society on Thrombosis and Haemostasis) bleeding, which included hospitalized bleeding. Detailed analysis [56] also showed a significant reduction in stroke occurrences in the rivaroxaban plus aspirin group over the aspirin alone group (0.9% vs. 1.6% per year, p < 0.0001). There were significantly fewer cardioembolic strokes (p = 0.006) and embolic strokes of undetermined source (p = 0.006) in the rivaroxaban plus aspirin arm, compared with aspirin alone (secondary analysis) [57]. Niessner et al. [58] commented that subclinical AF might have underlain such results, as AF can be quite prevalent among peripheral arterial disease patients. During the 23-month follow-up, 49 patients (0.2% of 27,395) were diagnosed with AF [57].

HBR Patients
Traditionally, to control for confounders and heterogeneity, APT trial recruitment often excludes patients with unstable bodily conditions that are not directly related to their CAD, including any risk of major bleeding, prior stroke, and the need for long-term oral anticoagulant use. As researchers realize the core importance of balancing between ischemic and bleeding risks in APT, more studies are addressing patients who fall into the "high bleeding risk" (HBR) category. Tools such as the PRECISE-DAPT score [59] (>25 points) and Academic Research Consortium for High Bleeding Risk (ARC-HBR) criteria [60] (one major or two minor criteria) have also been developed for identifying HBR patients.
Two recent international studies investigated DAPT duration for HBR patients. MASTER-DAPT [36] was a large-scale RCT powered to detect noninferiority in NACEs and MACEs, and superiority in major or clinically relevant bleeding. The XIENCE Short DAPT program [37] comprised three prospective, multicenter, non-randomized single-arm cohorts, which were compared using propensity score stratification. Criteria for HBR in these two studies varied, and included major bleeding history, stroke history, hematological disorders, and old age. In these two studies, 1 month of DAPT produced similar ischemic outcomes but reduced bleeding events, when compared with 3 months of DAPT. A MASTER-DAPT sub-analysis [61] also showed that BARC type 2, 3, or 5 bleeding was reduced in the 1-month DAPT arm, regardless of PCI complexity.
To minimize the decrease in ischemic protection for HBR CAD patients, besides optimizing the shortened DAPT duration, other studies have investigated the use of different stent types. (Conversely, when deciding on the appropriate APT for HBR patients, stent type may also be taken into consideration.) LEADERS FREE [66] and ONYX ONE [67] used similar sets of 13 criteria for determining HBR, including age ≥ 75 years (64% in LEADERS FREE; 62% in ONYX ONE), planned long-term oral anticoagulant use (36% in LEADERS FREE; 39% in ONYX ONE), and/or renal impairment (creatinine clearance <40 mL/min; 19% in LEADERS FREE; 15% in ONYX ONE). In both studies, patients received only 1 month of DAPT, followed by aspirin alone or P2Y 12 i alone thereafter. In LEADERS FREE [68], at 2 years, with a population that included 42% ACS patients [66], the primary safety composite endpoint of cardiac death, MI, or stent thrombosis occurred in 12.6% of patients fitted with polymer-free drug-coated stents, versus 15.3% of those fitted with bare metal stents (p = 0.039). Clinically driven target-lesion revascularization was performed in 6.8% and 12.0% of the two arms, respectively (p < 0.0001). BARC types 3-5 bleeding occurred in 8.9% and 9.2% of patients (N.S.). In ONYX ONE, in which 52% were ACS patients [69], at 2 years [67], the primary safety composite endpoint of cardiac death, MI, or stent thrombosis occurred in 21.2% of those who received polymer-based stents, and in 20.7% who received polymer-free stents (N.S.). Target lesion failure (secondary effectiveness endpoint) happened in 22.1% versus 21.0% (N.S.), and BARC types 3-5 bleeding developed in 7.1% and 5.5% (N.S.) of the two groups of patients, respectively.
The 2018 European Society of Cardiology (ESC)/European Association for Cardio-Thoracic Surgery Guidelines on Myocardial Revascularization [70] offers a Class IIa, Level of Evidence (LoE) B recommendation for stented ACS HBR patients (with PRECISE-DAPT score ≥ 25) to discontinue P2Y 12 i after 6 months. For sCAD HBR patients, the recommended DAPT duration is 3 months (Class IIa, LoE A). The 2021 American College of Cardiology/American Heart Association/Society for Cardiovascular Angiography & Interventions [71] also offers a Class 2a, LoE A recommendation for shortened DAPT (1-3 months) in selected patients to reduce the risk of bleeding, with subsequent transition to P2Y 12 i monotherapy. In both guidelines, drug-eluting stents are generally strongly preferred over bare metal stents (Class I, LoE A), but there is not yet any specific recommendation on stent types in HBR patients.

Asian Patient Characteristics
Jeong [72] was among the first authors to formulate the notion of the "East Asian Paradox": compared with Western patients, East Asian patients not only have higher risks of bleeding from APT, but also higher therapeutic levels of platelet reactivity. The difference in platelet reactivity may also influence ischemic risks, and some authors have observed that Asian studies tend to report low ischemic event rates [73]. Jeong derived the East Asian Paradox from two literature observations. First, whereas East Asian patients are more prone to warfarin-related intracranial hemorrhage compared with Western patients, an analogous pattern may be true for APT [72]. Second, in a platelet reactivity study, Japanese volunteers showed longer thrombotic occlusion time when compared with Western volunteers [74]. The East Asian Paradox suggests that the optimal APT regimens for East Asians may be different from those for Westerners and should be evaluated in further studies [72].
For example, in a meta-analysis of eight RCTs involving 37,775 ACS patients [75], DAPT de-escalation was associated with a significantly lower risk of major bleeding among East Asians (RR = 0.61, p = 0.048), but not among non-East Asians (RR = 0.73, p = 0.17). In both groups, the composite rates of all-cause death, MI, stroke, stent thrombosis, and revascularization were similar between the de-escalation and standard DAPT arms. An Asian expert consensus [76] suggested that demographics, comorbidities, and disease patterns in East Asian populations can influence therapeutic response and outcomes, which may help to explain this paradox. Figure 2 presents a theoretical representation of the general trends in ischemic and bleeding risks for different types of CAD patients, with reference to recent observations from the literature [12,73,76]. Immediately following the index event (e.g., PCI), all CAD patients tend to have both very high ischemic risk and high bleeding risk. These risks tend to gradually decline in the next 30 days, when the patient recovers from the ischemic event and/or surgery, and they continue to decline in the months that follow. The difference in magnitude between a patient's ischemic and bleeding risks provides a therapeutic window for receiving APT to prevent ischemic events. Figure 2 also illustrates that ACS patients have higher ischemic risks than sCAD patients; patients in the HBR category have elevated bleeding risks compared with non-HBR patients; and Asian patients may be more prone to bleeding than Western patients. 0.17). In both groups, the composite rates of all-cause death, MI, stroke, stent thromb and revascularization were similar between the de-escalation and standard DAPT a An Asian expert consensus [76] suggested that demographics, comorbidities, and di patterns in East Asian populations can influence therapeutic response and outco which may help to explain this paradox. Figure 2 presents a theoretical representation of the general trends in ischemic bleeding risks for different types of CAD patients, with reference to recent observa from the literature [12,73,76]. Immediately following the index event (e.g., PCI), all patients tend to have both very high ischemic risk and high bleeding risk. These risks to gradually decline in the next 30 days, when the patient recovers from the ischemic and/or surgery, and they continue to decline in the months that follow. The differen magnitude between a patient's ischemic and bleeding risks provides a therapeutic dow for receiving APT to prevent ischemic events. Figure 2 also illustrates that AC tients have higher ischemic risks than sCAD patients; patients in the HBR category elevated bleeding risks compared with non-HBR patients; and Asian patients ma more prone to bleeding than Western patients.

Risk Assessment in Asian Patients
Various ischemic and bleeding risk assessment instruments have been validat Asian populations. The DAPT score successfully stratified ischemic and bleeding ris a pooled cohort of 12,223 Japanese patients [77]; however, the authors noted that isch event rates were low, even in patients with high DAPT scores. To evaluate bleeding the PRECISE-DAPT score provides a standardized tool to predict out-of-hospital blee and has been validated in both Chinese and Korean populations [59,78]. Developed the records of 32,057 patients from Hong Kong, the CARDIAC score [79] helps to pr

Risk Assessment in Asian Patients
Various ischemic and bleeding risk assessment instruments have been validated in Asian populations. The DAPT score successfully stratified ischemic and bleeding risks in a pooled cohort of 12,223 Japanese patients [77]; however, the authors noted that ischemic event rates were low, even in patients with high DAPT scores. To evaluate bleeding risks, the PRECISE-DAPT score provides a standardized tool to predict out-of-hospital bleeding and has been validated in both Chinese and Korean populations [59,78]. Developed from the records of 32,057 patients from Hong Kong, the CARDIAC score [79] helps to predict the risk of major bleeding within 1 year after PCI, based on anticoagulation therapy, age, renal insufficiency, drop in hemoglobin levels, and baseline anemia. The reported discriminating power was an area-under-the-curve of 0.76, with an optimal cutoff that provides 63% sensitivity and 75% specificity. Physicians should also consider relevant clinical manifestations such as hemoglobin and creatinine levels, bruising and rectal bleeding. Table 4 provides a general list of common ischemic and bleeding risk factors, based on the ESC 2020 non-ST elevation ACS guidelines [80], the ARC-HBR consensus [60], and the DAPT [81], PRECISE-DAPT [82], and CARDIAC scores [79].  Because about 50% of East Asian patients have CYP2C19 LOF mutations [83,84], which interferes with cytochrome P450 activation of clopidogrel, genotyping may be considered to test for mutation. A sequencing study [85] of 1,116 unrelated Hong Kong Chinese enrolled from 2012 to 2019 identified 29 actionable pharmacogenetic variants. At the gene level, CYP2C19 was among several genes with the highest frequency of actionable phenotypes (57.2%), including 45.3% intermediate metabolizers and 12.0% poor metabolizers. Moreover, it should be noted that CYP2C19 mutations only account for a fraction of the pharmacodynamic response to clopidogrel. In The ABCD-GENE risk score [86] for predicting HPR during clopidogrel treatment includes four clinical factors: age >75 years, body mass index >30 kg/m 2 , glomerular filtration rate <60 mL/min, and diabetes mellitus. Together with CYP2C19 LOF alleles, these five factors produce a risk score with a C-statistic of 0.66 for all-cause death, stroke, or MI at 1 year [86].
Besides genotyping, point-of-care platelet reactivity test may also be performed to assess drug response while on APT. An international expert consensus [87] noted that PFT results and genetic markers have been reported to predict both thrombotic and bleeding events. Based on recent data, the panel agrees that, for patients on P2Y 12 i treatment, PFT results may provide useful prognostic data for CV risk prediction (both ischemic and bleeding events) after PCI. For ACS patients, although PFT is not recommended on a routine basis, for the purposes of treatment escalation or de-escalation, it may be considered in specific clinical scenarios. For sCAD patients, PFT is again not routinely recommended, but can be considered, in specific clinical scenarios, for switching to potent antiplatelet drugs in patients with increased thrombotic risk, and for determining which drug to keep upon DAPT cessation. Table 5 provides a brief summary of key patient considerations for whether to reduce APT duration.

Common P2Y 12 i Drug Interactions
Some authors noted that HPR may sometimes be attributable to potential drug-drug interactions. For example, rifampicin induces CYP2C19 activity, whereas ketoconazole inhibits CYP3A4, leading to increased and decreased clopidogrel activation, respectively [88]. Conversely, clopidogrel may have perpetrator potentials, such as on cerivastatin and repaglinide by inhibiting CYP2C8 activity [89,90]. Presumably, drug-drug interactions may have more clinically significant effects on patients who have high or low platelet reactivity levels than those with normal levels, as had been suggested in trial patients who received atorvastatin and DAPT [91]. Of note, meta-analyses demonstrated that the co-administration of morphine and potent P2Y 12 i increased both platelet reactivity [92] and residual platelet reactivity [93]. This may be particularly relevant to the acute setting. Table 5. Key patient considerations for reducing antiplatelet therapy (APT) duration.

Ischemic and Bleeding Risk Factors
Baseline Does the patient meet high bleeding risk (HBR) criteria? * 5.1, 5.2 Table 4 Medium-term (1-12 months) Will the patient's bleeding risk exceed his/her ischemic risk soon? * 2 Figure 2 Pharmacological Factors Observational studies have suggested some interaction effects between proton pump inhibitors and DAPT, with a high degree of heterogeneity [94]. While the only large-scale RCT on the prophylactic use of proton pump inhibitors in patients receiving clopidogrel demonstrated reduced upper gastrointestinal bleeding without increasing ischemic risks [95,96], guidelines vary in terms of patient selection for such prophylactic use [97].
In Asian patients, the use of traditional medicine (such as traditional Chinese medicine) has been shown in both animal and clinical studies to increase or decrease clopidogrel metabolism, by various proposed mechanisms [98]. Small exploratory trials on the concomitant use of traditional Chinese medicine and APT have been conducted to examine different hypotheses that include enhanced antiplatelet activity and reduced adverse effects [99].

Other Practical Considerations
There are a few caveats for interpreting the above trial results. First, trial designs often involve rather abrupt regimen changes in medication, dose adjustment, or discontinuation that might not be suitable for every patient. In practice, physicians may be able to implement changes more flexibly, coupled with close monitoring of risk factors and tolerance over time. In regions where patients have not been adequately represented in clinical trials, real-world studies may provide limited ideas on current practice patterns and outcomes. In Hong Kong, a retrospective matched cohort study of 6220 ACS patients treated in 14 hospitals between 2010 and 2017 [83] showed that potent P2Y 12 i use was associated with lower rates of ischemic stroke (HR = 0.57, p = 0.008) and thrombotic events (HR = 0.77, p = 0.001) compared with clopidogrel, while maintaining similar risks of intracranial hemorrhage (N.S.) and ISTH major bleeding (N.S.).
In Taiwan
When assessing patients' platelet reactivity, Korean studies have adopted a range of 85-275 PRU, compared with the usual 85-208 (or sometimes 85-240) PRU range used in international studies [103]. This suggests a different therapeutic window for APT in Koreans compared with Western populations. Two small retrospective analyses [103,104] of on-treatment platelet reactivity assessed by the VerifyNow P2Y 12 assay suggest that acute MI patients treated with standard-dose ticagrelor 90 mg BID resulted in average PRU values falling below 85. An upcoming phase 4 de-escalation trial will investigate the optimal dose (45 or 60 mg) of ticagrelor in Korean patients with acute MI (NCT05210595).
Ticagrelor monotherapy at a reduced dose of 60 mg BID (or even 45 mg BID) presents an attractive option for Asian patients, because of its potent, reversible antiplatelet activity, with the potential for less bleeding compared with the 90 mg BID dose. A recent 12-week prospective, single-center RCT [105] reported significantly improved brachial flow-mediated dilation in ACS patients treated with ticagrelor 60 mg BD monotherapy versus aspirin 100 mg OD alone: +3.48% vs. −1.26%, p < 0.001. Multi-omics signatures, including changes in amino acid and phospholipid metabolism and biosynthesis, were associated with the improved brachial artery flow-mediated dilation [105]. Future studies on low-dose ticagrelor, including monotherapy, are warranted.

Ticagrelor Reversal
To restore platelet activity in patients receiving ticagrelor, cardiac surgeons may give prophylactic platelet transfusion, fresh frozen plasma, and protamine infusion [106]. The use of an intravenous monoclonal antibody, bentracimab, for ticagrelor reversal was recently tested in a single-arm, prospective study with patients who required urgent surgery (n = 142) or had major bleeding (n = 8) [107]. The antiplatelet effects were reversed rapidly (within 5 to 10 min) and sustained for >24 h, with adjudicated hemostasis achieved in >90% of patients. This reversal agent, if available, may be particularly useful for patients with ST-elevation MI who require large surgical incisions and/or a prolonged operation period.

Comparing across APT Strategies
As emphasized early on in this review, it is a current technological limitation that APT cannot reduce both ischemic and bleeding risks. Hence, an APT strategy should be chosen depending on the specific treatment aim.
Nevertheless, sometimes more than one strategy appears feasible, and no direct comparative evidence is available. Indeed, while a plethora of trials have been conducted on the different APT strategies, head-to-head trials are lacking. Large-scale studies comparing APT strategies would be challenging to conduct, but highly informative. A recent metaanalysis of 30 extended, standard, and de-escalation APT RCTs supported the safety of two strategies: 3-month DAPT followed by ticagrelor monotherapy, as well as a short period of high potency DAPT followed by clopidogrel + aspirin [108]. Another meta-analysis of seven de-escalation trials favored early de-escalation of DAPT after 1 to 3 months to P2Y1 2 i monotherapy [109]. A network meta-analysis of 29 studies including 50,602 patients [46] (see also Section 3.3) calculated based on posterior probability the outcomes of various de-escalation strategies. Short DAPT followed by aspirin monotherapy generally led to increased trial-defined NACE; for example, when compared with short DAPT followed by P2Y 12 i monotherapy (RR = 1.22, 95% CI: 1.00-1.48). When compared with standard DAPT, short DAPT followed by P2Y 12 i monotherapy reduced NACE (RR = 0.85, 95% CI: 0.73-0.98), as did DAPT de-escalation to clopidogrel (RR = 0.77, 95% CI: 0.68-0.88) and DAPT de-escalation to halved dose (RR = 0.71, 95% CI: 0.54-0.93). These results should be interpreted with some caution because of the multiple comparisons, overall statistical complexity, and clinical heterogeneity.
Continued understanding and exploration of the molecular mechanisms of platelet aggregation may one day help to create antiplatelet agents that reduce both ischemic and bleeding risks. Meanwhile, the development of biomarkers (e.g., metabolomics) [110] and machine learning algorithms [111] may help to better predict ischemic risks, bleeding risks, and antiplatelet response in individual patients.

Conclusions
In recent years, the efficacy and safety of a spectrum of APT strategies, in addition to standard 1-year DAPT, have been investigated in numerous RCTs. These strategies include P2Y 12 i monotherapy, guided and unguided de-escalation, as well as extended DAPT. Because an optimal APT regimen hinges on a delicate balance between ischemic and bleeding risks, the selection of APT should be based on specific treatment aims, with consideration for evolving patient risk factors and time of treatment. Compared with Western populations, Asian patients may be more prone to CYP2C19 LOF mutations, increased platelet reactivity, and bleeding. Bleeding risk scores, genotyping, PFT, and low-dose ticagrelor therapy are among some of the potentially useful tools available for Asian populations.