Clinical Impact of Single and Dual Antiplatelet Therapy Beyond 12 Months on Ischemic Risk in Patients With Acute Myocardial Infarction

Background: There is ongoing debate regarding the optimal antiplatelet strategy beyond 12 months in patients with acute myocardial infarction (AMI) who undergo successful percutaneous coronary intervention (PCI). This study therefore aimed to investigate the clinical outcomes of single (SAPT) vs. dual antiplatelet therapy (DAPT) beyond 12 months in patients with stable AMI and second-generation drug-eluting stent (DES) implantation. Methods: Of 13,104 patients from the Korea Acute Myocardial Infarction Registry-National Institutes of Health database, we selected 4,604 patients who underwent PCI with second-generation DES and exhibited no adverse clinical events within 12 months; they were classified into SAPT (aspirin or clopidogrel) or DAPT (aspirin and clopidogrel) groups. The primary endpoints were major adverse cardiac and cerebrovascular events (MACCE), including the composite of all-cause death, myocardial infarction (MI), and stroke between 12 and 36 months. Results: The SAPT group (n = 1,862) was associated with a significantly lower risk of MACCE between 12 and 36 months [4.2 vs. 8.5%, hazard ratio (HR): 0.47, 95% confidence interval (CI): 0.37–0.61; p < 0.001] than the DAPT group (n = 2,742). The results were consistent after adjusting for confounders through multivariable and propensity score matching analysis. Moreover, in patients with complex features (defined as an unprotected left main PCI, implanted stent length of ≥38 mm, multivessel PCI, or ≥3 stents per patients), the SAPT group (n = 678) also demonstrated a significantly lower risk of MACCE between 12 and 36 months (4.9 vs. 9.9%, HR: 0.46, CI: 0.31–0.68, p < 0.001) than the DAPT group (n = 1,167). Conclusions: In patients with AMI who underwent successful PCI with second-generation DES and exhibited no adverse clinical events within 12 months, the use of SAPT was associated with a significantly lower MACCE between 12 and 36 months compared with the use of DAPT.


INTRODUCTION
The current guidelines recommend at least 12 months of dual antiplatelet therapy (DAPT)-including aspirin with a potent P2Y 12 inhibitor, such as ticagrelor or prasugrel-and lifelong antiplatelet therapy for patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) with drug-eluting stents (DESs) (1,2). After 12 months of DAPT treatment, the guidelines recommend determining whether to continue DAPT, or change to single antiplatelet therapy (SAPT) by considering the risk of coronary ischemic events in individual patients (3)(4)(5)(6). However, in recent randomized trials involving the development of DESs, evidence for short-term DAPT has increased, with favorable ischemic outcomes observed in patients with ACS who undergo second-generation DES implantation (7,8). Patients with ACS remained at an increased long-term risk of ischemic events (9,10); however, there are no dedicated studies regarding the optimal antiplatelet strategy beyond 12 months (SAPT vs. DAPT) in the setting of acute myocardial infarction (AMI). Moreover, it is not easy to determine the optimal strategy by performing risk stratification for each patient in daily practice; therefore, we aimed to investigate the clinical outcomes of SAPT vs. DAPT beyond 12 months in patients with AMI who underwent successful second-generation DES implantation, using a dedicated AMI registry.

Study Protocols and Population Selection
The study population was selected from the nationwide, multicenter, prospective Korea Acute Myocardial Infarction Registry-National Institutes of Health (KAMIR-NIH) registry. Twenty tertiary university cardiovascular centers in Korea were recruited between November 2011 and December 2015 (Supplementary Table 1); the detailed study protocols have been published previously (11). Trained research coordinators at each center collected patient data using a web-based report form on the Internet-based Clinical Research and Trial management system, supported by a grant from the Korea Centers for Disease Control and Prevention since November 2011 (iCreaT study No. C110016). The study protocols were approved by the institutional review board of each participating center and complied with the principles of the Declaration of Helsinki (IRB approval number: CNUH-2011-172). Informed consent was obtained from all patients for participation in the KAMIR registry. The standardized definitions of all variables were unified and determined by the KAMIR-NIH committee board.
The selection process of this study population is shown in Figure 1; among 13,104 patients enrolled in the KAMIR-NIH registry, we selected patients with AMI who underwent successful second-generation DES implantation without exhibiting adverse clinical events-including all-cause death, myocardial infarction (MI), stroke, revascularization, and stent thrombosis-within 12 months. The exclusion criteria included no PCI, failed PCI, or suboptimal PCI defined as the failure to restore optimal blood flow in the infarct-related coronary artery with >50% residual stenosis and did not achieve Thrombolysis In Myocardial Infarction 2 flow after PCI; plain old balloon angioplasty alone; PCI with bare-metal stent or first-generation DES; oral anticoagulation or cilostazole use; and follow-up loss before 1 year. Additionally, we excluded patients with prolonged use of potent P2Y 12 inhibitors, including prasugrel or ticagrelor, between 12 and 36 months; no data or terminated antiplatelet agent treatment; and who switched between DAPT and SAPT without adverse clinical events. We analyzed the clinical outcomes 12-36 months after the index procedure, stratified by antiplatelet strategy.

Study Procedures
All patients with AMI were managed according to practical guidelines (12,13). Patients received loading doses of antiplatelet agents, including 300 mg aspirin and a P2Y 12 inhibitor (clopidogrel: 300-600 mg, ticagrelor: 180 mg, or prasugrel: 60 mg) before PCI. The choice of antiplatelet agent before PCIas well as the selection of treated vessels, stent type, interventional devices (e.g., intravascular modalities including intravascular ultrasound, optical coherence tomography, fractional flow reserve, and thrombosuction), and the use of glycoprotein IIb/IIIa inhibitors-was at the operator's discretion. After PCI, daily aspirin (100 mg) and P2Y 12 inhibitors (clopidogrel: 75 mg once, ticagrelor: 90 mg twice, or prasugrel: 10 mg once daily) were prescribed.

Study Endpoints and Definitions
The primary endpoint was major adverse cardiac and cerebrovascular events (MACCE) between 12 and 36 months after the index procedure, defined as the composite of all-cause death, MI, and stroke. All-cause death was regarded as cardiac death unless a definite, non-cardiac cause could be identified. MI was defined according to evidence of myocardial necrosis in the vascular territory of a treated vessel, i.e., the third universal definition of MI (14). Stroke was defined as the loss of neurologic function caused by an ischemic or hemorrhagic event in the brain, with symptoms lasting at least 24 h. The secondary endpoint included individual components of MACCE and definite or probable stent thrombosis, defined according to the Academic Research Consortium definitions (15).

Statistical Analysis
Continuous variables were compared using Student's t-test or Mann-Whitney U test, as appropriate, and are expressed as mean ± standard deviation, or median (interquartile range). Categorical variables were compared using the Chi-square or Fisher's exact test and are expressed as numbers and percentages. The cumulative incidence of each endpoint between 12 and 36 months was calculated based on Kaplan-Meier censoring estimates, whereas the comparison of clinical outcomes between the DAPT and SAPT groups was performed using the logrank test. To correct differences in baseline and procedural characteristics, analyses were additionally performed to adjust for confounding factors. First, a multivariable Cox regression model was used for each cutoff value, with the following covariates which was significantly affect the MACCE (p <0.1): age ≥ 65 years, Killip class III/IV, diabetes mellitus, glucose level, history of PCI, history of cerebrovascular accident (CVA), estimated glomerular filtration rate ≤60 ml/min 1.73 m 2 , left ventricular ejection fraction ≤50%, left main disease, and long stent ≥38 mm. Second, we performed propensity score (PS) matching between the two groups using a multiple logistic regression model. The percent standardized mean difference after PS matching was within 10% across all matched covariates, indicating a successful balance between the two groups. All statistical analyses were performed using the R statistical package

Baseline Characteristics
Among the 4,604 patients with AMI who underwent PCI with second-generation DES and exhibited no adverse clinical events for 12 months, 1,862 (40.4%) and 2,742 (59.6%) patients were classified into the SAPT (aspirin, n = 1,347 or clopidogrel, n = 515) and DAPT groups, respectively. The age of the entire study population was 62.4 ± 12.1 years, and 3,562 patients (77.4%) were male; 2,317 patients (50.3%) presented with ST-elevation myocardial infarction (STEMI). The baseline clinical, lesion, and procedural characteristics of the two groups are summarized in Tables 1, 2. Patients in the SAPT group were younger, with a lower prevalence of Killip class III/IV; hypertension; diabetes mellitus; and previous history of MI, PCI, and CVA than the DAPT group. Regarding lesion and procedural characteristics, the SAPT group had a lower prevalence of multivessel disease, left main disease, ACC/AHA B2/C lesions, and glycoprotein IIb/IIIa inhibitor use; conversely, they had a higher prevalence of transradial approaches and image-guided PCI-including intravascular ultrasound or optical coherence tomography-than the DAPT group. Regarding the implanted stents, a significantly larger stent diameter, shorter total stent length, and fewer total stent numbers were observed in the SAPT group. After PS matching, the standardized differences between the groups were <10% for all variables, indicating proper matches. No significant differences existed regarding the baseline, lesion, and procedural characteristics between the groups in the PS-matched population.  Table 3). Adjusted analysis using multivariable Cox regression and PS matching consistently demonstrated a significantly lower risk of MACCE, all-cause death, and MI in the SAPT group than in the DAPT group. There were no significant differences regarding the risk of noncardiac death, stroke, and stent thrombosis between the groups (Figures 3C,D; Table 3).

Clinical Benefits of SAPT Than DAPT Beyond 12 Months in Patients With AMI and Complex Features
We compared the clinical outcomes by antiplatelet strategy between 12 and 36 months in patients with AMI and complex features. Considering the clinical condition of AMI and referring to the reference, the following were considered complex features: (1) unprotected left main PCI, (2) long lesion (implanted stent length ≥ 38 mm), (3) multivessel PCI, or (4) multiple stent implantation (≥3 stents per patient) (16). Of the 1,862 patients with SAPT, 678 (36.4%) had one or more complex feature, whereas among the 2,742 patients with DAPT, 1,167 (42.6%) had complex features. The SAPT group demonstrated a lower proportion of left main PCI, stent length of ≥38 mm, multivessel PCI and, ≥3 stent implantations compared with the DAPT group (Figure 4). Regarding the clinical outcomes, the SAPT group demonstrated a consistently lower rate of MACCE (4.9 vs. 9.9%, HR: 0.46, 95% CI: 0.31-0.68; p < 0.001) and MI (0.6 vs. 2.4%, HR: 0.24, 95% CI: 0.08-0.68; p < 0.007) between 12 and 36 months than the DAPT group in the adjusted analysis ( Figure 2B; Table 4; Supplementary Figure 1B). Adjusted analysis showed that the risk of all-cause mortality, stroke, and stent thrombosis was not different between the two groups (Supplementary Figure 1; Table 4). Figure 5 shows the prognostic impact of antiplatelet strategy beyond 12 months on the MACCE among the various subgroups using multivariable-adjusted hazard ratios. The lower risk of MACCE observed in the SAPT vs. DAPT group was consistent across all subgroups; moreover, there was no significant interaction among the subgroups.

DISCUSSION
This study compared clinical outcomes between 12 and 36 months according to antiplatelet strategy in patients with AMI who underwent successful second-generation DES implantation-with no clinical events within 12 months-using data from a nationwide, multicenter, dedicated AMI registry.
The main findings of the study were as follows: (1) the prevalence of MACCE beyond 12 months was significantly lower in the SAPT group (Figure 6), consistently observed with confounder adjustment by multivariable analysis and PS matching; (2) in AMI with complex features, SAPT was also associated with a significantly lower risk of MACCE between   Values are n (%) unless otherwise indicated. Abbreviations as in Tables 1, 3. 12 and 36 months than DAPT; and (3) the benefits of SAPT for MACCE were consistent across diverse subgroups, including each complex feature.
Previous randomized clinical trials-including ∼20% of patients treated with PCI-did not show significant benefits with prolonged DAPT (aspirin and clopidogrel) in reducing  MACCE for 28 months and possibility of bleeding compared with SAPT (aspirin) (17). However, subgroup analysis in patients with prior MI, stroke, or symptomatic peripheral artery disease demonstrated that prolonged DAPT was more effective than SAPT at reducing ischemic events (18). In another randomized trial, all patients with first-or secondgeneration DES implantation and prolonged DAPT using clopidogrel or prasugrel plus aspirin exhibited a significantly lower risk of stent thrombosis and MACCE than SAPT (aspirin); however, moderate-to-severe bleeding was significantly more frequent, and the rate of all-cause death was higher in the DAPT group (19). Through these two, important, large-scale randomized clinical trials, it was ascertained that prolonged DAPT did not improve mortality, while increasing bleeding events. Furthermore, a meta-analysis of six trials including 21,457 patients with DES implantation demonstrated no benefit of prolonged DAPT in patients with stable coronary artery disease regarding overall ischemic outcomes, even MI (20).
In this study, the prolonged DAPT (aspirin and clopidogrel) group did not exhibit benefits regarding MACCE, death, or MI. SAPT (aspirin or clopidogrel) demonstrated favorable clinical outcomes, and with the development of DES profile, the duration of DAPT maintenance is gradually decreasing. Unlike other studies, we only targeted patients with a second-generation DES, with a thinner strut thickness, and biocompatible or biodegradable polymer coating, to improve arterial healing and decrease the risk of thrombotic adverse events (21); this may reduce the need for prolonged intense platelet inhibition beyond 12 months. Our study was additionally analyzed in an East Asian population, with a lower number of thrombotic events observed than in Westerners (22). In a previous randomized trial including Korean patients who underwent PCI (primarily first-generation DES) exhibiting no adverse clinical events within 12 months, prolonged DAPT (aspirin and clopidogrel) for 12-36 months resulted in a small number of clinical events-including all-cause death, MI, and stroke-without associated benefits (23). Fewer absolute ischemic events observed in East Asians compared with Westerners may therefore reduce the need for prolonged DAPT. We analyzed only aspirin or clopidogrel, which are commonly used in real-world clinical practice. Since the use of DAPT including potent P2Y 12 inhibitors (including ticagrelor and prasugrel) beyond 12 months was excluded, the effect of reducing the ischemic risk of DAPT may be less prominent than in other studies; therefore, in the second-generation era, a large-scale, randomized study to determine the optimal antiplatelet strategy in patients-including Asians and Westerners with stable AMI beyond 12 months-is needed.
Additionally, the SAPT group exhibited favorable clinical outcomes in patients with complex features. Along with improvements in DES profile and adjunct pharmacological treatments, patients with complex lesions could now undergo treatment via PCI in more cases. Although there remains no clear definition of complex features for PCI, several studies and expert consensus commonly include bifurcation with two stents, chronic total occlusion, severely calcified lesions using rotational atherectomy, unprotected left main PCI, implanted long stent, multivessel PCI, and ≥3 stents implanted (4,24,25). Nevertheless, there are limited data regarding the appropriate antiplatelet strategy for complex PCI.
Recently, short DAPT with ticagrelor monotherapy exhibited significantly lower bleeding events, without increasing the ischemic risk in patients with complex PCI or STEMI (24,26); however, in real-world AMI settings, there is still no concept of complex PCI. Furthermore, chronic total occlusion, or bifurcation with two stents or rotational atherectomy, is rare; therefore, we only included left main PCI, implanted long stent, multivessel PCI, and ≥3 implanted stents, as components of complex features in AMI. Nevertheless, prolonged DAPT did not reduce ischemic risk compared with SAPT. Considering the reduction in the risk of ischemic events, our study results suggest that SAPT could be considered for patients with AMI and complex features who underwent second-generation DES implantation without adverse clinical events for 12 months.
This study has some limitations; first, there is an inherent limitation regarding nonrandomized, observational, registry data, which might have resulted in selection bias. However, we attempted to adjust for the measured confounders of different baseline characteristics through the adjusted analyses, including PS matching. Second, covariates used in PS matching were mainly derived from data during the index hospitalization, which did not allow adjustments for the differences in patient characteristics between 12 and 36 months after index hospitalization. Third, since there is no record of bleeding events beyond 12 months, it was difficult to analyze the extent to which bleeding events affect MACCE, including all-cause death. Our study therefore focused on ischemic risk reduction according to antiplatelet strategy beyond 12 months; complex features with a high ischemic burden were analyzed separately. Moreover, among P2Y 12 inhibitors, only clopidogrel was selected for this analysis beyond 12 months due to less bleeding tendency and most used in real world practice. Fourth, the definite reasons for DAPT vs. SAPT selection beyond 12 months is unclear, as it was decided by each clinician considering the balance of ischemic and bleeding risk in individual patients. Fifth, this study was conducted in a dedicated east Asian population and the result of this current study cannot be extrapolated to other ethnicities. Lastly, the KAMIR-NIH registry was designed for 3 years of follow-up; thus, we did not evaluate long-term ischemic risks beyond 3 years.
In conclusion, compared with DAPT with clopidogrel, SAPT using aspirin or clopidogrel alone demonstrated a significantly lower risk of MACCE between 12 and 36 months in patients with AMI treated with second-generation DES who remained uneventful for 12 months. Moreover, a reduction in ischemic risk was also observed for AMI with complex features in the SAPT group. Large-scale, multinational randomized trials are thus required to identify the optimal antiplatelet strategy beyond 12 months in patients with AMI in the second-generation DES era.

DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.

ETHICS STATEMENT
The studies involving human participants were reviewed and approved by Chonnam National University Hospital Institutional Review Board, IRB approval number: CNUH-2011-172. The patients/participants provided their written informed consent to participate in this study.