Circulation Journal ORIGINAL ARTICLE Circ J 2019; 83: 1317 – 1323 doi: 10.1253/circj.CJ-18-1283 Ischemic Heart Disease

Duration of Clopidogrel-Based Dual Antiplatelet Therapy and Clinical Outcomes in Patients With Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention ― A Real-World Observation in Taiwan From 2012 to 2015 ―

Yi-Heng Li, MD, PhD; Yu-Wei Chiu, MD; Jun-Jack Cheng, MD, PhD; I-Chang Hsieh, MD; Ping-Han Lo, MD; Meng-Huan Lei, MD; Kwo-Chang Ueng, MD, PhD; Fu-Tien Chiang, MD, PhD; Shih-Hsien Sung, MD, PhD; Jen-Yuan Kuo, MD; Ching-Pei Chen, MD; Wen-Ter Lai, MD; Wen-Lieng Lee, MD, PhD; Jyh-Hong Chen, MD, PhD; Taiwan ACS STENT Registry Investigators

Background: Little information is available in Asia about the real-world practice of dual antiplatelet therapy (DAPT) duration for acute coronary syndrome (ACS) and its influence on clinical outcomes.

Methods and Results: The Taiwan ACS STENT Registry was a prospective, multicenter study to observe ACS patients using clopidogrel-based DAPT after percutaneous coronary intervention (PCI). The primary outcome was a composite of cardiovascular death, myocardial infarction, and stroke. Overall, 2,221 ACS patients (62 years, 83% men) were included. DAPT duration was ≤9 months in 935 (42.1%). The incidence of primary outcome was higher in patients receiving DAPT ≤9 months compared with those receiving DAPT >9 months at 1 year (3.5% vs. 1.6%, P=0.0026). The incidence of stent thrombosis (overall 0.5%) was similar between groups. Multivariable analysis showed that DAPT >9 months was associated with a significantly lower risk of primary out- come (odds ratio 0.725, 95% confidence interval 0.545–0.965).

Conclusions: Our data showed that short duration of DAPT (≤9 months) was common (42.1%) in Taiwan for ACS patients under- going PCI. DAPT ≤9 months increased the risk of the primary outcome.

Key Words: Acute coronary syndrome; Dual antiplatelet therapy; Taiwan

ual antiplatelet therapy (DAPT) with aspirin and Recurrent Events) study and another 2 clinical trials of new- P2Y12 inhibitor is the standard treatment for patients generation P2Y12 inhibitors.5–7 The optimal duration of D with acute coronary syndrome (ACS) undergoing DAPT involves an assessment of the trade-off between isch- percutaneous coronary intervention (PCI). Current American emia and bleeding. Multiple lines of evidence suggest that and European guidelines all recommend DAPT for at least 12 East Asian patients have a higher bleeding risk than white months for ACS patients regardless of the stent used in PCI.1,2 patients when receiving antiplatelet treatment.8,9 In Taiwan, In Asia, guidelines or consensus from Taiwan and Japan also bare metal stents (BMS) are still commonly used because the suggest 12-month DAPT after acute myocardial infarction National Health Insurance only reimburses the price of BMS (MI).3,4 The current suggestion of 12-month DAPT after ACS and patients have to pay at least US$1,500–2,000 for each was arbitrarily determined based on the duration of follow-up drug-eluting stent (DES). The Taiwan National Health Insurance in the CURE (Clopidogrel in Unstable angina to prevent also reimburses only 9-month DAPT for ACS patients under-

Received December 4, 2018; revised manuscript received February 12, 2019; accepted March 12, 2019; J-STAGE Advance Publication released online April 27, 2019 Time for primary review: 21 days National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan (Y.-H.L.); Department of Computer Science and Engineering, Yuan Ze University, Far Eastern Memorial Hospital, New Taipei City (Y.-W.C.); Shin Kong Wu Ho-Su Memorial Hospital, Taipei (J.-J.C.); Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan (I.-C.H.); China Medical University Hospital and College of Medicine, Taichung (P.-H.L.); Lotung Poh-Ai Hospital, Lotung (M.-H.L.); Chung Shan Medical University Hospital, Taichung (K.-C.U.); National Taiwan University Hospital and Fu-Jen Catholic University Hospital, Taipei (F.-T.C.); Taipei Veterans General Hospital and National Yang Ming University, Taipei (S.-H.S.); Mackay Memorial Hospital, Taipei (J.-Y.K.); Changhua Christian Hospital, Changhua (C.-P.C.); Kaohsiung Medical University Hospital, Kaohsiung City (W.-T.L.); Taichung Veterans General Hospital, Taichung (W.-L.L.); and College of Medicine, China Medical University, Taichung (J.-H.C.), Taiwan Mailing address: Jyh-Hong Chen, MD, PhD, College of Medicine, China Medical University, No. 91 Hsueh-Shih Road, Taichung 40402, Taiwan. E-mail: [email protected] ISSN-1346-9843 All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: [email protected]

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from the study. The clinical data, including age, sex, vascular risk factors, previous disease history, clinical presentation, laboratory data, medications, and procedures used during the index admission, were collected prospectively according to a predetermined protocol.

Follow-up The patients were followed up regularly and clinical data were collected at discharge and at 1, 3, 6, 9, and 12 months after discharge. The use of DAPT and the timing of dis- continuation were recorded during each follow-up visit. The reasons for discontinuation were answered by the in- charge cardiologists and were related to adverse events, insurance regulations, doctor’s decision, preparation for invasive procedure or surgery, need for anticoagulation, or other unidentified cause. The patients were stratified according to DAPT duration (≤9 months vs. >9 months), and baseline characteristics, treatment variables, and pri- mary outcome events were compared. The primary out- come was a composite endpoint of cardiovascular (CV) death, stroke, and MI at 12-month follow-up. The second- Figure 1. Study population flowchart. ACS, acute coronary ary outcome was the individual incidence of CV death, syndrome; DAPT, dual antiplatelet therapy; PCI, percutane- stroke, MI, stent thrombosis, and bleeding events. A bleed- ous coronary intervention. ing event was defined as any spontaneous bleeding episode that was considered clinically significant by the in-charge physicians and reported as an adverse event during the follow-up. going PCI. These considerations and insurance regulations may influence physicians’ determination of DAPT duration Statistical Analysis and potentially cause deviation from guideline recommenda- Continuous and categorical variables are presented as tions. Most of the real-world data about DAPT duration come mean ± standard deviation or number (percentage). from Western countries, showing that 12-month DAPT is used Comparisons between DAPT groups were performed by in most patients with ACS and prolonged use of DAPT unpaired t test for continuous variables and chi-square test beyond 12 months is common.10–12 Information is scarce in for categorical variables. A multivariable logistic regres- Asia about contemporary real-world practice patterns of sion analysis was performed to identify independent pre- DAPT duration and the effect on clinical outcomes following dicting factors of DAPT duration ≤9 months. The odds PCI for ACS. ratios (ORs) and associated 95% confidence intervals (CIs) In the present prospective cohort study, we used an ACS were calculated. Kaplan-Meier curves were used to evalu- registry data in Taiwan to examine real-world practice pat- ate the time to primary outcome events and the log-rank terns, patient characteristics, and clinical outcomes following test was applied to compare the differences between groups PCI for ACS in relation to DAPT duration. of DAPT duration. To further assess the effect of DAPT duration on clinical outcome, propensity score adjustment Methods was performed using logistic regression models with the following covariates: age, oral anticoagulant, cardiac Study Participants arrest, prior MI, prior PCI, heart failure, transient isch- This study was a nationwide ACS registry performed from emic attack/stroke, atrial fibrillation, prior coronary artery April 2012 to December 2015 in Taiwan by the Taiwan Society bypass grafting, hypertension, diabetes, hyperlipidemia of Cardiology.13 Adult patients (age ≥20 years) admitted and clinical presentation. Marginal mean weighting because of ACS, including ST-segment elevation MI through stratification (MMWS) was adopted to perform (STEMI), non-STEMI (NSTEMI) and unstable angina, were the propensity score analysis. All propensity scores were enrolled consecutively from 24 major hospitals across Taiwan. estimated by multinomial logistic regression, with 4 pro- The diagnosis was based on clinical symptoms, ECG and pensity scores for each patient. The MMWS computed cardiac markers changes, and further confirmed by the in- weights on the basis of stratified propensity scores and charge cardiologists. In this registry, only patients undergoing equated the pretreatment composition of different groups PCI with stent placement during admission, treated with under the assumption that unmeasured covariates did not DAPT, and surviving to discharge were included. Because the confound the treatment effects. We stratified propensity 1st-generation DES were no longer used after 2012 in Taiwan, score into 5 quintiles per stratum in each DAPT duration all patients received 2nd- or newer generation DES and/or group, followed by the MMWS calculation in each stratum BMS. Because clopidogrel was the most commonly used and DAPT duration group. Data balance was adjusted by P2Y12 inhibitor and prasugrel was not available during the MMWS weights. Two adjusted estimates of the composite study period, only patients treated with aspirin and clopidogrel outcome were provided: using MMWS weights only or were included in this study. Patients were ineligible if they had adjusted by additional covariate for constructing the ACS accompanying traffic accident, trauma, or severe bleed- propensity score for a “doubly robust model”. All statistical ing. Patients with perioperative or periprocedural MI or had analyses were conducted using SAS software, version 9.4 already participated in other clinical trials were also excluded (SAS Institute Inc., Cary, NC, USA). A two-tailed P-value

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Table 1. Baseline Characteristics DAPT ≤9 months DAPT >9 months Clinical characteristics P value (n=935) (n=1,286) Age (years) 63.1±13.3 60.8±12.7 <0.0001 Male 754 (80.6%) 1,080 (84.0%) 0.0405 BMI (kg/m2) 25.4±3.8 25.9±3.7 0.0023 Medical history PCI 152 (16.3%) 191 (14.9%) 0.3658 Myocardial infarction 85 (9.1%) 104 (8.1%) 0.4026 TIA/stroke 65 (7.0%) 67 (5.2%) 0.0865 Heart failure 62 (6.6%) 56 (4.4%) 0.0182 Atrial fibrillation 42 (4.5%) 22 (1.7%) 0.0001 PAD 28 (3.0%) 22 (1.7%) 0.0136 CABG 25 (2.7%) 18 (1.4%) 0.0314 Risk factors Hypertension 591 (63.4%) 809 (63.0%) 0.8265 Diabetes 352 (37.8%) 404 (31.4%) 0.0019 Hyperlipidemia 416 (44.8%) 584 (45.5%) 0.7303 Current smoker 409 (43.7%) 601 (46.7%) 0.1623 Clinical presentation STEMI 513 (54.9%) 697 (54.2%) 0.8295 NSTEMI 286 (30.6%) 409 (31.8%) Unstable angina 135 (14.5%) 180 (14.0%) BMI, body mass index; CABG, coronary artery bypass graft; DAPT, dual antiplatelet therapy (aspirin+clopidogrel); ECG, electrocardiography; NSTEMI, non-ST-elevation myocardial infarction; PAD, peripheral artery disease; PCI, percutaneous coronary intervention; STEMI, ST-elevation myocardial infarction; TIA, transient ischemic attack.

<0.05 was considered statistically significant. predicting shorter DAPT, atrial fibrillation (OR 1.500, 95% CI 1.040–2.162), use of BMS (OR 1.650, 95% CI Results 1.254–2.171) and any physician-reported bleeding event (OR 1.798, 95% CI 1.217–2.657) were the independent Baseline Characteristics predictors of using DAPT ≤9 months (Supplementary Table 2). Of the initial 2,374 enrolled patients, 98 without a DAPT The most common identified reason for stopping clopido- record, 53 not prescribed DAPT at discharge, and 2 ceas- grel was the regulation of Taiwan National Health Insurance ing DAPT before discharge were excluded, leaving 2,221 (70.7%), followed by adverse events (3%), doctor’s decision patients included in the analysis (Figure 1). Among these (1.3%), patient’s decision (1.2%), and preparation for inva- 2,221 patients, DAPT duration was >9 months in 1,286 sive procedure or surgery (0.4%). (57.9%) and ≤9 months in 935 patients (42.1%). Overall, the mean duration of DAPT was 261.0±119.4 days (>9 vs. Clinical Outcomes ≤9 months group, 345.5±44.5 days vs. 144.8±88.5 days, Table 3 illustrates the outcome events during the 12-month P<0.0001). Table 1 shows the baseline characteristics strat- follow-up in the overall study population and after strati- ified by duration of DAPT. The group with shorter DAPT fication by duration of DAPT. The incidence of the pri- (≤9 months) were older, had more females, and lower body mary composite outcome was significantly lower in mass index. These subjects also had more heart failure, patients receiving DAPT >9 months (DAPT duration ≤ vs. atrial fibrillation, peripheral arterial disease, coronary >9 months: 3.5% vs. 1.6%, respectively; P=0.0026), which artery bypass graft, and diabetes. The proportion of was mainly driven by the lower rate of CV death and STEMI was similar between groups. Table 2 outlines the stroke. The cumulative event curve of the primary out- procedural characteristics of the index PCI during admis- come (Figure 3) showed a significantly increased risk in sion. BMS was more commonly used in the group with patients with a shorter duration of DAPT (log-rank test, shorter DAPT (≤9 months). The stent number, total P=0.0002). The risk of stent thrombosis was very low and length, and the distribution of target lesions were similar did not vary significantly between groups despite a signifi- between groups. The use of DAPT decreased from 99.4% cant difference in the type of stent. A significantly higher at discharge to 35.4% at 12-month follow-up (Figure 2). As incidence of physician-reported bleeding events was noted for the use of other secondary preventive medications, in the shorter DAPT duration group. In light of the sig- patients with the shorter duration of DAPT (≤9 months) nificant differences noted in patients’ characteristics, pro- were less often prescribed with statins compared with the pensity score analysis was applied for adjustments. The longer DAPT duration group at discharge and during results after propensity score-matching analysis further follow-up (Supplementary Table 1). The use of β-blockers consolidated the above observations. Longer DAPT dura- and angiotensin-converting enzyme inhibitors/angiotensin- tion >9 months was independently associated with a receptor blockers were similar between groups at 12-month decreased risk of the primary composite outcome com- follow-up. In a multivariable logistic regression model for pared with duration ≤9 months (Figure 4).

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Table 2. Procedural Characteristics of PCI DAPT ≤9 months DAPT >9 months PCI procedures P value (n=935) (n=1,286) Stent type BMS 519 (55.5%) 497 (38.6%) <0.0001 DES 393 (42.0%) 744 (57.9%) Both 20 (2.1%) 39 (3.0%) No. of lesions treated 1 545 (58.3%) 756 (58.8%) 0.5484 2 226 (24.2%) 328 (25.5%) 3 115 (12.3%) 134 (10.4%) >3 49 (5.2%) 68 (5.3%) No. of stents 1 622 (66.5%) 791 (61.5%) 0.1111 2 219 (23.4%) 343 (26.7%) 3 67 (7.2%) 111 (8.6%) >3 27 (2.9%) 41 (3.2%) Total length of stents (mm) 34.7±22.0 36.4±21.7 0.0707 PCI vessel LAD 516 (55.2%) 746 (58.0%) 0.1849 RCA 376 (40.2%) 493 (38.3%) 0.3706 LCX 248 (26.5%) 351 (27.3%) 0.6865 Left main 43 (4.6%) 48 (3.7%) 0.3092 Saphenous vein graft 6 (0.6%) 5 (0.4%) 0.4019 BMS, bare metal stent; DAPT, dual antiplatelet therapy (aspirin+clopidogrel); DES, drug-eluting stent; LAD, left anterior descending artery; LCX, left circumflex artery; PCI, percutaneous coronary intervention; RCA, right coronary artery.

Figure 2. Percentage of patients under aspi- rin monotherapy, clopidogrel monotherapy or aspirin+clopidogrel dual therapy at discharge and during follow-up.

Table 3. Clinical Outcomes in 12-Month Follow-up Overall DAPT ≤9 months DAPT >9 months Outcome events P value (n=2,221) (n=935) (n=1,286) Primary outcome* 53 (2.4%) 33 (3.5%) 20 (1.6%) 0.0026 Cardiovascular death 17 (0.8%) 16 (1.7%) 1 (0.1%) <0.0001 Myocardial infarction 29 (1.3%) 12 (1.3%) 17 (1.3%) 0.9371 Stroke 10 (0.5%) 8 (0.9%) 2 (0.2%) 0.0347 Stent thrombosis 12 (0.5%) 4 (0.4%) 8 (0.6%) 0.5375 Bleeding event 46 (2.1%) 32 (3.4%) 14 (1.1%) 0.0001 *Composite outcome of cardiovascular death, myocardial infarction, and stroke. DAPT, dual antiplatelet therapy (aspirin+clopidogrel).

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Figure 3. Kaplan-Meier curves of the primary composite outcome (cardiovascular death, myocardial infarction, or stroke) in patients with different DAPT duration: DAPT ≤9 months (blue) and DAPT >9 months (red). DAPT, dual antiplatelet therapy.

Figure 4. Adjusted primary com- posite outcome in relation to DAPT duration in the propensity score MMWS model and doubly robust model. CI, confidence interval; DAPT, dual antiplatelet therapy; MMWS, marginal mean weighting through stratification.

Discussion comes in patients receiving DAPT >9 months were superior to those with DAPT ≤9 months at 1-year follow- The major findings of our study were: (1) short-duration up. DAPT was common (42.1% had DAPT ≤9 months) in Taiwan In recent years, real-world studies from Western countries despite the guideline recommendation of ≥12-month dura- showed that prolonged DAPT is a common practice for ACS tion for patients; (2) atrial fibrillation, use of BMS in PCI treatment. In the FAST-MI (French Registry of Acute ST- and any bleeding event were the major independent pre- elevation or non ST-elevation Myocardial Infarction) study, dicting factors of DAPT ≤9 months; (3) the clinical out- 75% and 43% of patients were receiving DAPT at 1- and

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2-year follow-up10 and the results were similar to the PARIS ACS patients in Taiwan.23 (Patterns of Non-Adherence to Antiplatelet Regimens in Our study has both strengths and limitations. The strength Stented Patients) registry that recruited patients undergoing is the coverage of a wide range of ACS patients which PCI with stent implantation in the USA and Europe.11 The reflected the problems in real-world clinical practice in Taiwan. EPICOR (long-tErm follow-uPof antithrombotic management For example, many ACS patients were still treated with BMS patterns In acute CORonary syndrome patients) study despite the recommendation of new-generation DES in the recruited 8,593 ACS patients using DAPT in Europe and Latin guidelines. Use of BMS was an independent predictor of America; among them, 76% and 57% remained on uninter- shorter DAPT duration. Currently, the financial barrier is the rupted DAPT at 1- and 2-year follow-up.12 In Asia, several main reason that prevents the use of DES in Taiwan. Our randomized clinical trials with new-generation DES were per- study demonstrated the urgent need to revise the national formed in Japan, Korea, and China, demonstrating non-inferi- reimbursement policy. The major limitation of our study is ority of short (6 months) to standard (12 months) or longer (18 that there were many differences in the baseline characteristics months) DAPT.14–16 However, both stable coronary artery of the study groups, which could influence the clinical out- disease (CAD) and ACS patients were included in those stud- comes we observed. To deal with this, we used propensity ies. The SMART-DATE trial from Korea was a pure DAPT score-matching to reduce heterogeneity, but some unadjusted duration study for ACS in Asia.17 The trial randomized 2,712 potential confounders may still exist. Second, the BARC or ACS patients undergoing PCI to receive either 6-month or TIMI bleeding classification was not used to define bleeding 12-month DAPT. There was no significant difference in the events, so the severity of bleeding was unknown and its poten- primary composite endpoint of all-cause death, MI, or stroke tial effect on clinical outcomes could not be evaluated. Third, between the groups. But the post-hoc landmark analysis found only patients treated with clopidogrel were included in the a significant increased risk of recurrent MI in the 6-month study. We do not know if the results of this study can be DAPT group compared with those who had longer DAPT. extrapolated to other P2Y12 inhibitors. Ticagrelor was not The results from the SMART-DATE trial and our real-world reimbursed by the Taiwan National Health Insurance when the observation study reconfirm that DAPT duration of at least study started, and prasugrel was not available in Taiwan dur- 9–12 months after ACS is necessary for Asian patients. ing the study period. Therefore, the clinical efficacy and safety Real-world data of DAPT duration for ACS are scarce in between clopidogrel and ticagrelor or prasugrel was not com- Asia. The current study found 42.1% patients with ACS who pared in this study. Finally, our follow-up was not long underwent PCI had DAPT ≤9 months and only 35.4% enough. The long-term benefit and risk of DAPT longer than patients were being treated with DAPT at 12-month fol- 12 months were unknown. low-up in Taiwan. In Korea, a study using the database of the Korean National Health Insurance Service since 2009 Conclusions to 2011 found 31% of the 2,369 patients undergoing PCI with DES had early discontinuation of DAPT before 1 The current study found DAPT duration ≤9 months for year.18 Unfortunately, the percentage of ACS patients in that ACS patients undergoing PCI was a common practice in study cohort was unknown. In Japan, the PACIFIC (Prevention Taiwan. Extending clopidogrel-based DAPT to more than of AtherothrombotiC Incidents Following Ischemic Coronary 9 months improved the clinical outcomes of the patients. attack) registry showed that 62.9% of the 3,597 Japanese ACS patients were being treated with DAPT at 12-month follow- Acknowledgments 19 up. A more recent study using a medical information data- This study was supported by the Taiwan Society of Cardiology and base of 7,473 patients who underwent PCI in Japan sponsored by Sanofi Taiwan Co. Ltd. We express our gratitude and demonstrated that DAPT was used in only 42% patients at 12 appreciation to the physicians participating in the registry. months, in both stable CAD and ACS patients.20 It seems that Principal Investigators (by alphabetical order): Chien-Cheng Chen, Show Chwan Memorial Hospital; Zhih-Cherng Chen, Chi-Mei Hospital; the DAPT duration for ACS is shorter in Asian countries than Shu-Meng Cheng, Tri-Service General Hospital; Ching-Chang Fang, is reported from Western studies, which may more accurately Tainan Municipal Hospital; Chih-Neng Hsu, National Taiwan reflect the real-world situation in Asia. Cardiologists in this University Hospital, Yun-Lin Branch; Kwan-Lih Hsu, E-Da Hospital; region consider that East Asian patients have a different Eng-Thiam Ong, Cathay General Hospital; Chun-Ming Shih, Taipei 21 Medical University Hospital; Ji-Hung Wang, Hualien Tzu Chi General response to antiplatelet agents compared with Caucasians. Hospital; Chiung-Jen Wu, Kaohsiung Chang Gung Memorial Hospital; East Asian patients also have a higher risk of bleeding but Wei-Hsian Yin, Cheng-Hsin General Hospital. lower risk of ischemic events after PCI than Caucasians.9,22 Our study found that atrial fibrillation, use of BMS, and bleed- References ing events were the major predictors of short DAPT. Therefore, 1. Levine GN, Bates ER, Bittl JA, Brindis RG, Fihn SD, Fleisher LA, despite the risk being higher in the short-duration DAPT et al. 2016 ACC/AHA guideline focused update on duration of dual group in our study cohort, more cases of atrial fibrillation that antiplatelet therapy in patients with coronary artery disease: A report need anticoagulation and more bleeding events prevent these of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2016; patients receiving longer DAPT after PCI. After multivariable 68: 1082 – 1115. adjustment, we still found the clinical outcomes of DAPT 2. Valgimigli M, Bueno H, Byrne RA, Collet JP, Costa F, Jeppsson A, duration >9 months were better than with the short duration. et al. 2017 ESC focused update on dual antiplatelet therapy in coro- Together with the SMART-DATE trial from Korea, sticking nary artery disease developed in collaboration with EACTS: The Task Force for dual antiplatelet therapy in coronary artery disease of to the standard of care for DAPT duration for ACS patients is the European Society of Cardiology (ESC) and of the European necessary for Asian patients. The most common reason Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J reported by cardiologists in Taiwan for early discontinuation 2018; 39: 213 – 260. of clopidogrel was the regulation of National Health Insurance, 3. Ozaki Y, Katagiri Y, Onuma Y, Amano T, Muramatsu T, Kozuma K, et al. CVIT expert consensus document on primary percutaneous which only reimburses up to 9 months of DAPT for ACS. It coronary intervention (PCI) for acute myocardial infarction (AMI) reveals the need for updating the regulations in line with in 2018. Cardiovasc Interv Ther 2018; 33: 178 – 203. guideline recommendations to improve the quality of care for 4. Li YH, Wang YC, Wang YC, Liu JC, Lee CH, Chen CC, et al. 2018

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Guidelines of the Taiwan Society of Cardiology, Taiwan Society of 10: 1189 – 1198. Emergency Medicine and Taiwan Society of Cardiovascular 15. Hong SJ, Shin DH, Kim JS, Kim BK, Ko YG, Choi D, et al. 6-month Interventions for the management of non ST-segment elevation acute versus 12-month dual antiplatelet therapy following long everoli- coronary syndrome. J Formos Med Assoc 2018; 117: 766 – 790. mus-eluting stent implantation: The IVUS-XPL randomized clinical 5. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK; trial. JACC Cardiovasc Interv 2016; 9: 1438 – 1446. Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial 16. Han Y, Xu B, Xu K, Guan C, Jing Q, Zheng Q, et al. Six versus 12 Investigators. Effects of clopidogrel in addition to aspirin in patients months of dual antiplatelet therapy after implantation of biodegrad- with acute coronary syndromes without ST-segment elevation. N able polymer sirolimus-eluting stent: Randomized substudy of the Engl J Med 2001; 345: 494 – 502. I-LOVE-IT 2 trial. Circ Cardiovasc Interv 2016; 9: e003145. 6. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, 17. Hahn JY, Song YB, Oh JH, Cho DK, Lee JB, Doh JH, et al. 6-month Gottlieb S, et al. Prasugrel versus clopidogrel in patients with acute versus 12-month or longer dual antiplatelet therapy after percutane- coronary syndromes. N Engl J Med 2007; 357: 2001 – 2015. ous coronary intervention in patients with acute coronary syndrome 7. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, (SMART-DATE): A randomised, open-label, non-inferiority trial. Held C, et al. Ticagrelor versus clopidogrel in patients with acute Lancet 2018; 391: 1274 – 1284. coronary syndromes. N Engl J Med 2009; 361: 1045 – 1057. 18. Cho MH, Shin DW, Yun JM, Shin JH, Lee SP, Lee H, et al. Prevalence 8. Mak KH, Bhatt DL, Shao M, Hankey GJ, Easton JD, Fox KA, et al. and predictors of early discontinuation of dual-antiplatelet therapy Ethnic variation in adverse cardiovascular outcomes and bleeding after drug-eluting stent implantation in Korean population. Am J complications in the Clopidogrel for High Atherothrombotic Risk Cardiol 2016; 118: 1448 – 1454. and Ischemic Stabilization, Management, and Avoidance 19. Daida H, Miyauchi K, Ogawa H, Yokoi H, Matsumoto M, Kitakaze (CHARISMA) study. Am Heart J 2009; 157: 658 – 665. M, et al. Management and two-year long-term clinical outcome of 9. Kang J, Park KW, Palmerini T, Stone GW, Lee MS, Colombo A, et acute coronary syndrome in Japan: Prevention of atherothrombotic al. Racial differences in ischaemia/bleeding risk trade-off during incidents following ischemic coronary attack (PACIFIC) registry. anti-platelet therapy: Individual patient level landmark meta-analysis Circ J 2013; 77: 934 – 943. from seven RCTs. Thromb Haemost 2019; 119: 149 – 162. 20. Yokoi H, Oda E, Kaneko K, Matsuo H. Comparison of long DAPT 10. Schiele F, Puymirat E, Bonello L, Dentan G, Meneveau N, Collet JP, versus short DAPT in Japanese PCI patients based on healthcare et al. Impact of prolonged dual antiplatelet therapy after acute myo- information database. Eur Heart J 2018; 39(Suppl): 45. cardial infarction on 5-year mortality in the FAST-MI 2005 registry. 21. Levine GN, Jeong YH, Goto S, Anderson JL, Huo Y, Mega JL, et al. Int J Cardiol 2015; 187: 354 – 360. Expert consensus document: World Heart Federation expert consen- 11. Mehran R, Baber U, Steg PG, Ariti C, Weisz G, Witzenbichler B, et sus statement on antiplatelet therapy in East Asian patients with ACS al. Cessation of dual antiplatelet treatment and cardiac events after or undergoing PCI. Nat Rev Cardiol 2014; 11: 597 – 606. percutaneous coronary intervention (PARIS): 2 year results from a 22. Kang J, Kim HS. The evolving concept of dual antiplatelet therapy prospective observational study. Lancet 2013; 382: 1714 – 1722. after percutaneous coronary intervention: Focus on unique feature of 12. Bueno H, Pocock S, Danchin N, Annemans L, Gregson J, Medina J, East Asian and “Asian Paradox”. Korean Circ J 2018; 48: 537 – 551. et al. International patterns of dual antiplatelet therapy duration after 23. Wu CK, Juang JJ, Chiang JY, Li YH, Tsai CT, Chiang FT. The acute coronary syndromes. Heart 2017; 103: 132 – 138. Taiwan Heart Registries: Its influence on cardiovascular patient care. 13. Li YH, Chiu YW, Cheng JJ, Hsieh IC, Lo PH, Lei MH, et al. Changing J Am Coll Cardiol 2018; 71: 1273 – 1283. practice pattern of acute coronary syndromes in Taiwan from 2008 to 2015. Acta Cardiol Sin 2019; 35: 1 – 10. 14. Nakamura M, Iijima R, Ako J, Shinke T, Okada H, Ito Y, et al. Dual Supplementary Files antiplatelet therapy for 6 versus 18 months after biodegradable poly- Please find supplementary file(s); mer drug-eluting stent implantation. JACC Cardiovasc Interv 2017; http://dx.doi.org/10.1253/circj.CJ-18-1283

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