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Review

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

by
Chor-Cheung Tam
1,* and
Hung-Fat Tse
2
1
Division of Cardiology, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
2
Cardiology Division, Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
*
Author to whom correspondence should be addressed.
J. Clin. Med. 2022, 11(24), 7440; https://doi.org/10.3390/jcm11247440
Submission received: 12 November 2022 / Revised: 30 November 2022 / Accepted: 13 December 2022 / Published: 15 December 2022
(This article belongs to the Special Issue Current Therapeutic Options for Cardiovascular Diseases: From Bench to Bedside)
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Abstract

:
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”).

1. 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 P2Y12 receptor inhibitor (P2Y12i; 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.
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 undergone robust research in recent years.

2. 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 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 P2Y12i monotherapy by dropping aspirin (e.g., TWILIGHT [9]), or to a different P2Y12i 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.

3. Short-to-Medium Term APT

3.1. 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 (Table 2 and Table 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], TICAKOREA [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.

3.2. P2Y12i Monotherapy

Hypothetically, P2Y12i 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).
Notable trials include TWILIGHT [9,26], SMART-CHOICE [28], and STOPDAPT-2 [29,30]. TWILIGHT demonstrated significantly reduced bleeding at 15 months in patients treated with ticagrelor monotherapy after 3 months of DAPT, compared with those who continued DAPT, both in the overall population (4.0% [ticagrelor alone] vs. 7.1% [ticagrelor + aspirin], p < 0.001) [26] and the ACS subgroup (3.6% [ticagrelor alone] vs. 7.6% [ticagrelor + aspirin], p < 0.001), but not in the sCAD subgroup (4.8% [ticagrelor alone] vs. 6.2% [ticagrelor + aspirin]; N.S.) [9].
In the Asian studies SMART-CHOICE [28] and STOP-DAPT2 [29], with PCI patients, switching to P2Y12i 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.

3.3. 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 P2Y12i. 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 P2Y12i dosage or potency (total 29 trials; 50,602 patients), and found no difference in all-cause death between the two. Reducing P2Y12i 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 de-escalation 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 P2Y12 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 P2Y12i 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.
In a meta-analysis [49] of guided-DAPT, encompassing 11 RCTs (six PFT-guided and five genotype-guided trials) and three observational studies (all genotype-guided studies) with 20,743 patients, guided APT was associated with reduced trial-defined major adverse CV events (MACEs; RR = 0.78, p = 0.015), CV death (RR = 0.77, p = 0.049), MI (RR = 0.76, p = 0.021), stent thrombosis (RR = 0.64, p = 0.011), stroke (RR = 0.66, p = 0.010), and minor bleeding (RR = 0.78, p = 0.003), but not all-cause death and major bleeding. The authors noted that, generally, guided escalation was associated with a reduction in ischemic risks without safety tradeoffs, whereas guided de-escalation was associated with bleeding reductions without efficacy tradeoffs [49].
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 11 RCTs (11,740 patients) on genotype-guided APT vs. standard treatment demonstrated significant reductions across all reported efficacy outcomes, including trial-reported MACEs (RR = 0.60, p = 0.001), all-cause death (RR = 0.70, p = 0.02), CV death (RR = 0.71, p = 0.02), MI (RR = 0.53, p < 0.0001), stroke (RR = 0.64, p = 0.04), stent thrombosis (RR = 0.63, p = 0.01), and target vessel revascularization (RR = 0.79, p = 0.003). Differences in all bleeding outcomes were non-significant: BARC types 2,3,5: RR = 0.87, p = 0.13; BARC types 3,5: RR = 1.14, p = 0.44; TIMI major: RR = 1.05, p = 0.81; TIMI minor: RR = 1.04, p = 0.88. 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.

4. Long-Term APT

4.1. 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.

4.2. Long-Term P2Y12i Monotherapy

Trials have also considered long-term P2Y12i 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.
HOST-EXAM [33] enrolled PCI patients who were event-free after 6–18 months of prior DAPT. After another 24 months, compared with aspirin monotherapy, patients who received clopidogrel monotherapy had a reduced composite outcome of all-cause death, non-fatal MI, stroke, ACS re-admission, and BARC type ≥ 3 bleeding (5.7% vs. 7.7%, p = 0.003). One caution is that while both ischemic and bleeding endpoints decreased, all-cause deaths remained comparable (1.9% vs. 1.3%, p = 0.101).

4.3. 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].

5. Personalized Assessment

5.1. 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.
Some major APT trials have also conducted subgroup analysis on HBR patients. In the pre-specified TWILIGHT-HBR analysis [62], 17.2% of patients (1064 of 6178) met the ARC-HBR criteria. Compared with ticagrelor plus aspirin, ticagrelor monotherapy reduced BARC type 2, 3, or 5 bleeding in both the HBR (6.3% vs. 11.4%, p = 0.004) and non-HBR (3.5% vs. 5.9%, p < 0.001) subgroups. For BARC type 3 or 5 bleeding (i.e., more severe bleeding), there was a larger absolute risk reduction in the HBR group than the non-HBR group (−3.5% vs. −0.5%, p = 0.008). The key secondary endpoint of death, MI or stroke was similar between the two treatment arms, regardless of HBR status. In a post-hoc HBR subgroup analysis of STOP-DAPT2 [63], 1,054 of 3,009 patients (35%) were at HBR, according to the ARC-HBR criteria. The results showed consistent effects across the HBR and non-HBR subgroups, of 1-month DAPT followed by 11-month clopidogrel monotherapy versus 12-month DAPT. In line with TWILIGHT-HBR, there was also a numerically greater reduction in major bleeding in the STOP-DAPT2 HBR subgroup, compared with the non-HBR subgroup. In Chinese populations, 4-year post-hoc analysis of HBR (440 of 2737; 16%) patients from the I-LOVE-IT 2 trial [64] showed comparable efficacy and safety between 6- and 12-month DAPT. However, compared with non-HBR patients, HBR patients were associated with elevated risks of BARC type 3 or 5 (3.0% vs. 1.5%, p = 0.03), stroke (9.1% vs. 3.8%, p < 0.001), all-cause death (5.7% vs. 3.1%, p = 0.008), and NACE (31.8% vs. 26.0%, p = 0.01).
A meta-analysis [65] of six RCTs and three propensity-matched studies (i.e., the three XIENCE sub-studies [37]) compared ≤3-month DAPT with 6–12-month DAPT in 16,848 trial-defined HBR patients. The risks of ischemic events were similar, including MI (odds ratio [OR] = 1.16, 95% CI: 0.94–1.44), whereas major bleeding was lower with ≤3-month DAPT (OR = 0.68, 95% CI: 0.51–0.89). However, the authors noted a numerically higher incidence of late stent thrombosis (>30 days to 1 year) in their subgroup analysis, and suggested that, although newer stents are associated with lower late stent thrombosis rates, further investigations will be needed.
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 P2Y12i 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 P2Y12i 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 P2Y12i 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.

5.2. 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.

5.3. 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/m2, 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 P2Y12i 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.

5.4. Common P2Y12i 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 P2Y12i increased both platelet reactivity [92] and residual platelet reactivity [93]. This may be particularly relevant to the acute setting.
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].

5.5. 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 P2Y12i 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, a National Health Insurance Research Database study [100] of 27,339 acute MI patients (matched 1:8 ticagrelor: clopidogrel) reported lower all-cause death, acute MI, or stroke in the ticagrelor group versus the clopidogrel group (10.6% vs. 16.2%, HR = 0.78; 95% CI: 0.68–0.89), with similar major intracerebral or gastrointestinal bleeding (3.2% vs. 4.1%, HR = 0.73; 95% CI: 0.52–1.03 [N.S]).

6. Future Directions

6.1. Low-Dose Ticagrelor Monotherapy

Although studies on low-dose ticagrelor are still relatively uncommon, a meta-analysis [101] examined 16 trials including 1,629 ACS patients who received DAPT, of which 756 received low-dose ticagrelor: 484 received 90 mg QD, 240 received 45 mg BID, and 32 received 60 mg BID. Compared with clopidogrel 75 mg QD, low-dose ticagrelor significantly reduced CV death, MI, or stroke (OR = 0.39, 95% CI = 0.26–0.58, p < 0.01), without significantly increasing Study of Platelet Inhibition and Patient Outcomes (PLATO) major bleeding (OR = 1.16, p = 0.77). Also, in a patient-level meta-analysis [102] of six RCTs (24,096 patients) of P2Y12i monotherapy versus DAPT, P2Y12i monotherapy and DAPT showed similar composite risks of all-cause death, MI, or stroke. The risk of BARC type 3 or 5 bleeding was lower with P2Y12i monotherapy, when compared with DAPT (0.9% vs. 1.8%, p < 0.001), and particularly with newer P2Y12i (mainly ticagrelor).
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 P2Y12 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.

6.2. 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.

6.3. 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 meta-analysis 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 P2Y12i 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 P2Y12i monotherapy (RR = 1.22, 95% CI: 1.00–1.48). When compared with standard DAPT, short DAPT followed by P2Y12i 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.

7. 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 P2Y12i 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.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

Editorial assistance was provided by Best Solution Co. Ltd., which was funded by AstraZeneca Hong Kong. AstraZeneca Hong Kong had no role in review article design, data analysis/interpretation or manuscript preparation.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Montinari, M.R.; Minelli, S.; De Caterina, R. The first 3500 years of aspirin history from its roots—A concise summary. Vascul. Pharmacol. 2019, 113, 1–8. [Google Scholar] [CrossRef] [PubMed]
  2. Schomig, A.; Neumann, F.J.; Kastrati, A.; Schuhlen, H.; Blasini, R.; Hadamitzky, M.; Walter, H.; Zitzmann-Roth, E.M.; Richardt, G.; Alt, E.; et al. A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. N. Engl. J. Med. 1996, 334, 1084–1089. [Google Scholar] [CrossRef] [PubMed]
  3. Passacquale, G.; Sharma, P.; Perera, D.; Ferro, A. Antiplatelet therapy in cardiovascular disease: Current status and future directions. Br. J. Clin. Pharmacol. 2022, 88, 2686–2699. [Google Scholar] [CrossRef] [PubMed]
  4. Angiolillo, D.J.; Galli, M.; Collet, J.P.; Kastrati, A.; O’Donoghue, M.L. Antiplatelet therapy after percutaneous coronary intervention. EuroIntervention 2022, 17, e1371–e1396. [Google Scholar] [CrossRef]
  5. Fei, Y.; Lam, C.K.; Cheung, B.M.Y. Efficacy and safety of newer P2Y12 inhibitors for acute coronary syndrome: A network meta-analysis. Sci. Rep. 2020, 10, 16794. [Google Scholar] [CrossRef]
  6. Kang, S.H.; Chae, I.H.; Park, J.J.; Lee, H.S.; Kang, D.Y.; Hwang, S.S.; Youn, T.J.; Kim, H.S. Stent Thrombosis with Drug-Eluting Stents and Bioresorbable Scaffolds: Evidence from a Network Meta-Analysis of 147 Trials. JACC Cardiovasc. Interv. 2016, 9, 1203–1212. [Google Scholar] [CrossRef]
  7. Bonaca, M.P.; Bhatt, D.L.; Cohen, M.; Steg, P.G.; Storey, R.F.; Jensen, E.C.; Magnani, G.; Bansilal, S.; Fish, M.P.; Im, K.; et al. Long-term use of ticagrelor in patients with prior myocardial infarction. N. Engl. J. Med. 2015, 372, 1791–1800. [Google Scholar] [CrossRef] [Green Version]
  8. Kedhi, E.; Fabris, E.; van der Ent, M.; Buszman, P.; von Birgelen, C.; Roolvink, V.; Zurakowski, A.; Schotborgh, C.E.; Hoorntje, J.C.A.; Eek, C.H.; et al. Six months versus 12 months dual antiplatelet therapy after drug-eluting stent implantation in ST-elevation myocardial infarction (DAPT-STEMI): Randomised, multicentre, non-inferiority trial. BMJ 2018, 363, k3793. [Google Scholar] [CrossRef] [Green Version]
  9. Baber, U.; Dangas, G.; Angiolillo, D.J.; Cohen, D.J.; Sharma, S.K.; Nicolas, J.; Briguori, C.; Cha, J.Y.; Collier, T.; Dudek, D.; et al. Ticagrelor alone vs. ticagrelor plus aspirin following percutaneous coronary intervention in patients with non-ST-segment elevation acute coronary syndromes: TWILIGHT-ACS. Eur. Heart J. 2020, 41, 3533–3545. [Google Scholar] [CrossRef]
  10. Kim, H.S.; Kang, J.; Hwang, D.; Han, J.K.; Yang, H.M.; Kang, H.J.; Koo, B.K.; Rhew, J.Y.; Chun, K.J.; Lim, Y.H.; et al. Prasugrel-based de-escalation of dual antiplatelet therapy after percutaneous coronary intervention in patients with acute coronary syndrome (HOST-REDUCE-POLYTECH-ACS): An open-label, multicentre, non-inferiority randomised trial. Lancet 2020, 396, 1079–1089. [Google Scholar] [CrossRef]
  11. Cuisset, T.; Deharo, P.; Quilici, J.; Johnson, T.W.; Deffarges, S.; Bassez, C.; Bonnet, G.; Fourcade, L.; Mouret, J.P.; Lambert, M.; et al. Benefit of switching dual antiplatelet therapy after acute coronary syndrome: The TOPIC (timing of platelet inhibition after acute coronary syndrome) randomized study. Eur. Heart J. 2017, 38, 3070–3078. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  12. Rodriguez, F.; Harrington, R.A. Management of Antithrombotic Therapy after Acute Coronary Syndromes. N. Engl. J. Med. 2021, 384, 452–460. [Google Scholar] [CrossRef] [PubMed]
  13. Di Mario, C.; Mugelli, A.; Perrone Filardi, P.; Rosano, G.; Rossi, F. Long-term dual antiplatelet therapy: Pharmacological and clinical implications. J. Cardiovasc. Med. 2018, 19, 399–410. [Google Scholar] [CrossRef] [PubMed]
  14. Pilgrim, T.; Vranckx, P.; Valgimigli, M.; Stefanini, G.G.; Piccolo, R.; Rat, J.; Rothenbuhler, M.; Stortecky, S.; Raber, L.; Blochlinger, S.; et al. Risk and timing of recurrent ischemic events among patients with stable ischemic heart disease, non-ST-segment elevation acute coronary syndrome, and ST-segment elevation myocardial infarction. Am. Heart J. 2016, 175, 56–65. [Google Scholar] [CrossRef] [PubMed]
  15. Kikkert, W.J.; Hoebers, L.P.; Damman, P.; Lieve, K.V.; Claessen, B.E.; Vis, M.M.; Baan, J., Jr.; Koch, K.T.; de Winter, R.J.; Piek, J.J.; et al. Recurrent myocardial infarction after primary percutaneous coronary intervention for ST-segment elevation myocardial infarction. Am. J. Cardiol. 2014, 113, 229–235. [Google Scholar] [CrossRef] [PubMed]
  16. Peters, S.A.E.; Colantonio, L.D.; Dai, Y.; Zhao, H.; Bittner, V.; Farkouh, M.E.; Dluzniewski, P.; Poudel, B.; Muntner, P.; Woodward, M. Trends in Recurrent Coronary Heart Disease After Myocardial Infarction Among US Women and Men Between 2008 and 2017. Circulation 2021, 143, 650–660. [Google Scholar] [CrossRef] [PubMed]
  17. Yudi, M.B.; Clark, D.J.; Farouque, O.; Andrianopoulos, N.; Ajani, A.E.; Brennan, A.; Lefkovits, J.; Freeman, M.; Hiew, C.; Selkrig, L.A.; et al. Trends and predictors of recurrent acute coronary syndrome hospitalizations and unplanned revascularization after index acute myocardial infarction treated with percutaneous coronary intervention. Am. Heart J. 2019, 212, 134–143. [Google Scholar] [CrossRef]
  18. Peters, R.J.; Mehta, S.R.; Fox, K.A.; Zhao, F.; Lewis, B.S.; Kopecky, S.L.; Diaz, R.; Commerford, P.J.; Valentin, V.; Yusuf, S.; et al. Effects of aspirin dose when used alone or in combination with clopidogrel in patients with acute coronary syndromes: Observations from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study. Circulation 2003, 108, 1682–1687. [Google Scholar] [CrossRef]
  19. Wallentin, L.; Becker, R.C.; Budaj, A.; Cannon, C.P.; Emanuelsson, H.; Held, C.; Horrow, J.; Husted, S.; James, S.; Katus, H.; et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N. Engl. J. Med. 2009, 361, 1045–1057. [Google Scholar] [CrossRef]
  20. Wiviott, S.D.; Braunwald, E.; McCabe, C.H.; Montalescot, G.; Ruzyllo, W.; Gottlieb, S.; Neumann, F.J.; Ardissino, D.; De Servi, S.; Murphy, S.A.; et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N. Engl. J. Med. 2007, 357, 2001–2015. [Google Scholar] [CrossRef]
  21. Goto, S.; Huang, C.H.; Park, S.J.; Emanuelsson, H.; Kimura, T. Ticagrelor vs. clopidogrel in Japanese, Korean and Taiwanese patients with acute coronary syndrome—Randomized, double-blind, phase III PHILO study. Circ. J. 2015, 79, 2452–2460. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Park, D.W.; Kwon, O.; Jang, J.S.; Yun, S.C.; Park, H.; Kang, D.Y.; Ahn, J.M.; Lee, P.H.; Lee, S.W.; Park, S.W.; et al. Clinically Significant Bleeding with Ticagrelor Versus Clopidogrel in Korean Patients with Acute Coronary Syndromes Intended for Invasive Management: A Randomized Clinical Trial. Circulation 2019, 140, 1865–1877. [Google Scholar] [CrossRef] [PubMed]
  23. Nakamura, M.; Kitazono, T.; Kozuma, K.; Sekine, T.; Nakamura, S.; Shiosakai, K.; Iizuka, T. Prasugrel for Japanese Patients with Ischemic Heart Disease in Long-Term Clinical Practice (PRASFIT-Practice II)—1-Year Follow-up Results of a Postmarketing Observational Study. Circ. J. 2019, 84, 101–108. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  24. Nakamura, M.; Kitazono, T.; Kozuma, K.; Sekine, T.; Nakamura, S.; Shiosakai, K.; Tanabe, A.; Iizuka, T. Prasugrel for Japanese Patients with Ischemic Heart Disease in Long-Term Clinical Practice (PRASFIT-Practice II)—Final 2-year follow-up results of a postmarketing observational study. Circ. J. 2020, 84, 1981–1989. [Google Scholar] [CrossRef] [PubMed]
  25. Yusuf, S.; Zhao, F.; Mehta, S.R.; Chrolavicius, S.; Tognoni, G.; Fox, K.K.; Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial, I. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N. Engl. J. Med. 2001, 345, 494–502. [Google Scholar] [CrossRef] [Green Version]
  26. Mehran, R.; Baber, U.; Sharma, S.K.; Cohen, D.J.; Angiolillo, D.J.; Briguori, C.; Cha, J.Y.; Collier, T.; Dangas, G.; Dudek, D.; et al. Ticagrelor with or without Aspirin in High-Risk Patients after PCI. N. Engl. J. Med. 2019, 381, 2032–2042. [Google Scholar] [CrossRef]
  27. Kim, B.K.; Hong, S.J.; Cho, Y.H.; Yun, K.H.; Kim, Y.H.; Suh, Y.; Cho, J.Y.; Her, A.Y.; Cho, S.; Jeon, D.W.; et al. Effect of Ticagrelor Monotherapy vs Ticagrelor with Aspirin on Major Bleeding and Cardiovascular Events in Patients with Acute Coronary Syndrome: The TICO Randomized Clinical Trial. JAMA 2020, 323, 2407–2416. [Google Scholar] [CrossRef]
  28. Hahn, J.Y.; Song, Y.B.; Oh, J.H.; Chun, W.J.; Park, Y.H.; Jang, W.J.; Im, E.S.; Jeong, J.O.; Cho, B.R.; Oh, S.K.; et al. Effect of P2Y12 inhibitor monotherapy vs dual antiplatelet therapy on cardiovascular events in patients undergoing percutaneous coronary intervention: The SMART-CHOICE randomized clinical trial. JAMA 2019, 321, 2428–2437. [Google Scholar] [CrossRef] [Green Version]
  29. Watanabe, H.; Domei, T.; Morimoto, T.; Natsuaki, M.; Shiomi, H.; Toyota, T.; Ohya, M.; Suwa, S.; Takagi, K.; Nanasato, M.; et al. Effect of 1-Month Dual Antiplatelet Therapy Followed by Clopidogrel vs 12-Month Dual Antiplatelet Therapy on Cardiovascular and Bleeding Events in Patients Receiving PCI: The STOPDAPT-2 Randomized Clinical Trial. JAMA 2019, 321, 2414–2427. [Google Scholar] [CrossRef] [Green Version]
  30. Watanabe, H.; Morimoto, T.; Natsuaki, M.; Yamamoto, K.; Obayashi, Y.; Ogita, M.; Suwa, S.; Isawa, T.; Domei, T.; Yamaji, K.; et al. Comparison of Clopidogrel Monotherapy After 1 to 2 Months of Dual Antiplatelet Therapy With 12 Months of Dual Antiplatelet Therapy in Patients with Acute Coronary Syndrome: The STOPDAPT-2 ACS Randomized Clinical Trial. JAMA Cardiol. 2022, 7, 407–417. [Google Scholar] [CrossRef]
  31. Vranckx, P.; Valgimigli, M.; Juni, P.; Hamm, C.; Steg, P.G.; Heg, D.; van Es, G.A.; McFadden, E.P.; Onuma, Y.; van Meijeren, C.; et al. Ticagrelor plus aspirin for 1 month, followed by ticagrelor monotherapy for 23 months vs aspirin plus clopidogrel or ticagrelor for 12 months, followed by aspirin monotherapy for 12 months after implantation of a drug-eluting stent: A multicentre, open-label, randomised superiority trial. Lancet 2018, 392, 940–949. [Google Scholar] [CrossRef]
  32. Franzone, A.; McFadden, E.; Leonardi, S.; Piccolo, R.; Vranckx, P.; Serruys, P.W.; Benit, E.; Liebetrau, C.; Janssens, L.; Ferrario, M.; et al. Ticagrelor Alone Versus Dual Antiplatelet Therapy From 1 Month After Drug-Eluting Coronary Stenting. J. Am. Coll. Cardiol. 2019, 74, 2223–2234. [Google Scholar] [CrossRef]
  33. Koo, B.K.; Kang, J.; Park, K.W.; Rhee, T.M.; Yang, H.M.; Won, K.B.; Rha, S.W.; Bae, J.W.; Lee, N.H.; Hur, S.H.; et al. Aspirin versus clopidogrel for chronic maintenance monotherapy after percutaneous coronary intervention (HOST-EXAM): An investigator-initiated, prospective, randomised, open-label, multicentre trial. Lancet 2021, 397, 2487–2496. [Google Scholar] [CrossRef] [PubMed]
  34. Kim, C.J.; Park, M.W.; Kim, M.C.; Choo, E.H.; Hwang, B.H.; Lee, K.Y.; Choi, Y.S.; Kim, H.Y.; Yoo, K.D.; Jeon, D.S.; et al. Unguided de-escalation from ticagrelor to clopidogrel in stabilised patients with acute myocardial infarction undergoing percutaneous coronary intervention (TALOS-AMI): An investigator-initiated, open-label, multicentre, non-inferiority, randomised trial. Lancet 2021, 398, 1305–1316. [Google Scholar] [CrossRef] [PubMed]
  35. Han, Y.; Xu, B.; Xu, K.; Guan, C.; Jing, Q.; Zheng, Q.; Li, X.; Zhao, X.; Wang, H.; Zhao, X.; et al. Six Versus 12 Months of Dual Antiplatelet Therapy After Implantation of Biodegradable Polymer Sirolimus-Eluting Stent: Randomized Substudy of the I-LOVE-IT 2 Trial. Circ. Cardiovasc. Interv. 2016, 9, e003145. [Google Scholar] [CrossRef] [Green Version]
  36. Valgimigli, M.; Frigoli, E.; Heg, D.; Tijssen, J.; Juni, P.; Vranckx, P.; Ozaki, Y.; Morice, M.C.; Chevalier, B.; Onuma, Y.; et al. Dual Antiplatelet Therapy after PCI in Patients at High Bleeding Risk. N. Engl. J. Med. 2021, 385, 1643–1655. [Google Scholar] [CrossRef] [PubMed]
  37. Valgimigli, M.; Cao, D.; Angiolillo, D.J.; Bangalore, S.; Bhatt, D.L.; Ge, J.; Hermiller, J.; Makkar, R.R.; Neumann, F.J.; Saito, S.; et al. Duration of Dual Antiplatelet Therapy for Patients at High Bleeding Risk Undergoing PCI. J. Am. Coll. Cardiol. 2021, 78, 2060–2072. [Google Scholar] [CrossRef] [PubMed]
  38. Cayla, G.; Cuisset, T.; Silvain, J.; Leclercq, F.; Manzo-Silberman, S.; Saint-Etienne, C.; Delarche, N.; Bellemain-Appaix, A.; Range, G.; El Mahmoud, R.; et al. Platelet function monitoring to adjust antiplatelet therapy in elderly patients stented for an acute coronary syndrome (ANTARCTIC): An open-label, blinded-endpoint, randomised controlled superiority trial. Lancet 2016, 388, 2015–2022. [Google Scholar] [CrossRef]
  39. Sibbing, D.; Aradi, D.; Jacobshagen, C.; Gross, L.; Trenk, D.; Geisler, T.; Orban, M.; Hadamitzky, M.; Merkely, B.; Kiss, R.G.; et al. Guided de-escalation of antiplatelet treatment in patients with acute coronary syndrome undergoing percutaneous coronary intervention (TROPICAL-ACS): A randomised, open-label, multicentre trial. Lancet 2017, 390, 1747–1757. [Google Scholar] [CrossRef] [Green Version]
  40. Claassens, D.M.F.; Vos, G.J.A.; Bergmeijer, T.O.; Hermanides, R.S.; van ‘t Hof, A.W.J.; van der Harst, P.; Barbato, E.; Morisco, C.; Tjon Joe Gin, R.M.; Asselbergs, F.W.; et al. A Genotype-Guided Strategy for Oral P2Y12 Inhibitors in Primary PCI. N. Engl. J. Med. 2019, 381, 1621–1631. [Google Scholar] [CrossRef]
  41. Pereira, N.L.; Farkouh, M.E.; So, D.; Lennon, R.; Geller, N.; Mathew, V.; Bell, M.; Bae, J.H.; Jeong, M.H.; Chavez, I.; et al. Effect of genotype-guided oral P2Y12 inhibitor selection vs conventional clopidogrel therapy on ischemic outcomes after percutaneous coronary intervention: The TAILOR-PCI randomized clinical trial. JAMA 2020, 324, 761–771. [Google Scholar] [CrossRef] [PubMed]
  42. Zheng, Y.Y.; Wu, T.T.; Yang, Y.; Hou, X.G.; Gao, Y.; Chen, Y.; Yang, Y.N.; Li, X.M.; Ma, X.; Ma, Y.T.; et al. Personalized antiplatelet therapy guided by a novel detection of platelet aggregation function in stable coronary artery disease patients undergoing percutaneous coronary intervention: A randomized controlled clinical trial. Eur. Heart J. Cardiovasc. Pharmacother. 2020, 6, 211–221. [Google Scholar] [CrossRef] [PubMed]
  43. Mauri, L.; Kereiakes, D.J.; Yeh, R.W.; Driscoll-Shempp, P.; Cutlip, D.E.; Steg, P.G.; Normand, S.L.; Braunwald, E.; Wiviott, S.D.; Cohen, D.J.; et al. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N. Engl. J. Med. 2014, 371, 2155–2166. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  44. Bhatt, D.L.; Steg, P.G.; Mehta, S.R.; Leiter, L.A.; Simon, T.; Fox, K.; Held, C.; Andersson, M.; Himmelmann, A.; Ridderstrale, W.; et al. Ticagrelor in patients with diabetes and stable coronary artery disease with a history of previous percutaneous coronary intervention (THEMIS-PCI): A phase 3, placebo-controlled, randomised trial. Lancet 2019, 394, 1169–1180. [Google Scholar] [CrossRef] [PubMed]
  45. Eikelboom, J.W.; Connolly, S.J.; Bosch, J.; Dagenais, G.R.; Hart, R.G.; Shestakovska, O.; Diaz, R.; Alings, M.; Lonn, E.M.; Anand, S.S.; et al. Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease. N. Engl. J. Med. 2017, 377, 1319–1330. [Google Scholar] [CrossRef]
  46. Laudani, C.; Greco, A.; Occhipinti, G.; Ingala, S.; Calderone, D.; Scalia, L.; Agnello, F.; Legnazzi, M.; Mauro, M.S.; Rochira, C.; et al. Short duration of DAPT versus de-escalation after percutaneous coronary intervention for acute coronary syndromes. JACC Cardiovasc. Interv. 2022, 15, 268–277. [Google Scholar] [CrossRef]
  47. Cattaneo, M. High on-treatment platelet reactivity—Definition and measurement. Thromb. Haemost. 2013, 109, 792–798. [Google Scholar] [CrossRef] [Green Version]
  48. Song, B.L.; Wan, M.; Tang, D.; Sun, C.; Zhu, Y.B.; Linda, N.; Fan, H.W.; Zou, J.J. Effects of CYP2C19 Genetic Polymorphisms on the Pharmacokinetic and Pharmacodynamic Properties of Clopidogrel and Its Active Metabolite in Healthy Chinese Subjects. Clin. Ther. 2018, 40, 1170–1178. [Google Scholar] [CrossRef]
  49. Galli, M.; Benenati, S.; Capodanno, D.; Franchi, F.; Rollini, F.; D’Amario, D.; Porto, I.; Angiolillo, D.J. Guided versus standard antiplatelet therapy in patients undergoing percutaneous coronary intervention: A systematic review and meta-analysis. Lancet 2021, 397, 1470–1483. [Google Scholar] [CrossRef]
  50. Tang, B.; Wang, X.; Wang, X.; Liu, L.; Ma, Z. Genotype-Guided Antiplatelet Therapy Versus Standard Therapy for Patients with Coronary Artery Disease: An Updated Systematic Review and Meta-Analysis. J. Pharm. Pharm. Sci. 2022, 25, 9–23. [Google Scholar] [CrossRef]
  51. Bergmeijer, T.O.; Vos, G.J.; Claassens, D.M.; Janssen, P.W.; Harms, R.; der Heide, R.V.; Asselbergs, F.W.; Ten Berg, J.M.; Deneer, V.H. Feasibility and implementation of CYP2C19 genotyping in patients using antiplatelet therapy. Pharmacogenomics 2018, 19, 621–628. [Google Scholar] [CrossRef] [PubMed]
  52. Smolina, K.; Wright, F.L.; Rayner, M.; Goldacre, M.J. Long-term survival and recurrence after acute myocardial infarction in England, 2004 to 2010. Circ. Cardiovasc. Qual. Outcomes 2012, 5, 532–540. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. Bonaca, M.P.; Storey, R.F.; Bhatt, D.L.; Steg, P.G.; Cohen, M.; Im, K.P.; Johanson, P.; Braunwald, E.P.; Sabatine, M.S. Abstract 16658: Patient Selection for Long-Term Secondary Prevention with Ticagrelor: Insights From PEGASUS-TIMI 54. Circulation 2018, 138, A16658. [Google Scholar] [CrossRef]
  54. Vranckx, P.; Valgimigli, M.; Odutayo, A.; Serruys, P.W.; Hamm, C.; Steg, P.G.; Heg, D.; Mc Fadden, E.P.; Onuma, Y.; Benit, E.; et al. Efficacy and Safety of Ticagrelor Monotherapy by Clinical Presentation: Pre-Specified Analysis of the GLOBAL LEADERS Trial. J. Am. Heart Assoc. 2021, 10, e015560. [Google Scholar] [CrossRef] [PubMed]
  55. Ono, M.; Hara, H.; Kawashima, H.; Gao, C.; Wang, R.; Wykrzykowska, J.J.; Piek, J.J.; Garg, S.; Hamm, C.; Steg, P.G.; et al. Ticagrelor monotherapy versus aspirin monotherapy at 12 months after percutaneous coronary intervention: A landmark analysis of the GLOBAL LEADERS trial. EuroIntervention 2022, 18, e377–e388. [Google Scholar] [CrossRef]
  56. Sharma, M.; Hart, R.G.; Connolly, S.J.; Bosch, J.; Shestakovska, O.; Ng, K.K.H.; Catanese, L.; Keltai, K.; Aboyans, V.; Alings, M.; et al. Stroke Outcomes in the COMPASS Trial. Circulation 2019, 139, 1134–1145. [Google Scholar] [CrossRef]
  57. Perera, K.S.; Ng, K.K.H.; Nayar, S.; Catanese, L.; Dyal, L.; Sharma, M.; Connolly, S.J.; Yusuf, S.; Bosch, J.; Eikelboom, J.W.; et al. Association Between Low-Dose Rivaroxaban with or Without Aspirin and Ischemic Stroke Subtypes: A Secondary Analysis of the COMPASS Trial. JAMA Neurol. 2020, 77, 43–48. [Google Scholar] [CrossRef]
  58. Niessner, A.; Agewall, S. Critical appraisal of the COMPASS trial. Eur. Heart J. Cardiovasc. Pharmacother. 2018, 4, 191–192. [Google Scholar] [CrossRef]
  59. Zhao, X.; Li, J.; Liu, F.; Zhu, P.; Jiang, L.; Tang, X.; Xu, J.; Song, Y.; Chen, J.; Qiao, S.; et al. The PRECISE-DAPT score and five-year outcomes after percutaneous coronary intervention: A large-scale, real-world study from China. Eur. Heart J. Qual. Care Clin. Outcomes 2021, 8, 812–820. [Google Scholar] [CrossRef]
  60. Urban, P.; Mehran, R.; Colleran, R.; Angiolillo, D.J.; Byrne, R.A.; Capodanno, D.; Cuisset, T.; Cutlip, D.; Eerdmans, P.; Eikelboom, J.; et al. Defining high bleeding risk in patients undergoing percutaneous coronary intervention: A consensus document from the Academic Research Consortium for High Bleeding Risk. Eur. Heart J. 2019, 40, 2632–2653. [Google Scholar] [CrossRef]
  61. Valgimigli, M.; Smits, P.C.; Frigoli, E.; Bongiovanni, D.; Tijssen, J.; Hovasse, T.; Mafragi, A.; Ruifrok, W.T.; Karageorgiev, D.; Aminian, A.; et al. Duration of Antiplatelet Therapy After Complex Percutaneous Coronary Intervention in Patients at High Bleeding Risk: A MASTER DAPT trial sub-analysis. Eur. Heart J. 2022, 43, 3100–3114. [Google Scholar] [CrossRef] [PubMed]
  62. Escaned, J.; Cao, D.; Baber, U.; Nicolas, J.; Sartori, S.; Zhang, Z.; Dangas, G.; Angiolillo, D.J.; Briguori, C.; Cohen, D.J.; et al. Ticagrelor monotherapy in patients at high bleeding risk undergoing percutaneous coronary intervention: TWILIGHT-HBR. Eur. Heart J. 2021, 42, 4624–4634. [Google Scholar] [CrossRef] [PubMed]
  63. Watanabe, H.; Domei, T.; Morimoto, T.; Natsuaki, M.; Shiomi, H.; Toyota, T.; Ohya, M.; Suwa, S.; Takagi, K.; Nanasato, M.; et al. Details on the effect of very short dual antiplatelet therapy after drug-eluting stent implantation in patients with high bleeding risk: Insight from the STOPDAPT-2 trial. Cardiovasc. Interv. Ther. 2021, 36, 91–103. [Google Scholar] [CrossRef]
  64. Zhang, J.; Qiu, M.; Na, K.; Ma, S.; Jiang, Z.; Li, J.; Li, Y.; Han, Y. Impact of 6- versus 12-month dual antiplatelet therapy on clinical prognosis in patients with high bleeding risk: Insights from the 4-year results of the I LOVE IT 2 study. Catheter. Cardiovasc. Interv. 2021, 97 (Suppl. 2), 1025–1031. [Google Scholar] [CrossRef] [PubMed]
  65. Garg, A.; Rout, A.; Farhan, S.; Waxman, S.; Giustino, G.; Tayal, R.; Abbott, J.D.; Huber, K.; Angiolillo, D.J.; Rao, S.V. Dual antiplatelet therapy duration after percutaneous coronary intervention using drug eluting stents in high bleeding risk patients: A systematic review and meta-analysis. Am. Heart J. 2022, 250, 1–10. [Google Scholar] [CrossRef] [PubMed]
  66. Urban, P.; Meredith, I.T.; Abizaid, A.; Pocock, S.J.; Carrie, D.; Naber, C.; Lipiecki, J.; Richardt, G.; Iniguez, A.; Brunel, P.; et al. Polymer-free Drug-Coated Coronary Stents in Patients at High Bleeding Risk. N. Engl. J. Med. 2015, 373, 2038–2047. [Google Scholar] [CrossRef] [Green Version]
  67. Windecker, S.; Latib, A.; Kedhi, E.; Kirtane, A.J.; Kandzari, D.E.; Mehran, R.; Price, M.J.; Abizaid, A.; Simon, D.I.; Worthley, S.G.; et al. Polymer-Based Versus Polymer-Free Stents in High Bleeding Risk Patients: Final 2-Year Results from Onyx ONE. JACC Cardiovasc. Interv. 2022, 15, 1153–1163. [Google Scholar] [CrossRef]
  68. Garot, P.; Morice, M.C.; Tresukosol, D.; Pocock, S.J.; Meredith, I.T.; Abizaid, A.; Carrie, D.; Naber, C.; Iniguez, A.; Talwar, S.; et al. 2-Year Outcomes of High Bleeding Risk Patients After Polymer-Free Drug-Coated Stents. J. Am. Coll. Cardiol. 2017, 69, 162–171. [Google Scholar] [CrossRef] [Green Version]
  69. Windecker, S.; Latib, A.; Kedhi, E.; Kirtane, A.J.; Kandzari, D.E.; Mehran, R.; Price, M.J.; Abizaid, A.; Simon, D.I.; Worthley, S.G.; et al. Polymer-based or Polymer-free Stents in Patients at High Bleeding Risk. N. Engl. J. Med. 2020, 382, 1208–1218. [Google Scholar] [CrossRef]
  70. Neumann, F.J.; Sousa-Uva, M.; Ahlsson, A.; Alfonso, F.; Banning, A.P.; Benedetto, U.; Byrne, R.A.; Collet, J.P.; Falk, V.; Head, S.J.; et al. 2018 ESC/EACTS Guidelines on myocardial revascularization. Eur. Heart J. 2019, 40, 87–165. [Google Scholar] [CrossRef]
  71. Lawton, J.S.; Tamis-Holland, J.E.; Bangalore, S.; Bates, E.R.; Beckie, T.M.; Bischoff, J.M.; Bittl, J.A.; Cohen, M.G.; DiMaio, J.M.; Don, C.W.; et al. 2021 ACC/AHA/SCAI Guideline for Coronary Artery Revascularization: Executive Summary: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 2022, 145, e4–e17. [Google Scholar] [CrossRef] [PubMed]
  72. Jeong, Y.H. “East Asian Paradox”: Challenge for the current antiplatelet strategy of “one-guideline-fits-all races” in acute coronary syndrome. Curr. Cardiol. Rep. 2014, 16, 485. [Google Scholar] [CrossRef] [PubMed]
  73. Kang, J.; Kim, H.S. The Evolving Concept of Dual Antiplatelet Therapy after Percutaneous Coronary Intervention: Focus on Unique Feature of East Asian and “Asian Paradox”. Korean Circ. J. 2018, 48, 537–551. [Google Scholar] [CrossRef] [PubMed]
  74. Gorog, D.A.; Yamamoto, J.; Saraf, S.; Ishii, H.; Ijiri, Y.; Ikarugi, H.; Wellsted, D.M.; Mori, M.; Yamori, Y. First direct comparison of platelet reactivity and thrombolytic status between Japanese and Western volunteers: Possible relationship to the “Japanese paradox”. Int. J. Cardiol. 2011, 152, 43–48. [Google Scholar] [CrossRef]
  75. Wang, G.; Wang, X.; Zhao, G.; Huang, X.; Guo, R.; Nie, S. De-escalation of antiplatelet therapy after percutaneous coronary intervention among East Asians and non-East Asians: A meta-analysis of randomized controlled trials. BMC Cardiovasc. Disord. 2022, 22, 29. [Google Scholar] [CrossRef]
  76. Kim, H.K.; Tantry, U.S.; Smith, S.C., Jr.; Jeong, M.H.; Park, S.J.; Kim, M.H.; Lim, D.S.; Shin, E.S.; Park, D.W.; Huo, Y.; et al. The East Asian Paradox: An Updated Position Statement on the Challenges to the Current Antithrombotic Strategy in Patients with Cardiovascular Disease. Thromb. Haemost. 2021, 121, 422–432. [Google Scholar] [CrossRef]
  77. Yoshikawa, Y.; Shiomi, H.; Watanabe, H.; Natsuaki, M.; Kondo, H.; Tamura, T.; Nakagawa, Y.; Morimoto, T.; Kimura, T. Validating Utility of Dual Antiplatelet Therapy Score in a Large Pooled Cohort From 3 Japanese Percutaneous Coronary Intervention Studies. Circulation 2018, 137, 551–562. [Google Scholar] [CrossRef]
  78. Choi, S.Y.; Kim, M.H.; Cho, Y.R.; Sung Park, J.; Min Lee, K.; Park, T.H.; Yun, S.C. Performance of PRECISE-DAPT Score for Predicting Bleeding Complication During Dual Antiplatelet Therapy. Circ. Cardiovasc. Interv. 2018, 11, e006837. [Google Scholar] [CrossRef]
  79. Ng, A.K.-Y.; Ng, P.Y.; Ip, A.; Ling, I.W.-H.; Lam, L.-T.; Siu, C.-W. Incidence, Prediction, and Outcomes of Major Bleeding After Percutaneous Coronary Intervention in Chinese Patients. JACC Asia 2022, 2, 341–350. [Google Scholar] [CrossRef]
  80. Collet, J.P.; Thiele, H.; Barbato, E.; Barthelemy, O.; Bauersachs, J.; Bhatt, D.L.; Dendale, P.; Dorobantu, M.; Edvardsen, T.; Folliguet, T.; et al. 2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur. Heart J. 2021, 42, 1289–1367. [Google Scholar] [CrossRef]
  81. Yeh, R.W.; Secemsky, E.A.; Kereiakes, D.J.; Normand, S.L.; Gershlick, A.H.; Cohen, D.J.; Spertus, J.A.; Steg, P.G.; Cutlip, D.E.; Rinaldi, M.J.; et al. Development and Validation of a Prediction Rule for Benefit and Harm of Dual Antiplatelet Therapy Beyond 1 Year After Percutaneous Coronary Intervention. JAMA 2016, 315, 1735–1749. [Google Scholar] [CrossRef] [Green Version]
  82. Costa, F.; van Klaveren, D.; James, S.; Heg, D.; Raber, L.; Feres, F.; Pilgrim, T.; Hong, M.K.; Kim, H.S.; Colombo, A.; et al. Derivation and validation of the predicting bleeding complications in patients undergoing stent implantation and subsequent dual antiplatelet therapy (PRECISE-DAPT) score: A pooled analysis of individual-patient datasets from clinical trials. Lancet 2017, 389, 1025–1034. [Google Scholar] [CrossRef] [PubMed]
  83. Ng, A.K.-Y.; Ng, P.Y.; Ip, A.; Lau, K.K.; Siu, C.-W. Risk of ischaemic and haemorrhagic stroke in Chinese undergoing percutaneous coronary intervention treated with potent P2Y12 inhibitor versus clopidogrel. Stroke Vasc. Neurol. 2022, 7, e001294. [Google Scholar] [CrossRef] [PubMed]
  84. Tam, C.C.; Kwok, J.; Wong, A.; Yung, A.; Shea, C.; Kong, S.L.; Tang, W.H.; Siu, D.; Chan, R.; Lee, S. Genotyping-guided approach versus the conventional approach in selection of oral P2Y12 receptor blockers in Chinese patients suffering from acute coronary syndrome. J. Int. Med. Res. 2017, 45, 134–146. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  85. Yu, M.H.C.; Chan, M.C.Y.; Chung, C.C.Y.; Li, A.W.T.; Yip, C.Y.W.; Mak, C.C.Y.; Chau, J.F.T.; Lee, M.; Fung, J.L.F.; Tsang, M.H.Y.; et al. Actionable pharmacogenetic variants in Hong Kong Chinese exome sequencing data and projected prescription impact in the Hong Kong population. PLoS Genet. 2021, 17, e1009323. [Google Scholar] [CrossRef] [PubMed]
  86. Angiolillo, D.J.; Capodanno, D.; Danchin, N.; Simon, T.; Bergmeijer, T.O.; Ten Berg, J.M.; Sibbing, D.; Price, M.J. Derivation, Validation, and Prognostic Utility of a Prediction Rule for Nonresponse to Clopidogrel: The ABCD-GENE Score. JACC Cardiovasc. Interv. 2020, 13, 606–617. [Google Scholar] [CrossRef] [PubMed]
  87. Sibbing, D.; Aradi, D.; Alexopoulos, D.; Ten Berg, J.; Bhatt, D.L.; Bonello, L.; Collet, J.P.; Cuisset, T.; Franchi, F.; Gross, L.; et al. Updated Expert Consensus Statement on Platelet Function and Genetic Testing for Guiding P2Y12 Receptor Inhibitor Treatment in Percutaneous Coronary Intervention. JACC Cardiovasc. Interv. 2019, 12, 1521–1537. [Google Scholar] [CrossRef] [PubMed]
  88. Warlo, E.M.K.; Arnesen, H.; Seljeflot, I. A brief review on resistance to P2Y(12) receptor antagonism in coronary artery disease. Thromb. J. 2019, 17, 11. [Google Scholar] [CrossRef] [PubMed]
  89. Schilling, U.; Dingemanse, J.; Ufer, M. Pharmacokinetics and Pharmacodynamics of Approved and Investigational P2Y12 Receptor Antagonists. Clin. Pharmacokinet. 2020, 59, 545–566. [Google Scholar] [CrossRef]
  90. Wang, Z.Y.; Chen, M.; Zhu, L.L.; Yu, L.S.; Zeng, S.; Xiang, M.X.; Zhou, Q. Pharmacokinetic drug interactions with clopidogrel: Updated review and risk management in combination therapy. Ther. Clin. Risk Manag. 2015, 11, 449–467. [Google Scholar] [CrossRef]
  91. Tantry, U.S.; Jeong, Y.H.; Gurbel, P.A. The clopidogrel-statin interaction. Circ. J. 2014, 78, 592–594. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  92. Vaidya, G.N.; Khan, A.; Ghafghazi, S. Effect of morphine use on oral P2Y12 platelet inhibitors in acute myocardial infarction: Meta-analysis. Indian Heart J. 2019, 71, 126–135. [Google Scholar] [CrossRef] [PubMed]
  93. Zhang, Y.; Wang, N.; Gu, Q. Effects of morphine on P2Y(12) platelet inhibitors in patients with acute myocardial infarction: A meta-analysis. Am. J. Emerg. Med. 2021, 41, 219–228. [Google Scholar] [CrossRef] [PubMed]
  94. Li, Y.; Ren, X.; Fang, Z. Systematic Review and Meta-analysis: The Effects of Prophylactic Proton Pump Inhibitor Treatment in Patients with Coronary Heart Disease Receiving Dual Antiplatelet Therapy. J. Cardiovasc. Pharmacol. 2021, 77, 835–861. [Google Scholar] [CrossRef]
  95. Bhatt, D.L.; Cryer, B.L.; Contant, C.F.; Cohen, M.; Lanas, A.; Schnitzer, T.J.; Shook, T.L.; Lapuerta, P.; Goldsmith, M.A.; Laine, L.; et al. Clopidogrel with or without omeprazole in coronary artery disease. N. Engl. J. Med. 2010, 363, 1909–1917. [Google Scholar] [CrossRef] [Green Version]
  96. Vaduganathan, M.; Bhatt, D.L.; Cryer, B.L.; Liu, Y.; Hsieh, W.H.; Doros, G.; Cohen, M.; Lanas, A.; Schnitzer, T.J.; Shook, T.L.; et al. Proton-Pump Inhibitors Reduce Gastrointestinal Events Regardless of Aspirin Dose in Patients Requiring Dual Antiplatelet Therapy. J. Am. Coll. Cardiol. 2016, 67, 1661–1671. [Google Scholar] [CrossRef]
  97. Saven, H.; Zhong, L.; McFarlane, I.M. Co-prescription of Dual-Antiplatelet Therapy and Proton Pump Inhibitors: Current Guidelines. Cureus 2022, 14, e21885. [Google Scholar] [CrossRef]
  98. Hu, Y.; Wang, J. Interactions between clopidogrel and traditional Chinese medicine. J. Thromb. Thrombolysis 2019, 48, 491–499. [Google Scholar] [CrossRef]
  99. Yu, Z.; Li, X.; Zhang, X.; Li, D.; Gu, Y.; Wu, M.; Liu, L. Combined Therapy with Traditional Chinese Medicine and Antiplatelet Drugs for Ischemic Heart Disease: Mechanism, Efficacy, and Safety. Evid. Based Complement. Alternat. Med. 2021, 2021, 9956248. [Google Scholar] [CrossRef]
  100. Lee, C.H.; Cheng, C.L.; Kao Yang, Y.H.; Chao, T.H.; Chen, J.Y.; Li, Y.H. Cardiovascular and Bleeding Risks in Acute Myocardial Infarction Newly Treated with Ticagrelor vs. Clopidogrel in Taiwan. Circ. J. 2018, 82, 747–756. [Google Scholar] [CrossRef]
  101. Chen, Q.; Zhang, Y.; Wang, Z.; Wang, S.; Zhang, H.; Wang, Y.; Lu, C.; Xuan, H.; Wang, C.; Li, D.; et al. Efficacy and safety of low dose ticagrelor in patients with acute coronary syndrome: A systematic review and meta-analysis. Postgrad. Med. J. 2020, 96, 693–702. [Google Scholar] [CrossRef] [PubMed]
  102. Valgimigli, M.; Gragnano, F.; Branca, M.; Franzone, A.; Baber, U.; Jang, Y.; Kimura, T.; Hahn, J.Y.; Zhao, Q.; Windecker, S.; et al. P2Y12 inhibitor monotherapy or dual antiplatelet therapy after coronary revascularisation: Individual patient level meta-analysis of randomised controlled trials. BMJ 2021, 373, n1332. [Google Scholar] [CrossRef] [PubMed]
  103. Lee, J.H.; Ahn, S.G.; Park, B.; Park, S.W.; Kang, Y.S.; Lee, J.W.; Youn, Y.J.; Ahn, M.S.; Kim, J.Y.; Yoo, B.S.; et al. A pharmacodynamic study of the optimal P2Y12 inhibitor regimen for East Asian patients with acute coronary syndrome. Korean J. Intern. Med. 2015, 30, 620–628. [Google Scholar] [CrossRef]
  104. Kim, Y.; Johnson, T.W.; Jeong, M.H. Potent P2Y(1)(2) Receptor Inhibition in Korean Patients with Acute Myocardial Infarction. Korean Circ. J. 2019, 49, 1199–1200. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  105. Tam, C.F.; Chan, Y.H.; Wong, Y.K.; Li, Z.; Zhu, X.; Su, K.J.; Ganguly, A.; Hwa, K.; Ling, X.B.; Tse, H.F. Multi-Omics Signatures Link to Ticagrelor Effects on Vascular Function in Patients with Acute Coronary Syndrome. Arterioscler. Thromb. Vasc. Biol. 2022, 42, 789–798. [Google Scholar] [CrossRef]
  106. Makhdoum, A.; Dhingra, N.K.; Kirubaharan, A.; Eikelboom, R.; Luc, J.; Dagher, O.; Bierer, J.; Cartier, A.; Vaillancourt, O.; Vo, T.X.; et al. Ticagrelor use and practice patterns among Canadian cardiac surgeons. J. Card. Surg. 2021, 36, 2793–2801. [Google Scholar] [CrossRef]
  107. Bhatt, D.L.; Pollack, C.V.; Mazer, C.D.; Angiolillo, D.J.; Steg, P.G.; James, S.K.; Weitz, J.I.; Ramnath, R.; Arnold, S.E.; Mays, M.C.; et al. Bentracimab for Ticagrelor Reversal in Patients Undergoing Urgent Surgery. NEJM Evid. 2022, 1, EVIDoa2100047. [Google Scholar] [CrossRef]
  108. Ullah, W.; Zahid, S.; Sandhyavenu, H.; Faisaluddin, M.; Khalil, F.; Pasha, A.K.; Alraies, M.C.; Cuisset, T.; Rao, S.V.; Sabouret, P.; et al. Extended, standard or De-escalation antiplatelet therapy for patients with CAD undergoing PCI? A trial-sequential, bivariate, influential and network meta-analysis. Eur. Heart J. Cardiovasc. Pharmacother. 2022. [Google Scholar] [CrossRef]
  109. Khan, S.U.; Khan, M.Z.; Khan, M.S.; Mahmood, A.; Kalra, A.; Kaluski, E.; Michos, E.D.; Alkhouli, M. De-escalation of antiplatelets after percutaneous coronary intervention: A Bayesian network meta-analysis of various de-escalation strategies. Eur. Heart J. Cardiovasc. Pharmacother. 2021, 7, 209–215. [Google Scholar] [CrossRef]
  110. Chiang, J.Y.; Lee, S.H.; Chen, Y.C.; Wu, C.K.; Chuang, J.Y.; Lo, S.C.; Yeh, H.M.; Yeh, S.S.; Hsu, C.A.; Lin, B.B.; et al. Metabolomic Analysis of Platelets of Patients with Aspirin Non-Response. Front. Pharmacol. 2019, 10, 1107. [Google Scholar] [CrossRef]
  111. Rayfield, C.; Agasthi, P.; Mookadam, F.; Yang, E.H.; Venepally, N.R.; Ramakrishna, H.; Slomka, P.; Holmes, D.R., Jr.; Arsanjani, R. Machine Learning on High-Dimensional Data to Predict Bleeding Post Percutaneous Coronary Intervention. J. Invasive Cardiol. 2020, 32, E122–E129. [Google Scholar] [CrossRef] [PubMed]
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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.
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.
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Figure 2. Schematic representation of usual changes in ischemic and bleeding risks over time (from an index time point) for several different populations, relative to all CAD patients (reference group). Note that the patient populations may overlap.
Figure 2. Schematic representation of usual changes in ischemic and bleeding risks over time (from an index time point) for several different populations, relative to all CAD patients (reference group). Note that the patient populations may overlap.
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Table
Table 1. Treatment aims and strategies of antiplatelet therapy at various periods.
Table 1. Treatment aims and strategies of antiplatelet therapy at various periods.
Patient
Population		RiskTreatment Aims at Different Phases
Short Term (<1 Month)Medium Term (1–12 Months)Long Term (>12 Months)
ACSIschemic↓↓↓Avoid unacceptable ↑↓
BleedingAvoid excessive ↑↓Avoid excessive ↑
sCADIschemic↓Avoid unacceptable ↑↓
BleedingAvoid excessive ↑↓Avoid excessive ↑
Example StrategiesDAPT using a potent P2Y12i (ticagrelor or prasugrel) + aspirinDAPT duration adjustment
P2Y12i monotherapy
De-escalation (P2Y12i dosage or potency)		Extended DAPT
P2Y12i monotherapy
Anticoagulant
Abbreviations: “↓”, decrease; “↑”, increase; ACS, acute coronary syndrome; DAPT, dual antiplatelet therapy; P2Y12i, purinergic receptor P2Y12 inhibitor; sCAD, stable coronary artery disease.
Table
Table 2. Study designs of major international and Asian randomized controlled trials investigating the efficacy and safety of popular antiplatelet therapy strategies.
Table 2. Study designs of major international and Asian randomized controlled trials investigating the efficacy and safety of popular antiplatelet therapy strategies.
CAD PopulationPrior ProcedureRegion(s)Experiment StrategyBlindingTrial NameComparison ArmsStudy Duration (Months)Sample Size
ExperimentControl
Standard 1-year DAPT
Landmark Trials
ACS (STEMI excluded)Exclude PCI in past 3 monthsInternational1-year DAPTDouble-blindCURE [18,25]ASA (75–325 mg) ± clopidogrel (300 mg loading + 75 mg QD)1262596303
ACSPCIInternational (91.7% Caucasians)1-year DAPTDouble-blindPLATO [19]Ticagrelor (180 mg loading + 90 mg BID) vs. clopidogrel (300–600 mg loading + 75 mg QD)1293339291
ACSPCI: 99%
CABG: 1%		International (92–93% Caucasian)1-year DAPTDouble-blindTRITON [20]Prasugrel (60 mg loading + 10 mg QD) vs. clopidogrel (300 mg loading + 75 mg QD)1568136795
Asian Trials
ACSPCI: 85%Japan, Taiwan, Korea1-year DAPTDouble-blindPHILO [21]Ticagrelor (180 mg loading + 90 mg BID) vs. clopidogrel (300 mg loading + 75 mg QD)12401400
ACSInvasive managementKorea1-year DAPTOpen-label, adjudicator-blindedTICAKOREA [22]Ticagrelor (180 mg loading + 90 mg BID) vs. clopidogrel (600 mg loading + 75 mg QD)12400400
57% ACSPCIJapan2-year DAPTNot specifiedPRASFIT-Practice II [23,24]Observational only:
Prasugrel (20 mg loading + 3.75 mg QD)		244155
P2Y12i Monotherapy
Landmark Trial
65% ACSPCIInternational (23.0% enrolled from Asia)3-month DAPT + 12-month P2Y12i monotherapyDouble-blindTWILIGHT [9,26]Ticagrelor (90 mg BID) ± ASA15 NSTE-ACS:
22732341
sCAD:
12811222
Asian Trials
ACSBioresorbable polymer sirolimus-eluting stentKorea3-month DAPT + 9-month P2Y12i monotherapyUnblindedTICO [27]3-month DAPT (ticagrelor 90 mg BID + ASA) + 9-month ticagrelor 90 mg BID, vs. 12-month DAPT with ticagrelor 90 mg BID1215271529
58% ACSPCI (certain stent types)Korea3-month DAPT + 9-month P2Y12i monotherapyOpen-label, adjudicator-blindedSMART-CHOICE [28]3-month DAPT with P2Y12i (clopidogrel 75 mg QD, prasugrel 10 mg QD or ticagrelor 90 mg BID + ASA) + 9-month P2Y12i, vs. 12-month DAPT1214951498
38% ACSPCI with cobalt chromium everolimus-eluting stentJapan1-month DAPT + 11-month P2Y12i monotherapyOpen-label, adjudicator-blindedSTOPDAPT-2 [29]ASA + clopidogrel (75 mg QD) or prasugrel (3.75 mg QD) for 1 month, followed by clopidogrel (75 mg QD) alone, vs. ASA + clopidogrel (75 mg QD) for 12 months1215001509
ACS onlyOpen-labelSTOPDAPT-2 ACS [30]20782091
Long-term P2Y12i Monotherapy
Landmark Trial
47% ACSPCI with DESInternational1-month DAPT + 23-month P2Y12i monotherapyOpen-label, adjudicator-blindedGLOBAL LEADERS [31]ASA + ticagrelor 90 mg BID for 1 month, followed by ticagrelor 90 mg BID alone for 23 months, vs. ASA + clopidogrel 75 mg QD (in sCAD patients) or ticagrelor 90 mg BID (in ACS patients) for 12 months, followed by ASA alone for 12 months 2479807988
GLASSY (GLOBAL LEADERS sub-study of top 20 enrolling sites) [32] 37943791
Asian Trial
72% ACS; had 6–18 months prior DAPTPCI Korea 24-month P2Y12i monotherapyOpen-label, adjudicator-blindedHOST-EXAM [33]24-month clopidogrel (75 mg QD) alone vs. ASA (100 mg QD) alone2427102728
Unguided De-escalation
European Trials
ACSPCIFrance1-month DAPT with ticagrelor or prasugrel + 11-month DAPT with clopidogrelOpen-label, adjudicator-blindedTOPIC [11]1-month ticagrelor (180 mg loading + 90 BID) or prasugrel (60 mg loading + 10 mg QD), followed by 11-month clopidogrel (75 mg), vs. 12-month ticagrelor or prasugrel 12322323
STEMIPCI with second generation
zotarolimus-eluting stent		Europe6-month DAPT (at baseline) + 6-month ASA monotherapyOpen-label, adjudicator-blindedDAPT-STEMI [8]ASA ± P2Y12i (prasugrel: 60 mg loading + 10 mg QD; ticagrelor: 180 mg loading + 90 mg BID; or clopidogrel: 600 mg loading + 75 mg QD) for 6 months18432438
Asian Trials
ACSPCI with durable or absorbable polymer DESKorea1-month DAPT + 11-month DAPT at reduced prasugrel doseOpen-label, adjudicator-blindedHOST-REDUCE POLYTECH-ACS [10]ASA + prasugrel (10 mg QD) for 1 month, followed by ASA + prasugrel (5 mg vs. 10 mg) for 11 months 1211701168
STEMI and NSTEMIPCI with DESKorea1-month DAPT with ticagrelor + 11-month DAPT with clopidogrelOpen-label, adjudicator-blindedTALOS-AMI [34]1-month ticagrelor (180 mg loading + 90 mg BID) + 11-month clopidogrel (75 mg QD), vs. 12-month ticagrelor (90 mg BID) 1213491348
82% ACSPCI with biodegradable polymer sirolimus-eluting stent China6-month DAPTAssessor-blindedI-LOVE-IT 2 [35]6-month v. 12-month DAPT with clopidogrel (300 mg loading + 75 mg QD)18909920
HBR Patients
HBR; 48% ACSPCI with biodegradable polymer sirolimus-eluting stentInternational1-month DAPTOpen-label, adjudicator-blindedMASTER-DAPT [36]1-month vs. ≥3-month DAPT (median: 193 days)335 days22952284
HBR; 35% ACSPCI with cobalt chromium everolimus-eluting stentInternational1- or 3-month DAPTOpen-label, adjudicator-blindedXIENCE Short DAPT [37]1-month vs. 3-month DAPT (3 single-arm studies)1213921972
Guided Escalation and De-escalation
European Trials
ACSPCI with stentFrancePFT-guided escalation or de-escalationOpen-label, adjudicator-blindedANTARTIC [38]DAPT with prasugrel (5 or 10 mg QD) or clopidogrel 75 mg QD (monitoring group), vs. prasugrel 5 mg QD (conventional group)12442435
ACSPCIEuropePFT-guided de-escalationOpen-label, adjudicator-blindedTROPICAL-ACS [39]DAPT with 1-week prasugrel (5 or 10 mg QD) + 1-week clopidogrel (75 mg QD) + PFT-guided prasugrel or clopidogrel, vs. prasugrel (5 or 10 mg)1213041306
STEMIPCI with stent The NetherlandsGenotype-guided APTOpen-label, adjudicator-blindedPOPular Genetics [40]DAPT with ticagrelor or prasugrel (CYP2C19 carriers) or clopidogrel (noncarriers), vs. ticagrelor or prasugrel (standard group)1212421246
Asian Trials
82% ACSPCIInternational (23% East Asians)Genotype-guided APTOpen-label, adjudicator-blindedTAILOR-PCI [41]Aspirin 81 mg + ticagrelor (CYP2C19 LOF carriers) or clopidogrel (noncarriers)12903 * 946 *
sCADPCI with DESChinaPFT-guided DAPTOpen-label, adjudicator-blindedPATH-PCI [42]DAPT with ticagrelor 90 mg BID (if maximum aggregation rate [MAR] > 55%) or 75 mg clopidogrel QD (if MAR ≤55%), vs. DAPT with clopidogrel 75 mg QD (standard group)611231114
Extended DAPT
Landmark Trials
43% ACSDES implantationInternational (91.2% Caucasian)30-month DAPTOpen-label, adjudicator-blindedDAPT [43]30-month vs. 12-month clopidogrel (75 mg QD) or prasugrel (5 or 10 mg QD)3050204941
Prior MI (1–3 years ago)83% had PCIInternational (86.6% Caucasian)3-year DAPTDouble-blindPEGASUS-TIMI 54 [7]Ticagrelor 90 mg BID vs. ticagrelor 60 mg BID vs. placebo367050 (90 mg)/7045 (60 mg)7067
sCAD and DM58% had PCIInternational (22.9% Asians)Long-term DAPTDouble-blindTHEMIS-PCI [44]Ticagrelor (90 mg until May 2015, then 60 mg) + ASA vs. ASA aloneMedian follow-up: 3.3 yearsPCI:
55585596
No PCI:
40614005
Long-term Anticoagulant + ASA
Landmark Trial
Stable atherosclerotic vascular disease (62% had previous MI)--International (12.6% Asians)Rivaroxaban + ASADouble-blindCOMPASS [45]Rivaroxaban 2.5 mg BID + ASA, vs. rivaroxaban 5 mg BID alone, vs. ASA aloneMean follow-up: 23 months (stopped for superiority of rivaroxaban + ASA combination)9152 (2.5 mg)/9117 (5 mg)9126
* Primary analysis (all CYP2C19 loss-of-function carriers). Abbreviations: ACS, acute coronary syndrome; ASA, aspirin; BID, twice daily; CABG, coronary artery bypass graft; DES, drug-eluting stent; DM, diabetes mellitus; HBR, high bleeding risk; MI, myocardial infarction; NSTE, non-ST elevation; P2Y12i, purinergic P2Y12 receptor inhibitor; PCI, percutaneous coronary intervention; PFT, platelet function test; QD, once daily; sCAD, stable coronary artery disease; STEMI, ST-elevation myocardial infarction.
Table
Table 3. Outcomes of major international and Asian randomized controlled trials investigating the efficacy and safety of popular antiplatelet therapy strategies.
Table 3. Outcomes of major international and Asian randomized controlled trials investigating the efficacy and safety of popular antiplatelet therapy strategies.
Trial NameMain Composite Ischemic Endpoint *Main Ischemic Outcome
(Experiment vs. Control) *		Main Bleeding Criteria *Main Bleeding Outcome
(Experiment vs. Control) *
Standard 1-year DAPT
CURE [18,25]CV death, MI, strokeASA ≤ 100 mg:
8.6% vs. 10.5%, RR = 0.81 (0.68–0.97)
ASA 101–199 mg: 9.5% vs. 9.8%, RR = 0.97 (N.S.)
ASA ≥ 200 mg: 9.8% vs. 13.6%, RR = 0.71 (0.59–0.85)		Significantly disabling, intraocular bleeding leading to significant loss of vision, or bleeding requiring transfusion of 2 or 3 units of red blood cells (or equivalent
whole blood).		3.7% vs. 2.7%, RR = 1.4 (1.1–1.7)
PLATO [19]Vascular death, MI, stroke9.8% vs. 11.7%, p < 0.001Fatal bleeding, intracranial bleeding, intrapericardial
bleeding with cardiac tamponade, hypovolemic shock or severe hypotension due to bleeding and requiring pressors or surgery, a decline in the hemoglobin level ≥ 5.0 g/dL, or requiring transfusion of ≥ 4 units of red cells.		11.6% vs. 11.2% (N.S.)
TRITON [20]CV death, MI, stroke9.9% vs. 12.1%, p < 0.001TIMI major2.4% vs. 1.8%, p = 0.03
PHILO [21]Vascular death, MI, stroke9.0% vs. 6.3% (N.S.) PLATO major10.3% vs. 6.8% (N.S.)
TICAKOREA [22]CV death, MI, stroke9.2% vs. 5.8% (N.S.)PLATO major + minor bleeding (clinically significant bleeding)11.7% vs. 5.3%, p = 0.002
PRASFIT-Practice II [23,24]CV death, MI, stroke, stent thrombosis1-year: 1.6%
2-year: 3.3%		TIMI major1-year: 1.0%
2-year: 2.7%
P2Y12i Monotherapy
TWILIGHT [9,26]All-cause death, MI, strokeNSTE-ACS: 4.3% vs. 4.4% (N.S.)
sCAD: 3.1% vs. 3.2% (N.S.)		BARC 2,3,5NSTE-ACS: 3.6% vs. 7.6%, p < 0.001
sCAD: 4.8% vs. 6.2% (N.S.)
TICO [27]Death, MI, stroke, stent thrombosis, target-vessel revascularization2.3% vs. 3.4% (N.S.)TIMI major1.7% vs. 3.0%, p = 0.02
SMART-CHOICE [28]All-cause death, MI, stroke2.9% vs. 2.5%, p = 0.007 for noninferiorityBARC ≥ 22.0% vs. 3.4%, p = 0.02
STOPDAPT-2 [29]CV death, MI, stroke, stent thrombosis2.0% vs. 2.5%, p = 0.005 for noninferiorityTIMI major and minor0.4% vs. 1.5%, p = 0.004 for superiority
STOPDAPT-2 ACS [30]2.8% vs. 1.9%, HR = 1.50 (0.99–2.26)0.5% vs. 1.2%, HR = 0.46 (0.23–0.94)
Long-term P2Y12i Monotherapy
GLOBAL LEADERS [31]All-cause death, MI3.8% vs. 4.4% (N.S.)BARC 3,52.0% vs. 2.1% (N.S.)
GLASSY (GLOBAL LEADERS sub-study of top 20 enrolling sites) [32]All-cause death, MI, stroke, urgent revascularization7.1% vs. 8.5%, p < 0.001 for noninferiorityBARC 3,52.5% vs. 2.5% (N.S.)
HOST-EXAM [33]All-cause death, MI, stroke, re-admission to due ACS3.7% vs. 5.5%, p = 0.003BARC ≥ 31.2% vs. 2.0%, p = 0.035
Unguided De-escalation
TOPIC [11]CV death, stroke, urgent revascularization9.3% vs. 11.5% (N.S.)BARC ≥ 24% vs. 14.9%, p < 0.01
DAPT-STEMI [8]Net clinical benefit composite (all-cause death, MI, stroke, revascularization, TIMI major bleeding):
4.8% vs. 6.6%, p = 0.004 for noninferiority
HOST-REDUCE POLYTECH-ACS [10]CV death, MI, ischemic stroke, stent thrombosis1.4% vs. 1.8% (N.S.)BARC ≥ 22.9% vs. 5.9%, p < 0.0007
TALOS-AMI [34]CV death, MI, stroke2.1% vs. 3.1% (N.S.)BARC 2,3,53.0% vs. 5.6%, p = 0.001
I-LOVE-IT 2 [35]Net adverse clinical and cerebral events composite (all-cause death, MI, stroke, BARC ≥ 3 bleeding):
12-month: 7.2 vs. 6.4% (N.S.)
18-month: 7.8% vs. 7.3% (N.S.)
MASTER-DAPT [36]All-cause death, MI, stroke6.0% vs. 6.1% (N.S.)BARC 2,3,56.5% vs. 9.4%, p < 0.001 for suepriority
XIENCE Short DAPT [37]All-cause death or MI1–12 months: 7.3% vs. 7.5% (N.S)BARC ≥ 21–12 months: 7.6% vs. 10.0%, p = 0.012
Guided Escalation and De-escalation
ANTARTIC [38]CV death, MI, stroke, stent thrombosis, urgent revascularization9% vs. 10% (N.S.)BARC 2,3,520% vs. 21% (N.S.)
TROPICAL-ACS [39]CV death, MI, stroke3% vs. 3%, p = 0.01 for noninferiorityBARC ≥ 25% vs. 6% (N.S.)
POPular Genetics [40]all-cause death, MI, stroke, stent thrombosis2.7% vs. 3.3% (N.S.)PLATO9.8% vs. 12.5%, p = 0.04
TAILOR-PCI [41]CV death, MI, stroke, stent thrombosis, severe recurrent ischemia4.0% vs. 5.9%, p = 0.06 (N.S.)TIMI major and minor1.9% vs. 1.6% (N.S.)
PATH-PCI [42]Net clinical adverse events composite (cardiac death, MI, stroke, stent thrombosis, urgent revascularization, BARC 2,3,5 bleeding):
5.1% vs. 7.5%, p = 0.023
Extended DAPT
DAPT [43]All-cause death, MI, stroke4.3% vs. 5.9%, p < 0.001GUSTO moderate or severe2.5% vs. 1.6%, p = 0.001
PEGASUS-TIMI 54 [7]CV death, MI, stroke7.85% vs. 7.77% vs. 9.04%
Ticagrelor 90 mg vs. placebo: p = 0.008
Ticagrelor 60 mg vs. placebo: p = 0.004		TIMI major2.60% vs. 2.30% vs. 1.06%, p < 0.001 for each dose vs. placebo
THEMIS-PCI [44]CV death, MI, strokePCI group:
7.3% vs. 8.6% (p = 0.013)
No PCI group:
8.2% vs. 8.4% (N.S.) 		TIMI majorPCI group:
2.0% vs. 1.1%, p < 0.0001
No PCI group:
2.4% vs. 1.0%, p < 0.0001
Long-term Anticoagulant + ASA
COMPASS [45]CV death, MI, stroke4.1% vs. 4.9% vs. 5.4%
Rivaroxaban + ASA vs. ASA alone: p < 0.001
Rivaroxaban alone vs. ASA alone: N.S.		Modified ISTH, including fatal bleeding, symptomatic bleeding into a critical organ, bleeding into a surgical site requiring reoperation, and bleeding that led to hospitalization (including presentation to an acute care facility without an overnight stay)3.1% vs. 2.8% vs. 1.9%
Rivaroxaban + ASA vs. ASA alone: p < 0.001
Rivaroxaban alone vs. ASA alone: p < 0.001
* Main ischemic and bleeding outcomes are listed here separately for easier reading. However, some studies use a combined ischemic and bleeding endpoint for the primary outcome, and/or do not report ischemic and bleeding outcomes separately. Abbreviations: ACS, acute coronary syndrome; ASA, aspirin; BARC, Bleeding Academic Research Consortium; CV, cardiovascular; GUSTO, Global Use of Streptokinase and Tissue plasminogen activator to Open occluded coronary arteries; HR, hazard ratio; ISTH, International Society on Thrombosis and Haemostasis; MI, myocardial infarction; N.S., non-significant; NSTE, non-ST elevation; P2Y12i, purinergic P2Y12 receptor inhibitor; PCI, percutaneous coronary intervention; PLATO, Study of Platelet Inhibition and Patient Outcomes; RR, relative risk; sCAD, stable coronary artery disease; TIMI, Thrombolysis in Myocardial Infarction.
Table
Table 4. Common (a) ischemic and (b) bleeding risk factors for patients with coronary artery disease (CAD) receiving antiplatelet therapy (APT).
Table 4. Common (a) ischemic and (b) bleeding risk factors for patients with coronary artery disease (CAD) receiving antiplatelet therapy (APT).
(a) Ischemic Risks
ReferenceESC 2020 [80]DAPT [81]
Organ System
CardiovascularRecurrent MIMI at presentation
Multivessel diseasePrior PCI or MI
Multiple stents or treated lesionsPaclitaxel-eluting stent
Complex revascularization (e.g., left main, bifurcation with ≥2 stents, chronic total occlusion, stented last patent vessel)Narrow stent (<3 mm diameter)
History of stent thrombosisVein graft stent *
Early onset or aggressive CADCongestive heart failure, * or left ventricular ejection fraction <30% *
Peripheral arterial disease
KidneyModerate or severe CKD
Physical Condition
Systemic ConditionDiabetes mellitusDiabetes mellitus
Systemic inflammatory diseases (e.g., HIV infection, systemic lupus erythematosus, chronic arthritis)
Lifestyle Smoking (within 1 year)
Age >65 years
>75 years *
(b) Bleeding Risks
ReferenceARC-HBR † [60]PRECISE-DAPT [82]CARDIAC [79]
MajorMinor
Organ System
BloodSpontaneous bleeding requiring hospitalization or transfusion (past 6 months, or recurrent)Non-major spontaneous bleeding requiring hospitalization or transfusion (past 12 months)Previous bleedingHemoglobin ↓ from lowest value during hospital stay for PCI
Hemoglobin <11 g/dLHemoglobin 11 − <13 g/dL in men, or 11 − <12 g/dL in womenHemoglobin <12 g/dLHemoglobin <12 g/dL
Moderate-to-severe thrombocytopeniaWhite blood cell count ≥ 5 × 103 cells/μL
Chronic bleeding diathesis
BrainModerate or severe ischemic stroke (past 6 months)Non-major ischemic stroke
Traumatic (past 12 months) or spontaneous (anytime) intracranial hemorrhage
KidneySevere CKDModerate CKDeGFR ≤ 100 mL/min/1.73 m2eGFR ≤ 60 mL/min/1.73 m2
LiverLiver cirrhosis with portal hypertension
Physical Condition
SurgeryMajor surgery or trauma (< 30 days before PCI)
Major surgery while on APT
Systemic ConditionMalignancy (past 12 months)
Co-medicationLong-term oral anticoagulant useLong-term oral NSAID or steroid use
Age ≥75 years≥50 years ≥50 years
* Further increased risk. † A patient is considered to be at HBR when fulfilling ≥1 major or ≥2 minor criteria. Abbreviations: CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; HIV, human immunodeficiency virus; MI, myocardial infarction; NSAID, non-steroidal anti-inflammatory drug; PCI, percutaneous coronary intervention. “↓”, decrease.
Table
Table 5. Key patient considerations for reducing antiplatelet therapy (APT) duration.
Table 5. Key patient considerations for reducing antiplatelet therapy (APT) duration.
CategoryKey ConsiderationCovered in this Review
Section (s)Illustration
Ischemic and Bleeding Risk Factors
BaselineDoes the patient meet high bleeding risk (HBR) criteria? *5.1, 5.2Table 4
Medium-term (1–12 months)Will the patient’s bleeding risk exceed his/her ischemic risk soon? * 2Figure 2
Pharmacological Factors
Platelet ReactivityIs platelet reactivity within normal range? * 5.3 (ABCD-GENE score, genotyping, and/or platelet reactivity test may be useful)--
Drug–drug InteractionsIs any concurrent medication (present or future) affecting platelet reactivity? †5.4--
* “Yes” may favor reducing APT duration. † May increase or decrease APT effects.
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Tam, C.-C.; Tse, H.-F. Antiplatelet Therapy Aims and Strategies in Asian Patients with Acute Coronary Syndrome or Stable Coronary Artery Disease. J. Clin. Med. 2022, 11, 7440. https://doi.org/10.3390/jcm11247440

AMA Style

Tam C-C, Tse H-F. Antiplatelet Therapy Aims and Strategies in Asian Patients with Acute Coronary Syndrome or Stable Coronary Artery Disease. Journal of Clinical Medicine. 2022; 11(24):7440. https://doi.org/10.3390/jcm11247440

Chicago/Turabian Style

Tam, Chor-Cheung, and Hung-Fat Tse. 2022. "Antiplatelet Therapy Aims and Strategies in Asian Patients with Acute Coronary Syndrome or Stable Coronary Artery Disease" Journal of Clinical Medicine 11, no. 24: 7440. https://doi.org/10.3390/jcm11247440

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