Long‐term antithrombotic management patterns in Asian patients with acute coronary syndrome: 2‐year observations from the EPICOR Asia study

Abstract Background Despite guideline recommendations, dual antiplatelet therapy (DAPT) is frequently used for longer than 1 year after an acute coronary syndrome (ACS) event. In Asia, information on antithrombotic management patterns (AMPs), including DAPT post discharge, is sparse. This analysis evaluated real‐world AMPs up to 2 years post discharge for ACS. Hypothesis There is wide variability in AMP use for ACS management in Asia. Methods EPICOR Asia (NCT01361386) is a prospective observational study of patients discharged after hospitalization for an ACS in eight countries/regions in Asia, followed up for 2 years. Here, we describe AMPs used and present an exploratory analysis of characteristics and outcomes in patients who received DAPT for ≤12 months post discharge compared with >12 months. Results Data were available for 12 922 patients; of 11 639 patients discharged on DAPT, 2364 (20.3%) received DAPT for ≤12 months and 9275 (79.7%) for >12 months, with approximately 60% still on DAPT at 2 years. Patients who received DAPT for >12 months were more likely to be younger, obese, lower Killip class, resident in India (vs China), and to have received invasive reperfusion. Clinical event rates during year 2 of follow‐up were lower in patients with DAPT >12 vs ≤12 months, but no causal association can be implied in this non‐randomized study. Conclusions Most ACS patients remained on DAPT up to 1 year, in accordance with current guidelines, and over half remained on DAPT at 2 years post discharge. Patients not on DAPT at 12 months are a higher risk group requiring careful monitoring.

>12 months, with approximately 60% still on DAPT at 2 years. Patients who received DAPT for >12 months were more likely to be younger, obese, lower Killip class, resident in India (vs China), and to have received invasive reperfusion. Clinical event rates during year 2 of follow-up were lower in patients with DAPT >12 vs ≤12 months, but no causal association can be implied in this non-randomized study.
Conclusions: Most ACS patients remained on DAPT up to 1 year, in accordance with current guidelines, and over half remained on DAPT at 2 years post discharge.
Patients not on DAPT at 12 months are a higher risk group requiring careful monitoring. The pivotal CHARISMA (Clopidogrel for High atherotherombotic Risk and Ischemic Stablization, Management, and Avoidance) trial demonstrated that dual antiplatelet therapy (DAPT) with clopidogrel plus aspirin for a median of 28 months was effective in reducing a composite endpoint (myocardial infarction [MI], stroke, or death from cardiovascular causes) compared with aspirin alone in patients with clinically evident atherothrombosis, but not the overall population with either clinically evident cardiovascular disease or multiple risk factors. 4 A subsequent subgroup analysis from CHARISMA confirmed the benefit of DAPT in patients with prior MI, ischemic stroke, or symptomatic peripheral arterial disease, with a significant reduction in the composite endpoint but no difference in severe bleeding compared with aspirin alone. 5 As a result of this and subsequent studies, recent national and international guidelines recommend the use of DAPT for patients surviving an ACS, including those with ST-elevation myocardial infarction (STEMI) or non-ST-elevation ACS (NSTE-ACS), the latter comprising non-ST-elevation myocardial infarction (NSTEMI) and unstable angina (UA). [6][7][8][9][10][11][12] In general, guidelines recommend the use of DAPT for up to 12 months post-ACS, with a switch to single antiplatelet therapy (SAPT) as appropriate, if bleeding risk is increased. However, guidelines are emerging that support prolonged DAPT in patients with ACS deemed to be at high risk of further ischemic events, particularly where the risk of ischemic events and cardiovascular death outweigh the risk of life-threatening bleeding. [12][13][14] A recent real-world observational study showed that the proportion of patients receiving DAPT for more than a year after discharge post MI was higher in the APAC region (39%) than in Europe (12%), 15 but data describing the impact of prolonged DAPT on outcomes in Asia are limited. The real-world EPICOR Asia (long-tErm follow-uP of antithrombotic management patterns In acute CORonary syndrome patients in Asia) study (NCT01361386) followed ACS survivors across eight countries and regions in Asia for up to 2 years after an ACS event. 3 EPICOR Asia had two co-primary outcomes analyses performed; the first, reported elsewhere, examined the relationship between patient characteristics and long-term outcomes according to index event diagnosis. 16 The second, reported here, examined the relationship between patient characteristics and antithrombotic management patterns (AMPs) used, and observed long-term clinical outcomes. Economic outcomes have also been examined. 17 Overall, 13 005 patients were enrolled in EPICOR Asia, most from China (63.6%) and India (19.1%). Among these, 12 922 were eligible for inclusion; 83 patients were excluded (19 did not survive to discharge, ie, were incorrectly enrolled, and 64 were excluded-from one site-due to critical data quality issues). Data on patient demographics, medical history, and management were collected from symptom onset to discharge and AMPs at hospital discharge and post discharge by means of telephone interviews scheduled at 6 weeks and then every Where appropriate, to avoid "loss" of patients whose last interview was 1 or 2 weeks prior to the 24-month timepoint, medication status at 23 months is reported. For patients on SAPT or DAPT at discharge, the proportions remaining on SAPT or DAPT, or who switched to another antiplatelet pattern, were evaluated. Possible associations between baseline factors, SAPT use at discharge, and DAPT duration >12 months vs ≤12 months were investigated.
Time from discharge to event (including time to first major bleeding event) was assessed, including analysis by EPICOR 2-year risk score, based on previously published data from the EPICOR 19 and EPICOR Asia studies. 20 Clinical events were death and the composite of death, non-fatal MI, or non-fatal ischemic stroke (with or without major bleeding).
All outcomes were validated as previously described. 3

| Statistical analysis
Patient characteristics are described using appropriate descriptive statistics, with P values derived from chi-square test for categorical variables, two-sample t-test for comparison of means, and Wilcoxon test for comparison of medians. Logistic regression models were used to evaluate relationships between baseline characteristics, and (a) SAPT use at discharge, and (b) DAPT use >12 vs ≤12 months, with odds ratio (OR) and two-sided 95% confidence interval (CI) presented. A stepwise model selection was made with the P value cut-offs for selection at P < .01 and retention at P < .20.
Data are presented in terms of OR and associated two-sided 95% CIs and P values. The proportion of patients discharged on DAPT who remained on DAPT beyond 12 months is also described by percentile (≤60th, >60th and ≤80th, >80th and ≤90th, and >90th, referred to as low, moderate, high, and very high risk categories, respectively) for each EPICOR 2-year risk score category.
An exploratory analysis of time from 12 months after discharge to each clinical event during the second year of follow-up by DAPT duration (>12 or ≤ 12 months) was made based on Cox proportional hazards models with stepwise model selection with DAPT duration (>12 or ≤12 months), index event diagnosis, age (<60, 60 to <75, and

| Patient characteristics
Details of baseline patient characteristics have been published previously. 3 Table S3). By 12 months post discharge, 86.4% were still receiving DAPT, which decreased to 62.5% by 2 years (Figure 1).
Demographics, index diagnosis, and general health status of patients discharged on DAPT who survived ≥12 months and continued on DAPT for ≤12 vs >12 months a and 9275 for more than 12 months (median 23.6 months) ( Table 1).
Twelve-month survivors who received DAPT for more than 12 months post discharge, compared with ≤12 months, were younger, had a higher BMI, and were more likely to be male and to have received an in-hospital invasive procedure for the index event ( predictor of SAPT/no antiplatelet vs DAPT at discharge was anticoagulant use (Supporting information, Table S4). Other significant predictors of SAPT/no antiplatelet use were any degree of physical dependence (vs no dependence), Killip class >I, female sex, and residency in India vs China, whereas patients with ejection fraction ≥30% and those who underwent in-hospital intervention (PCI/CABG) were more likely to be discharged on DAPT.
When evaluated in terms of EPICOR 2-year risk score, the number of patients remaining on continuous DAPT were generally lower as risk percentiles increased, up to the 15-month visit, although this pattern was less apparent thereafter ( Figure 2; Supporting information, Table S5). There was greater loss to follow-up at each timepoint in the highest percentile group (>90th).
When comparing the groups who were treated with DAPT >12 months vs ≤12 months in the 12-month survivors, the hazard of composite of death, MI, and stroke was much lower in the group treated with DAPT >12 months (adjusted HR 0.39) (Figure 3), seemingly lower than would be expected should treatment allocation bias and confounding have been sufficiently reduced. This was also apparent insofar as the adjusted HR was quite similar to the unadjusted HR (0.33). The same trend was shown for both mortality and when major bleeding was added to the above composite. Similarly, the incidence of each endpoint (number of first events per 100 patient-years) was lower in the DAPT >12 months population.

| DISCUSSION
The EPICOR Asia study revealed that, despite guideline recommendations at the time of the study, most patients with ACS in Asia In summary, this analysis of results from EPICOR Asia has shown that most patients surviving an ACS in Asia were discharged on DAPT, and more than half remained on DAPT for up to 2 years of follow-up.
Prolonged DAPT was more likely to be employed in younger patients, and those with DES placement or in-hospital PCI/CABG, and less likely to be used in China compared with India. Patients in whom DAPT treatment was stopped earlier than 12 months post discharge had higher rates of mortality and adverse cardiovascular events. While a causal relationship between outcomes and DAPT duration in this study cannot be inferred, the findings do suggest that patients who receive DAPT for ≤12 months are a high-risk population and may require greater medical attention after discontinuation of DAPT than patients who receive DAPT for longer.