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Korean Circulation Journal logoLink to Korean Circulation Journal
. 2018 Jun 20;48(7):537–551. doi: 10.4070/kcj.2018.0166

The Evolving Concept of Dual Antiplatelet Therapy after Percutaneous Coronary Intervention: Focus on Unique Feature of East Asian and “Asian Paradox”

Jeehoon Kang 1, Hyo-Soo Kim 1,✉
PMCID: PMC6031716  PMID: 29968428

Abstract

Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor is essential after percutaneous coronary intervention (PCI), while many studies have focused on determining the optimal degree of platelet inhibition and optimal DAPT duration to minimize complications after PCI. Current guidelines developed by the American College of Cardiology/American Heart Association and the European Society of Cardiology summarize previous studies and provide recommendations. However, these guidelines are mainly based on Western patients, and their characteristics might differ from those of East Asian patients. Previous data suggested that East Asian patients have unique features with regard to the response to antiplatelet agents. On comparing Western and East Asian patients, it was found that East Asian patients have a lower rate of ischemic events and higher rate of bleeding events after PCI, despite a higher on-treatment platelet reactivity, which is referred to as the “East Asian paradox.” As the main purpose of DAPT is to minimize ischemic and bleeding complications after PCI, these differences should be clarified before adopting the guidelines for East Asian patients. Therefore, in this article, we will review various issues regarding DAPT in East Asian patients, with a focus on the unique characteristics of East Asian patients, previous studies regarding antiplatelet agents in East Asian patients, and a guideline from an East Asian perspective.

Keywords: Dual antiplatelet therapy, Percutaneous coronary intervention, East Asians, Ischemic risk, Bleeding risk

INTRODUCTION

Optimal medical treatment after percutaneous coronary intervention (PCI) has been an important issue since the first coronary angioplasty performed by Andreas Gruentzig in 1977. Medical treatment is provided to decrease the incidence of acute and chronic complications, such as restenosis and stent thrombosis, after PCI. The superiority of dual antiplatelet therapy (DAPT) over anticoagulation was initially demonstrated in a randomized clinical trial (RCT),1) and subsequently, many studies have focused on refining DAPT strategies. The primary drug in DAPT is aspirin (an adenosine diphosphate receptor antagonist), and combinations with various P2Y12 inhibitors have been studied to reduce thrombotic complications. The initial P2Y12 inhibitor ticlopidine was replaced by clopidogrel owing to adverse effects, such as neutropenia and thrombotic thrombocytopenic purpura.2) Subsequently, there were issues regarding the optimal dosage and duration of DAPT involving aspirin and clopidogrel, and long-term DAPT (>12 months) was found to help in the secondary prevention of ischemic events.3),4) Later, more potent P2Y12 inhibitors, such as prasugrel and ticagrelor, were introduced to achieve greater platelet inhibition, decrease inter-individual variability in platelet inhibition, and reduce thrombotic complications. However, high platelet inhibition was often associated with an increased bleeding risk. Thus, there is a trade-off between decreasing ischemic risk and increasing bleeding risk. Meanwhile, there is a lower need for stronger platelet inhibition in the current PCI population when compared to that in the PCI population a decade ago. Advances in current PCI devices, including new-generation stents, have reduced the risk of stent thrombosis, and more patients with a high bleeding risk are being treated with PCI, leading to a shorter DAPT duration.

The DAPT issue is a current topic in the East Asian population owing to their unique racial characteristics that are distinct from those of Westerners. However, current guidelines are mostly based on Western trials performed in the Western population.5),6) This discrepancy has led to confusion among East Asian physicians and low adherence to the current guidelines. For example, data from the Korean Health Insurance Review and Assessment Service indicated that new-generation P2Y12 inhibitors (prasugrel and ticagrelor) were used in only 40% of the acute myocardial infarction (AMI) population, despite the fact that these agents are recommended over clopidogrel for patients with AMI in the current guidelines.7)

Therefore, in this review, we will discuss various issues regarding DAPT in East Asian patients. Specifically, we will discuss topics, including clopidogrel usage in East Asian patients, the unique characteristics of East Asian patients, new-generation antiplatelet agents in East Asian patients, and the optimal DAPT duration according to current risk scores for DAPT duration. Finally, we will discuss the need for East Asian-specific guidelines according to the results of a dedicated Asian study.

CLOPIDOGREL IN EAST ASIAN PATIENTS

The benefit of clopidogrel as a key drug in DAPT for acute coronary syndrome (ACS) was established by the CURE, COMMIT, and CLARITY trials.8),9),10) Clopidogrel combined with aspirin could reduce the incidence of 1-year clinical events by up to 20% when compared to the incidence with single antiplatelet therapy using aspirin. Later, DAPT involving aspirin and clopidogrel was included in the guidelines as a mandatory treatment. However, some patients still presented with ischemic outcomes after PCI. Thus, studies focused on individual heterogeneity with regard to the responsiveness to clopidogrel. Clopidogrel is a prodrug that needs to be converted into active metabolites by the hepatic cytochrome P450 (CYP) system before it irreversibly binds to the P2Y12 receptor and inhibits platelet aggregation (Figure 1).11) Therefore, genetic polymorphisms of the CYP system may affect the conversion of clopidogrel into active metabolites. Various mutations of CYP2C19, CYP3A4/5,12) CYP1A2, and CYP2B6 are known to decrease clopidogrel activity and increase the risk of cardiovascular events.13)

Figure 1. Mechanism of clopidogrel activation and representative candidate genes involved each step.

Figure 1

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CYP = cytochrome P450.

In addition, many studies have suggested that East Asians might have a distinct response to clopidogrel owing to their unique profile of CYP polymorphisms. We previously reported that the mean on-treatment platelet reactivity in 1,431 consecutive Korean patients was 241.9±70.3 P2Y12 reaction units (PRU), which is significantly higher than that in previous reports from Western countries.14) Similar findings have been reported in Japanese and Chinese patients, indicating that this may be related with racial characteristics.15),16) One of the proposed mechanisms of clopidogrel hypo-responsiveness in East Asians is associated with polymorphism of the CYP2C19 gene, which has a role in the hepatic activation of clopidogrel. Overall, approximately 60% of East Asians have CYP2C19 loss-of-function alleles (*2 allele, *3 allele), while only 30% of Caucasians have these alleles.17) In various previous clinical studies, including our study, the cut-off value for ‘high on-treatment platelet reactivity’ was greater in East Asian patients than in Caucasian patients.18),19),20)

Various attempts have been made to overcome clopidogrel hypo-responsiveness. High-dose clopidogrel (150 mg/day) was evaluated in the OPTIMUS study for high-risk patients with type 2 diabetes mellitus21) and in the CURRENT-OASIS RCT for ACS patients. In the CILON-T study, triple antiplatelet therapy (aspirin, clopidogrel, and cilostazol) was compared with DAPT.18) These studies showed greater reduction in platelet reactivity with additional therapy. There was an association between greater platelet inhibition and less ischemic events; however, the reduction in ischemic events by the intensified regimens did not reach statistical significance probably because of the insufficient number of patients. In the HOST-ASSURE RCT, 2 different intensified antiplatelet regimens for 1 month were compared (double-dose clopidogrel with aspirin versus triple agents [DAPT and cilostazol]).22) The PRU value was lower and the incidence of ischemic events tended to be lower for triple agents than for double-dose clopidogrel on top of aspirin. Both regimens were comparable and very effective for reducing target lesion failure rate to less than 3% at 1 year with a contemporary drug-eluting stent (DES). Thus, such intensified regimens for 1 month may be beneficial in patients undergoing PCI, who have high risks of thrombosis and bleeding.

Many studies have been performed to examine whether platelet function monitoring and genetic testing might be able to identify patients with a high risk of ischemic outcomes, which may allow appropriate modification of DAPT. However, unexpectedly, all randomized trials failed to demonstrate any benefit of platelet function monitoring.23),24),25),26) Therefore, currently, platelet function testing and genetic testing are not recommended for tailoring DAPT according to patient characteristics.5)

UNIQUE CHARACTERISTICS OF EAST ASIANS AND THE ASIAN PARADOX

According to the abovementioned studies, the frequency of clopidogrel hypo-responsiveness is known to be greater in East Asian patients than in Caucasian patients. Many trials have shown that clopidogrel hypo-responsiveness is a strong and independent risk factor for post-PCI thrombotic complications.12),19),27),28) However, East Asian patients are known to have less thrombotic events and more bleeding events when compared to the findings in Caucasian patients. This concept was termed the “Asian Paradox,” which led to the suggestion of different thresholds of platelet reactivity between East Asian and Caucasian patients.17) The Asian paradox is not the first concept to suggest a racial difference in the ischemic/bleeding threshold between East Asian and Caucasian patients. Shen et al.29) reported that Asian patients with atrial fibrillation were at greater risk for warfarin-related intracranial hemorrhage, and Mak et al.30) reported that the Asian ethnicity was an independent predictor of moderate bleeding complications in the CHARISMA trial. Moreover, a patient-level meta-analysis of seven RCTs suggested that prolonged DAPT was a significant predictor of bleeding complications in only the East Asian population (Figure 2).31)

Figure 2. Ischemic and bleeding events according to prolonged versus short DAPT in East Asians and Westerners. Absolute frequency of ischemic events was half in Asians than Caucasians, while incidence of bleeding was 2-times in Asians than Caucasians. Prolonged DAPT failed to reduce ischemic events in both Asians and Caucasians, while increased bleeding events, remarkably in East Asian patients. This figure was modified from the original version.31).

Figure 2

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DAPT = dual antiplatelet therapy.

There are some plausible explanations for these findings. First, the unique demographics, comorbidities, and disease patterns of East Asian patients can potentially influence the different responses to antiplatelet agents.32) Particularly, East Asians have a low body mass index, and it has been shown that a high body mass index is associated with a hypercoagulable state.33) Second, genetic polymorphisms of thrombosis-related factors (i.e., factor V Leiden [G1691A] and prothrombin G20210A gene), different levels of hemostatic factors (i.e., fibrinogen, D-dimer, and factor VIII), and differences in plasma endothelial activation markers (i.e., von Willebrand factors, ICAM-1, and E-selectin) might contribute to the racial differences in thrombogenicity.17) According to these findings, in a consensus statement paper from the World Heart Federation, Levine et al.34) stated that the risk profiles for both ischemia and bleeding differ between East Asian patients and Caucasian patients and that a different “therapeutic window” of on-treatment platelet reactivity might be appropriate for East Asian patients.

NEW-GENERATION ANTIPLATELET AGENTS IN EAST ASIAN PATIENTS

To overcome the limitations of clopidogrel, 2 new-generation P2Y12 inhibitors (prasugrel and ticagrelor) have been introduced. The TRITON-TIMI 38 study was a landmark trial comparing prasugrel to clopidogrel in ACS patients undergoing PCI.35) This study showed that prasugrel decreased the incidence of adverse cardiovascular events (primary endpoint: hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.73–0.90), but increased the incidence of bleeding events, especially in elderly patients, patients with a low body weight, and those with a history of stroke. Subsequent sub-studies confirmed the mortality benefit of prasugrel in various populations,36),37) and some nationwide studies revealed the favorable effects of prasugrel on mortality.38) The other P2Y12 inhibitor ticagrelor significantly reduced the incidence of the primary ischemic endpoint (HR, 0.84; 95% CI, 0.77–0.92) with no increase in major bleeding events in the PLATO study.39) The beneficial effects of ticagrelor on mortality have been consistently confirmed in sub-studies40),41),42) and in registry-based studies.43) Based on the findings of these studies, prasugrel and ticagrelor were included in the current guidelines and were recommended for patients with ACS.5) However, it should be noted that the effects of these new-generation P2Y12 inhibitors have not been clearly clarified in East Asian patients. Kang et al.44) analyzed the East Asian subset of the PLATO trial and showed consistent beneficial effects of ticagrelor in East Asian patients. However, only 551 East Asian patients were analyzed, and the results showed a similar trend for the East Asian population and the Western population, without statistical significance. Additionally, Goto et al.45) performed an RCT on ticagrelor in Japanese ACS patients and found that ticagrelor did not reduce the incidence of ischemic outcomes and increased the bleeding risk. We previously performed a retrospective analysis of a nationwide cohort of Korean AMI patients and found that the new P2Y12 inhibitors were associated with a significantly higher bleeding risk (aspirin plus prasugrel vs. aspirin plus clopidogrel: HR, 2.14; 95% CI, 1.53–2.99; p<0.001; aspirin plus ticagrelor vs. aspirin plus clopidogrel: HR, 2.26; 95% CI, 1.73–2.95; p<0.001), with no decrease in the incidence of thrombotic events (Figure 3).32) Saito et al.46) confirmed the efficacy and safety of prasugrel in Japanese ACS patients, but the authors used a lower dose than that mentioned in the current guidelines (20 mg loading dose and 3.75 mg maintenance dose). Additionally, a recent study based on the Health Insurance Review and Assessment Service Korean database showed that the new-generation P2Y12 inhibitors had favorable effects on 30-day mortality in AMI patients undergoing PCI.7) However, this was a limited study owing to the lack of information in the nationwide database (data on the predictors of acute complications, such as clinical presentation, left ventricular function, angiographic disease extent, and medication, were not available). Collectively, previous studies failed to provide concrete evidence for the beneficial effects of the new-generation P2Y12 inhibitors in East Asian patients. Before the current guidelines are adopted, we should consider the unique features of East Asian patients in terms of the ischemic/bleeding threshold.

Figure 3. Results from a retrospective analysis of a nationwide cohort of Korean AMI patients. During a 1-year follow-up period after index PCI, ischemic outcomes and bleeding outcomes were analyzed. Compared with clopidogrel (AC), new generation P2Y12 receptor inhibitors prasugrel (AP) and ticagrelor (AT) could not decrease ischemic outcomes, while significantly increased bleeding outcomes. Consistent results were shown in multivariate cox regression analysis, propensity score matching analysis, inverse probability weighted regression analysis, and pooled analysis after multiple imputation. This figure was modified from the original version.32).

Figure 3

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AMI = acute myocardial infarction; CI = confidence interval; DAPT = dual antiplatelet therapy; HR = hazard ratio; MACCE = major adverse cardiac and cerebral events; PCI = percutaneous coronary intervention.

PREVIOUS CLINICAL STUDIES ON OPTIMAL DAPT DURATION

Although DAPT is essential after PCI, the optimal DAPT duration has not been established. In the DES era, 14 large-scale RCTs have compared the efficacy and safety of long-term and short-term DAPT (Table 1). Among these studies, 6 RCTs compared long-term DAPT (24–48 months) to short-term DAPT (6–12 months) in order to determine the efficacy and safety of extended therapy.47),48),49),50),51),52) These studies reported that long-term DAPT reduced late and very late stent thromboses and prevented ischemic events in other non-stented sites. The Dual Antiplatelet Therapy study was the largest trial in which patients without ischemic or bleeding events during the initial 12 months after PCI were randomized to receive additional DAPT for 18 months or to receive aspirin monotherapy.50) Extended DAPT resulted in a 1.0% absolute reduction in stent thrombosis, a 1.6% absolute reduction in major adverse cardiac events, and a 0.9% absolute increase in moderate or severe bleeding events.

Table 1. Current large-scale RCTs comparing the efficacy and safety of long-term and short-term DAPT.

Study Study performed nation Year DAPT duration and Patient number Trial design Primary endpoint Result
EXCELLENT East Asia (Korea) 2012 6 months (n=722), 12 months (n=721) Non-inferiority Cardiac death/MI/Ischemia driven TVR Non-inferiority of 6 months DAPT demonstrated
RESET East Asia (Korea) 2012 3 months (n=1,059), 12 months (n=1,058) Non-inferiority Cardiac death/MI/ST/TVR/Major bleeding Non-inferiority of 3 months DAPT demonstrated
DES-LATE East Asia (Korea) 2014 12 months (n=2,514), 24 months (n=2,531) Equivalence Cardiac death/MI/Stroke Equal effect of 12 months and 24 months DAPT
I-LOVE-IT2 East Asia (China) 2016 6 months (n=909), 12 months (n=920) Non-inferiority Cardiac death/TVMI/Ischemia driven TLR Non-inferiority of 6 months DAPT demonstrated
IVUS-XPL East Asia (Korea) 2016 6 months (n=699), 12 months (n=701) Equivalence Cardiac death/MI/Stroke/Major bleeding Equal effect of 6 months and 12 months DAPT
NIPPON East Asia (Japan) 2016 6 months (n=1,886), 18 months (n=1,887) Non-inferiority Death/MI/Stroke/Major bleeding Non-inferiority of 6 months DAPT demonstrated
PRODIGY Europe 2012 6 months (n=751), 24 months (n=750) Superiority Death/MI/Stroke Superiority of 24 months DAPT was not demonstrated
OPTIMIZE South America 2013 3 months (n=1,563), 12 months (n=1,556) Non-inferiority Death/MI/Stroke/Major bleeding Non-inferiority of 3 months DAPT demonstrated
ARCTIC INT Europe 2014 12 months (n=624), 24 months (n=635) Superiority Death/MI/ST/Stroke/Urgent revascularization Superiority of 24 months DAPT was not demonstrated
DAPT America, Australia, Europe 2014 12 months (n=4,941), 30 months (n=5,020) Superiority ST and All cause death/MI/Stroke Superiority of 30 months DAPT was demonstrated
SECURITY Europe 2014 6 months (n=682), 12 months (n=1,717) Non-inferiority Cardiac death/MI/ST/Stroke/Major Bleeding Non-inferiority of 6 months DAPT demonstrated
ISAR-SAFE Europe 2015 6 months (n=1,997), 12 months (n=2,003) Non-inferiority Death/MI/ST/Stroke/Major bleeding Non-inferiority of 6 months DAPT demonstrated (premature termination)
ITALIC Europe, Middle East 2015 6 months (n=953), 24 months (n=941) Non-inferiority Death/MI/TVR/Stroke/Major bleeding Non-inferiority of 6 months DAPT demonstrated
OPTIDUAL Europe 2016 12 months (n=690), 48 months (n=695) Superiority Death/MI/Stroke/Major bleeding Superiority of 48 months DAPT was not demonstrated
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DAPT = dual antiplatelet therapy; MI = myocardial infarction; RCT = randomized clinical trial; ST = stent thrombosis; TLR = target lesion revascularization; TVMI = target vessel myocardial infarction; TVR = target vessel revascularization.

On the other hand, eight RCTs compared short-term DAPT (3–6 months) to long-term DAPT (12–18 months) in order to determine the efficacy and safety of reduced-duration DAPT.53),54),55),56),57),58),59),60) These studies were mostly designed as non-inferiority trials, and they confirmed the safety of short-term DAPT. The EXCELLENT trial was the first RCT to compare short-term and long-term DAPT, and it showed that 6-month DAPT did not increase the risk of target vessel failure at 12 months after DES implantation when compared to the finding with 12-month DAPT.53)

Interestingly, a weighted risk-benefit analysis and systemic review of previous RCTs performed by the Evidence Review Committee reported that prolonged DAPT decreased the incidences of myocardial infarction by 6 per 1,000 patients and stent thrombosis by 3 per 1,000 patients, but increased the incidence of major bleeding events by 5 per 1,000 patients. With regard to reduced-duration DAPT, there were no increased risks of stent thrombosis and fewer bleeding complications.61)

Among these RCTs, a difference in design can be noted, reflecting the different needs of short DAPT between Eastern and Western populations. Five out of 6 RCTs in East Asian countries compared short-term DAPT (3–6 months) to long-term DAPT (12–18 months). However, in Western countries, 3 (OPTIMIZE, SECURITY, and ISAR-SAFE) out of 8 RCTs evaluated the safety of short-term DAPT (3–6 months) (Table 1). Collectively, we can assume that there is a greater need for short-term DAPT (less than 12 months) in East Asian patients than in Western patients.

WESTERN RISK SCORES TO DETERMINE DAPT DURATION

The recent trend of DAPT is based on the concept of “one size does not fit all.”62) Until now, three scoring systems have been used to assess the ischemic/bleeding risk in the PCI population (the PARIS score, PRECISE-DAPT score, and DAPT score), and the current guidelines recommend using 2 specific scores to assess the appropriate DAPT duration (the PRECISE-DAPT and DAPT scores).6),63) However, these scores have limitations that should be considered. First, the PRECISE-DAPT score only evaluates bleeding risk to determine DAPT duration. However, as a high bleeding risk does not warrant a low ischemic risk, both the bleeding and ischemic risks should be considered when deciding the optimal DAPT duration. Second, the DAPT score was developed in a DAPT study, which involved a population free from clinical events within the first 12 months after PCI.50) Therefore, this score should be used to decide whether an individual should continue DAPT beyond 1 year after PCI. Furthermore, this scoring system was derived from the findings of a RCT that included vein graft PCI and paclitaxel-eluting stents, which are not applicable in the new-generation DES era. Moreover, both scoring systems were mainly developed in Western patients, who showed an ischemic/bleeding threshold different from that in real-world East Asian patients. Table 2 presents a brief overview of the current scores.

Table 2. Currently used scoring systems in deciding the optimal DAPT duration.

PARIS score DAPT score PRECISE DAPT score
Derivation cohort 4,190 patients from the PARIS (Patterns of Non-Adherence to Anti-Platelet Regimen in Stented Patients) registry 11,648 patients from the DAPT trial 14,963 patients from 8 contemporary multicenter randomized clinical trials
Validation cohort ADAPT-DES (Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents) registry Patient-Related Outcomes With Endeavor vs. Cypher Stenting (PROTECT) trial The PLATelet inhibition and patient Outcomes (PLATO) trial
Settings Patients who received PCI and are on DAPT Patients who received PCI and were event free for 12 months Patients who received PCI and are on DAPT
Variables Coronary thrombotic risk score: 6 clinical variables 5 clinical, 3 procedural variables 5 clinical variables
- Diabetes mellitus - Age - Age
- Acute coronary syndrome - Current smoking - Prior bleeding event
- Current smoking - Diabetes mellitus - Creatinine clearance
- Creatinine clearance <60 mL/min - MI at presentation - Hemoglobin level
- Prior PCI - Prior PCI or MI - WBC count
- Prior CABG - Congestive heart failure or LVEF <30%
Major bleeding risk score: 6 clinical variables - Paclitaxel-eluting stent
- Age - Stent diameter <3 mm
- Body mass index - Vein graft stent
- Current smoking
- Anemia
- Creatinine clearance <60 mL/min
- Triple antiplatelet therapy on discharge
Score range Coronary thrombotic risk score: 0 to 15 points −2 to 10 points 0 to 100 points
Major bleeding risk score: 0 to 12 points
Predicted outcome Ischemic/Bleeding endpoints at 24 months after PCI Ischemic/Bleeding endpoints between 12–30 months Bleeding events at 12 months after PCI
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CABG = coronary artery bypass grafting; DAPT = dual antiplatelet therapy; LVEF = left ventricular ejection fraction; MI = myocardial infarction; PCI = percutaneous coronary intervention; WBC = white blood cell.

Based on these findings, we propose the need for an East Asian-specific scoring system that fulfills the following requirements. First, the system should consider the unique characteristics of East Asian patients. The bleeding risk is higher and ischemic risk is lower in East Asian patients than in Western patients,17),34) and these differences should be reflected in the scoring system. Second, the system should be applicable to real-world East Asian PCI populations using new-generation DESs. New-generation DESs have been shown to be safer than previous-generation DESs or even BMSs with regard to restenosis and thrombotic complications,64) and therefore, the DAPT duration may be shortened. Third, both ischemic and bleeding risks should be considered to evaluate the overall ischemic/bleeding risk of an individual. A high bleeding risk does not necessarily indicate a short DAPT duration, as a high bleeding risk frequently overlaps with a high thrombotic risk. The benefit of DAPT after evaluating the possibility of ischemic and bleeding events should be considered. Moreover, the scoring system should assess the optimal DAPT duration immediately after PCI.

CONCEPT OF HIGH BLEEDING RISK AND ULTRA-SHORT DAPT

After the inclusion of DAPT with aspirin plus clopidogrel in the guidelines as a mandatory treatment, 2 groups with regard to DAPT duration have emerged. The first group places emphasis on the prevention of stent thrombosis and progressive atherothrombosis with long-term DAPT, while the second group places emphasis on the reduction in the risk of bleeding events with short-term DAPT. This debate on DAPT duration has led to the concept of personalized medicine, where the risks of ischemia and bleeding in a particular individual are considered when deciding the optimal DAPT duration. However, the current general trend is moving toward shortening the mandatory DAPT duration. Particularly, after the LEADERS FREE trial confirmed the safety and efficacy of ultra-short DAPT (1 month) in patients with high bleeding risk,65) many trials are being conducted to confirm the safety of short-term DAPT in high bleeding risk subsets. These trials are in line with improvements in PCI devices and techniques, which have reduced the thrombotic risk associated with devices implanted in the coronary artery. Trials, such as the MASTER DAPT trial (Trial registry at ClinicalTrials.gov: NCT03023020), EVOLVE Short trial (NCT02605447), XIENCE Short trial (NCT03218787), Onyx ONE trial (NCT03344653), and COBRA-REDUCE trial (NCT02594501) will soon provide information on the efficacy and safety of 1-month DAPT in the contemporary DES era. The criteria for high bleeding risk in each on-going trial are shown in Table 3.

Table 3. The criteria for ‘high-bleeding risk’ of each on-going trial.

Criteria for high bleeding risk Primary endpoint
MASTER DAPT trial (NCT03023020) At least 1 of the pre-specified criteria, including 1. NACE defined as a composite of all-cause death, MI, stroke and BARC 3/5 bleeding events (at 11 months)
1. Clinical indication for treatment with oral anticoagulants for at least 12 months 2. MACCE defined as a composite of all-cause death, myocardial infarction and stroke (at 11 months)
2. Recent (<12 months) non-access site bleeding episodes, which required medical attention 3. Major or clinically relevant non-major bleeding defined as a BARC type 2, 3 and 5 BARC bleeding events (at 11 months)
3. Previous bleeding episodes which required hospitalization if the underlying cause has not been definitively treated
4. Age equal or greater than 75 years
5. Systemic conditions associated with an increased bleeding risk (e.g., hematological disorders, thrombocytopenia), or any known coagulation disorder
6. Documented anemia (hemoglobin <11 g/dL) or transfusion within 4 weeks before randomization
7. Need for chronic treatment with steroids or NSAIDs
8. Diagnosed malignancy (other than skin) considered at high bleeding risk including gastrointestinal, genitourinary/renal and pulmonary
9. Stroke at any time or TIA in the previous 6 months
10. PRECISE DAPT score of 25 or greater
EVOLVE Short trial (NCT02605447) At least 1 of the pre-specified criteria at the time of enrollment, including 1. Death or myocardial infarction (at 3 to 15 months)
1. Age ≥75 and, in the opinion of the investigator, the risk of major bleeding associated with >3 months of DAPT outweighs the benefit 2. Definite or probable ST, using the ARC definition (at 3 to 15 months)
2. Need for chronic or lifelong anticoagulation
3. History of major bleeding (severe/life threatening or moderate bleeding by GUSTO) within 12 months of the index procedure
4. History of stroke (ischemic or hemorrhagic)
5. Renal insufficiency (creatinine ≥2.0 mg/dL) or failure (dialysis dependent)
6. Platelet count ≤100,000/uL
XIENCE Short trial (NCT03218787) At least 1 of the pre-specified criteria, including All-cause death or myocardial infarction (at 1 year)
1. Age ≥75
2. Clinical indication for chronic (at least 6 months) or lifelong anticoagulation therapy
3. History of major bleeding which required medical attention within 12 months of the index procedure
4. History of stroke (ischemic or hemorrhagic)
5. Renal insufficiency (creatinine ≥2.0 mg/dL) or failure (dialysis dependent)
6. Systemic conditions associated with an increased bleeding risk (e.g., hematological disorders, including a history of or current thrombocytopenia defined as a platelet count <100,000/mm3, or any known coagulation disorder associated with increased bleeding risk)
7. Anemia with hemoglobin <11 g/dL
Onyx ONE trial (NCT03344653) At least 1 of the pre-specified criteria, including Cardiac death, myocardial infarction, or stent thrombosis (at 1 year)
1. Age ≥75
2. Any prior documented intracerebral bleed
3. Any documented stroke in the last 12 months
4. Hospital admission for bleeding during the prior 12 months
5. Non-skin cancer diagnosed or treated ≤3 years
6. Planned surgery within the next 12 months
7. Renal failure defined as: Creatinine clearance <40 mL/min
8. Thrombocytopenia (platelet count <100,000/mm3)
9. Severe chronic liver disease defined as: subjects who have developed any of the following: variceal hemorrhage, ascites, hepatic encephalopathy or jaundice
COBRA-REDUCE trial (NCT02594501) 1. Patient receiving or with an indication for new treatment with long-term oral anticoagulation with a coumadin derivatives or non-vitamin K oral anticoagulants 1. BARC ≥2 bleeding after discharge (at 6 months)
2. All-cause death, myocardial infarction, definite or probable stent thrombosis, or ischemic stroke (at 6 months)
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ARC = Academic Research Consortium; DAPT = dual antiplatelet therapy; MACCE = major adverse cardiac and cerebral events; NACE = net adverse clinical endpoints; NSAIDs = nonsteroidal anti-inflammatory drugs; PCI = percutaneous coronary intervention; ST = stent thrombosis; TIA = transient ischemic attack.

USE OF DAPT IN EAST ASIAN PATIENTS AND THE NEED FOR AN ASIAN DAPT SCORE

Ethnicity is an important factor that should be considered when determining the optimal DAPT duration. As mentioned above, East Asian patients have a unique ischemic and bleeding risk profile, which has been conformed in various studies involving ex-vivo and real-world data. However, the racial effect on the benefit of DAPT has not been well considered by current studies and current guidelines derived from various studies. Thus, physicians in East Asia are reluctant to apply the Western guidelines for antiplatelet agent use after PCI in clinical practice. For example, the new-generation P2Y12 inhibitors are prescribed within 1 year after PCI in less than 50% of all ACS patients, although a decade has passed since landmark studies, such as the TRITON-TIMI 38 and PLATO trials, demonstrated their benefits.35),39) A guideline specifically for East Asian patients and a unique regimen for these patients might help in the fine-tuning of DAPT for this population. We are designing an East Asian-specific scoring system, which is being tentatively named the “A-DAPT (Asian dual antiplatelet agent) score.” This score will reflect the unique ischemic/bleeding risk of East Asian patients and will be directly applicable to real-world East Asian PCI populations using new-generation DESs. The validation results of the A-DAPT score will soon be reported.

Footnotes

Funding: This study was supported by a grant of the Korea Health Technology R&D Project “Korea Research-Driven Hospital” through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI14C1277).

Conflict of Interest: The authors have no financial conflicts of interest.

Author Contributions:
  • Writing - original draft: Kim HS.
  • Writing - review & editing: Kang J.

References

  • 1.Schömig A, Neumann FJ, Kastrati A, 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. doi: 10.1056/NEJM199604253341702. [DOI] [PubMed] [Google Scholar]
  • 2.Bertrand ME, Rupprecht HJ, Urban P, Gershlick AH CLASSICS Investigators. Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting: the clopidogrel aspirin stent international cooperative study (CLASSICS) Circulation. 2000;102:624–629. doi: 10.1161/01.cir.102.6.624. [DOI] [PubMed] [Google Scholar]
  • 3.Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med. 2006;354:1706–1717. doi: 10.1056/NEJMoa060989. [DOI] [PubMed] [Google Scholar]
  • 4.Steinhubl SR, Berger PB, Mann JT, 3rd, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002;288:2411–2420. doi: 10.1001/jama.288.19.2411. [DOI] [PubMed] [Google Scholar]
  • 5.Valgimigli M, Bueno H, Byrne RA, et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS. Kardiol Pol. 2017;75:1217–1299. doi: 10.5603/KP.2017.0224. [DOI] [PubMed] [Google Scholar]
  • 6.Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines: an update of the 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention, 2011 ACCF/AHA guideline for coronary artery bypass graft surgery, 2012 ACC/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease, 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction, 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes, and 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery. Circulation. 2016;134:e123–e155. doi: 10.1161/CIR.0000000000000404. [DOI] [PubMed] [Google Scholar]
  • 7.Kim C, Shin DH, Ahn CM, et al. The use pattern and clinical impact of new antiplatelet agents including prasugrel and ticagrelor on 30-day outcomes after acute myocardial infarction in Korea: Korean Health Insurance Review and Assessment data. Korean Circ J. 2017;47:888–897. doi: 10.4070/kcj.2017.0072. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Chen ZM, Jiang LX, Chen YP, et al. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet. 2005;366:1607–1621. doi: 10.1016/S0140-6736(05)67660-X. [DOI] [PubMed] [Google Scholar]
  • 9.Yusuf S, Zhao F, Mehta SR, et al. 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. doi: 10.1056/NEJMoa010746. [DOI] [PubMed] [Google Scholar]
  • 10.Sabatine MS, Cannon CP, Gibson CM, et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med. 2005;352:1179–1189. doi: 10.1056/NEJMoa050522. [DOI] [PubMed] [Google Scholar]
  • 11.Hulot JS, Bura A, Villard E, et al. Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood. 2006;108:2244–2247. doi: 10.1182/blood-2006-04-013052. [DOI] [PubMed] [Google Scholar]
  • 12.Park KW, Kang J, Park JJ, et al. Amlodipine, clopidogrel and CYP3A5 genetic variability: effects on platelet reactivity and clinical outcomes after percutaneous coronary intervention. Heart. 2012;98:1366–1372. doi: 10.1136/heartjnl-2012-301892. [DOI] [PubMed] [Google Scholar]
  • 13.Bonello L, Tantry US, Marcucci R, et al. Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate. J Am Coll Cardiol. 2010;56:919–933. doi: 10.1016/j.jacc.2010.04.047. [DOI] [PubMed] [Google Scholar]
  • 14.Park KW, Park JJ, Jeon KH, et al. Clinical predictors of high posttreatment platelet reactivity to clopidogrel in Koreans. Cardiovasc Ther. 2012;30:5–11. doi: 10.1111/j.1755-5922.2010.00249.x. [DOI] [PubMed] [Google Scholar]
  • 15.Park KW, Kim HS. Options to overcome clopidogrel response variability. Circ J. 2012;76:287–292. doi: 10.1253/circj.cj-11-1494. [DOI] [PubMed] [Google Scholar]
  • 16.Xie X, Ma YT, Yang YN, et al. CYP2C19 phenotype, stent thrombosis, myocardial infarction, and mortality in patients with coronary stent placement in a Chinese population. PLoS One. 2013;8:e59344. doi: 10.1371/journal.pone.0059344. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Jeong YH. “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. doi: 10.1007/s11886-014-0485-4. [DOI] [PubMed] [Google Scholar]
  • 18.Suh JW, Lee SP, Park KW, et al. Multicenter randomized trial evaluating the efficacy of cilostazol on ischemic vascular complications after drug-eluting stent implantation for coronary heart disease: results of the CILON-T (influence of CILostazol-based triple antiplatelet therapy ON ischemic complication after drug-eluting stenT implantation) trial. J Am Coll Cardiol. 2011;57:280–289. doi: 10.1016/j.jacc.2010.08.631. [DOI] [PubMed] [Google Scholar]
  • 19.Park KW, Jeon KH, Kang SH, et al. Clinical outcomes of high on-treatment platelet reactivity in Koreans receiving elective percutaneous coronary intervention (from results of the CROSS VERIFY study) Am J Cardiol. 2011;108:1556–1563. doi: 10.1016/j.amjcard.2011.07.012. [DOI] [PubMed] [Google Scholar]
  • 20.Lee K, Yoo SY, Suh J, et al. Efficacy of cilostazol on inhibition of platelet aggregation, inflammation and myonecrosis in acute coronary syndrome patients undergoing percutaneous coronary intervention: The ACCEL-LOADING-ACS (ACCELerated inhibition of platelet aggregation, inflammation and myonecrosis by adjunctive cilostazol loading in patients with acute coronary syndrome) study. Int J Cardiol. 2015;190:370–375. doi: 10.1016/j.ijcard.2015.04.180. [DOI] [PubMed] [Google Scholar]
  • 21.Angiolillo DJ, Shoemaker SB, Desai B, et al. Randomized comparison of a high clopidogrel maintenance dose in patients with diabetes mellitus and coronary artery disease: results of the Optimizing Antiplatelet Therapy in Diabetes Mellitus (OPTIMUS) study. Circulation. 2007;115:708–716. doi: 10.1161/CIRCULATIONAHA.106.667741. [DOI] [PubMed] [Google Scholar]
  • 22.Park KW, Kang SH, Park JJ, et al. Adjunctive cilostazol versus double-dose clopidogrel after drug-eluting stent implantation: the HOST-ASSURE randomized trial (Harmonizing optimal strategy for treatment of coronary artery stenosis-safety & effectiveness of drug-eluting stents & anti-platelet regimen) JACC Cardiovasc Interv. 2013;6:932–942. doi: 10.1016/j.jcin.2013.04.022. [DOI] [PubMed] [Google Scholar]
  • 23.Price MJ, Berger PB, Teirstein PS, et al. Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. JAMA. 2011;305:1097–1105. doi: 10.1001/jama.2011.290. [DOI] [PubMed] [Google Scholar]
  • 24.Collet JP, Cuisset T, Rangé G, et al. Bedside monitoring to adjust antiplatelet therapy for coronary stenting. N Engl J Med. 2012;367:2100–2109. doi: 10.1056/NEJMoa1209979. [DOI] [PubMed] [Google Scholar]
  • 25.Cayla G, Cuisset T, Silvain J, 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. doi: 10.1016/S0140-6736(16)31323-X. [DOI] [PubMed] [Google Scholar]
  • 26.Roberts JD, Wells GA, Le May MR, et al. Point-of-care genetic testing for personalisation of antiplatelet treatment (RAPID GENE): a prospective, randomised, proof-of-concept trial. Lancet. 2012;379:1705–1711. doi: 10.1016/S0140-6736(12)60161-5. [DOI] [PubMed] [Google Scholar]
  • 27.Parodi G, Marcucci R, Valenti R, et al. High residual platelet reactivity after clopidogrel loading and long-term cardiovascular events among patients with acute coronary syndromes undergoing PCI. JAMA. 2011;306:1215–1223. doi: 10.1001/jama.2011.1332. [DOI] [PubMed] [Google Scholar]
  • 28.Brar SS, ten Berg J, Marcucci R, et al. Impact of platelet reactivity on clinical outcomes after percutaneous coronary intervention. A collaborative meta-analysis of individual participant data. J Am Coll Cardiol. 2011;58:1945–1954. doi: 10.1016/j.jacc.2011.06.059. [DOI] [PubMed] [Google Scholar]
  • 29.Shen AY, Yao JF, Brar SS, Jorgensen MB, Chen W. Racial/ethnic differences in the risk of intracranial hemorrhage among patients with atrial fibrillation. J Am Coll Cardiol. 2007;50:309–315. doi: 10.1016/j.jacc.2007.01.098. [DOI] [PubMed] [Google Scholar]
  • 30.Mak KH, Bhatt DL, Shao M, et al. Ethnic variation in adverse cardiovascular outcomes and bleeding complications in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) study. Am Heart J. 2009;157:658–665. doi: 10.1016/j.ahj.2008.08.031. [DOI] [PubMed] [Google Scholar]
  • 31.Kang J, Palmerini KP, Stone G, et al. Ethnic differences in ischemia/bleeding risk tradeoff during antiplatelet therapy after drug-eluting stent implantation: individual patient level meta-analysis from seven RCTs. J Am Coll Cardiol. 2018;71:A1320 [Google Scholar]
  • 32.Kang J, Han JK, Ahn Y, et al. Third-generation P2Y12 inhibitors in East Asian acute myocardial infarction patients: a nationwide prospective multicentre study. Thromb Haemost. 2018;118:591–600. doi: 10.1055/s-0038-1626697. [DOI] [PubMed] [Google Scholar]
  • 33.Faber DR, de Groot PG, Visseren FL. Role of adipose tissue in haemostasis, coagulation and fibrinolysis. Obes Rev. 2009;10:554–563. doi: 10.1111/j.1467-789X.2009.00593.x. [DOI] [PubMed] [Google Scholar]
  • 34.Levine GN, Jeong YH, Goto S, et al. Expert consensus document: World Heart Federation expert consensus statement on antiplatelet therapy in East Asian patients with ACS or undergoing PCI. Nat Rev Cardiol. 2014;11:597–606. doi: 10.1038/nrcardio.2014.104. [DOI] [PubMed] [Google Scholar]
  • 35.Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357:2001–2015. doi: 10.1056/NEJMoa0706482. [DOI] [PubMed] [Google Scholar]
  • 36.Montalescot G, Wiviott SD, Braunwald E, et al. Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial. Lancet. 2009;373:723–731. doi: 10.1016/S0140-6736(09)60441-4. [DOI] [PubMed] [Google Scholar]
  • 37.Smith PK, Goodnough LT, Levy JH, et al. Mortality benefit with prasugrel in the TRITON-TIMI 38 coronary artery bypass grafting cohort: risk-adjusted retrospective data analysis. J Am Coll Cardiol. 2012;60:388–396. doi: 10.1016/j.jacc.2012.03.030. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Olier I, Sirker A, Hildick-Smith DJ, et al. Association of different antiplatelet therapies with mortality after primary percutaneous coronary intervention. Heart. 2018:heartjnl-2017-312366. doi: 10.1136/heartjnl-2017-312366. [DOI] [PubMed] [Google Scholar]
  • 39.Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045–1057. doi: 10.1056/NEJMoa0904327. [DOI] [PubMed] [Google Scholar]
  • 40.Steg PG, James S, Harrington RA, et al. Ticagrelor versus clopidogrel in patients with ST-elevation acute coronary syndromes intended for reperfusion with primary percutaneous coronary intervention: a Platelet Inhibition and Patient Outcomes (PLATO) trial subgroup analysis. Circulation. 2010;122:2131–2141. doi: 10.1161/CIRCULATIONAHA.109.927582. [DOI] [PubMed] [Google Scholar]
  • 41.James S, Budaj A, Aylward P, et al. Ticagrelor versus clopidogrel in acute coronary syndromes in relation to renal function: results from the Platelet Inhibition and Patient Outcomes (PLATO) trial. Circulation. 2010;122:1056–1067. doi: 10.1161/CIRCULATIONAHA.109.933796. [DOI] [PubMed] [Google Scholar]
  • 42.James S, Angiolillo DJ, Cornel JH, et al. Ticagrelor vs. clopidogrel in patients with acute coronary syndromes and diabetes: a substudy from the PLATelet inhibition and patient Outcomes (PLATO) trial. Eur Heart J. 2010;31:3006–3016. doi: 10.1093/eurheartj/ehq325. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Sahlén A, Varenhorst C, Lagerqvist B, et al. Outcomes in patients treated with ticagrelor or clopidogrel after acute myocardial infarction: experiences from SWEDEHEART registry. Eur Heart J. 2016;37:3335–3342. doi: 10.1093/eurheartj/ehw284. [DOI] [PubMed] [Google Scholar]
  • 44.Kang HJ, Clare RM, Gao R, et al. Ticagrelor versus clopidogrel in Asian patients with acute coronary syndrome: a retrospective analysis from the Platelet Inhibition and Patient Outcomes (PLATO) Trial. Am Heart J. 2015;169:899–905.e1. doi: 10.1016/j.ahj.2015.03.015. [DOI] [PubMed] [Google Scholar]
  • 45.Goto S, Huang CH, Park SJ, 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. doi: 10.1253/circj.CJ-15-0112. [DOI] [PubMed] [Google Scholar]
  • 46.Saito S, Isshiki T, Kimura T, et al. Efficacy and safety of adjusted-dose prasugrel compared with clopidogrel in Japanese patients with acute coronary syndrome: the PRASFIT-ACS study. Circ J. 2014;78:1684–1692. doi: 10.1253/circj.cj-13-1482. [DOI] [PubMed] [Google Scholar]
  • 47.Lee CW, Ahn JM, Park DW, et al. Optimal duration of dual antiplatelet therapy after drug-eluting stent implantation: a randomized, controlled trial. Circulation. 2014;129:304–312. doi: 10.1161/CIRCULATIONAHA.113.003303. [DOI] [PubMed] [Google Scholar]
  • 48.Valgimigli M, Campo G, Monti M, et al. Short- versus long-term duration of dual-antiplatelet therapy after coronary stenting: a randomized multicenter trial. Circulation. 2012;125:2015–2026. doi: 10.1161/CIRCULATIONAHA.111.071589. [DOI] [PubMed] [Google Scholar]
  • 49.Collet JP, Silvain J, Barthélémy O, et al. Dual-antiplatelet treatment beyond 1 year after drug-eluting stent implantation (ARCTIC-Interruption): a randomised trial. Lancet. 2014;384:1577–1585. doi: 10.1016/S0140-6736(14)60612-7. [DOI] [PubMed] [Google Scholar]
  • 50.Mauri L, Kereiakes DJ, Yeh RW, et al. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med. 2014;371:2155–2166. doi: 10.1056/NEJMoa1409312. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.Gilard M, Barragan P, Noryani AA, et al. 6- versus 24-month dual antiplatelet therapy after implantation of drug-eluting stents in patients nonresistant to aspirin: the randomized, multicenter ITALIC trial. J Am Coll Cardiol. 2015;65:777–786. doi: 10.1016/j.jacc.2014.11.008. [DOI] [PubMed] [Google Scholar]
  • 52.Helft G, Steg PG, Le Feuvre C, et al. Stopping or continuing clopidogrel 12 months after drug-eluting stent placement: the OPTIDUAL randomized trial. Eur Heart J. 2016;37:365–374. doi: 10.1093/eurheartj/ehv481. [DOI] [PubMed] [Google Scholar]
  • 53.Gwon HC, Hahn JY, Park KW, et al. Six-month versus 12-month dual antiplatelet therapy after implantation of drug-eluting stents: the Efficacy of Xience/Promus Versus Cypher to Reduce Late Loss After Stenting (EXCELLENT) randomized, multicenter study. Circulation. 2012;125:505–513. doi: 10.1161/CIRCULATIONAHA.111.059022. [DOI] [PubMed] [Google Scholar]
  • 54.Kim BK, Hong MK, Shin DH, et al. A new strategy for discontinuation of dual antiplatelet therapy: the RESET Trial (REal Safety and Efficacy of 3-month dual antiplatelet Therapy following Endeavor zotarolimus-eluting stent implantation) J Am Coll Cardiol. 2012;60:1340–1348. doi: 10.1016/j.jacc.2012.06.043. [DOI] [PubMed] [Google Scholar]
  • 55.Han Y, Xu B, Xu K, 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. doi: 10.1161/CIRCINTERVENTIONS.115.003145. [DOI] [PubMed] [Google Scholar]
  • 56.Hong SJ, Shin DH, Kim JS, et al. 6-month versus 12-month dual-antiplatelet therapy following long everolimus-eluting stent implantation: The IVUS-XPL randomized clinical trial. JACC Cardiovasc Interv. 2016;9:1438–1446. doi: 10.1016/j.jcin.2016.04.036. [DOI] [PubMed] [Google Scholar]
  • 57.Nakamura M, Iijima R, Ako J, et al. Dual antiplatelet therapy for 6 versus 18 months after biodegradable polymer drug-eluting stent implantation. JACC Cardiovasc Interv. 2017;10:1189–1198. doi: 10.1016/j.jcin.2017.04.019. [DOI] [PubMed] [Google Scholar]
  • 58.Feres F, Costa RA, Abizaid A, et al. Three vs twelve months of dual antiplatelet therapy after zotarolimus-eluting stents: the OPTIMIZE randomized trial. JAMA. 2013;310:2510–2522. doi: 10.1001/jama.2013.282183. [DOI] [PubMed] [Google Scholar]
  • 59.Colombo A, Chieffo A, Frasheri A, et al. Second-generation drug-eluting stent implantation followed by 6- versus 12-month dual antiplatelet therapy: the SECURITY randomized clinical trial. J Am Coll Cardiol. 2014;64:2086–2097. doi: 10.1016/j.jacc.2014.09.008. [DOI] [PubMed] [Google Scholar]
  • 60.Schulz-Schüpke S, Byrne RA, Ten Berg JM, et al. ISAR-SAFE: a randomized, double-blind, placebo-controlled trial of 6 vs. 12 months of clopidogrel therapy after drug-eluting stenting. Eur Heart J. 2015;36:1252–1263. doi: 10.1093/eurheartj/ehu523. [DOI] [PubMed] [Google Scholar]
  • 61.Bittl JA, Baber U, Bradley SM, Wijeysundera DN. Duration of dual antiplatelet therapy: a systematic review for the 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines. J Am Coll Cardiol. 2016;68:1116–1139. doi: 10.1016/j.jacc.2016.03.512. [DOI] [PubMed] [Google Scholar]
  • 62.Patil RK, Swaminathan RV, Feldman DN. Continuation of dual-antiplatelet therapy following percutaneous revascularization with a drug-eluting stent: what duration is optimal? Curr Atheroscler Rep. 2015;17:63. doi: 10.1007/s11883-015-0543-4. [DOI] [PubMed] [Google Scholar]
  • 63.Valgimigli M, Bueno H, Byrne RA, et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: The Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS) Eur Heart J. 2018;39:213–260. doi: 10.1093/eurheartj/ehx419. [DOI] [PubMed] [Google Scholar]
  • 64.Bittl JA, Baber U, Bradley SM, Wijeysundera DN, Evidence Review Committee Members Duration of dual antiplatelet therapy: a systematic review for the 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines. Circulation. 2016;134:e156–e178. doi: 10.1161/CIR.0000000000000405. [DOI] [PubMed] [Google Scholar]
  • 65.Urban P, Meredith IT, Abizaid A, et al. Polymer-free drug-coated coronary stents in patients at high bleeding risk. N Engl J Med. 2015;373:2038–2047. doi: 10.1056/NEJMoa1503943. [DOI] [PubMed] [Google Scholar]

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