Prolonged dual antiplatelet therapy in patients with non‐ST‐segment elevation myocardial infarction: 2‐year findings from EPICOR Asia

Abstract Background Patients with non‐ST‐segment elevation myocardial infarction (NSTEMI) have a generally poor prognosis and antithrombotic management patterns (AMPs) used post‐acute coronary syndrome (ACS) remain unclear. Duration of dual antiplatelet therapy (DAPT) and patient characteristics was evaluated in NSTEMI patients enrolled in EPICOR Asia. Hypothesis Patients stopping DAPT early may benefit from more intensive monitoring. Methods EPICOR Asia was a prospective, real‐world, primary data collection, cohort study in adults with an ACS, conducted in eight countries/regions in Asia, with 2 year follow‐up. Eligible patients were hospitalized within 48 hours of symptom onset and survived to discharge. We describe AMPs and baseline characteristics in NSTEMI patients surviving ≥12 months with DAPT duration ≤12 and > 12 months post‐discharge. Clinical outcomes (composite of death, myocardial infarction, and stroke; and bleeding) were also explored. Results At discharge, 90.8% of patients were on DAPT (including clopidogrel, 99%). At 1‐ and 2‐year follow‐up, this was 79.2% and 60.0%. Patients who stopped DAPT ≤12 months post‐discharge tended to be older, female, less obese, have prior cardiovascular disease, and have renal dysfunction. While causality cannot be inferred, the incidence of the composite endpoint over the subsequent 12 months was 10.6% and 3.1% with shorter vs longer use of DAPT, and mortality risk over the same period was 8.4% and 1.6%. Conclusions Over 90% of NSTEMI patients were discharged on DAPT, with 60% on DAPT at 2 years. Patients stopping DAPT early were more likely to have higher baseline risk and may therefore benefit from more intensive monitoring during long‐term follow‐up.

Global Burden of Disease Study showed that CHD remained the leading cause of premature death worldwide in 2016, with an agestandardized mortality rate of 149.7 per 100 000. 1 While mortality from CHD has progressively declined since 1990 in middle-and highincome countries, it has increased in low-income regions. 1 Suggested causes include the growing proportion of people aged ≥60 years, lifestyle factors (such as tobacco and alcohol use, and increasing consumption of foods with high energy/fat content), lack of preventative measures, low availability of CHD management, and lack of rehabilitation and secondary prevention programmes. 2,3 In fact, increasingly westernized lifestyles have been implicated in the increasing prevalence of overweight, diabetes, and associated cardiovascular diseases (CVD) among affluent people within low-to middle-income countries. 3 In the United States, approximately 70% of patients presenting with an acute coronary syndrome (ACS) have a non-ST-segment elevation (NSTE)-ACS, comprising non-ST-segment elevation myocardial infarction (NSTEMI) and unstable angina (UA), and only 30% have an STsegment elevation myocardial infarction (STEMI). 4 In Asia, the ratio is reversed, with 60-80% of patients presenting with STEMI, but there is evidence that the proportion of Asian patients with NSTE-ACS is growing. 5 Furthermore, although short-term mortality is higher with STEMI, the risk of death during long-term follow-up is greater with NSTEMI. 6,7 Recent guidelines in the United States and Europe include a class 1 recommendation for 12 months of dual antiplatelet therapy (DAPT) with aspirin and a P2Y 12 inhibitor following ACS. 4,8,9 However, in some populations with high risk, 12 months' duration of DAPT is not long enough. The subgroup analysis of the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance trial showed that patients with clinically evident atherothrombosis (documented prior MI, ischemic stroke, or symptomatic peripheral artery disease) benefitted from long-term DAPT (median duration 27.6 months) beyond aspirin alone. 10,11 Another trial, PEGASUS-TIMI 54 (Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis in Myocardial Infarction 54) showed that in patients with a MI more than 1 year previously, treatment with long-term DAPT (median duration 33 months) significantly reduced the risk of cardiovascular (CV) death, MI, or stroke compared with aspirin therapy alone. 12 Several meta-analyses and a systematic review of randomized trials have also indicated that prolonging DAPT to more than 1 year following myocardial infarction (MI) can reduce CV event rates, although at the risk of increased (nonfatal) bleeding. [13][14][15][16] However, the benefits of continuing DAPT beyond a year in real-world populations are less well defined, and there is relatively little evidence from Asian countries. The EPICOR Asia (long-tErm follow-uP of antithrombotic management patterns In Acute CORonary syndrome patients in Asia) study was an observational, primary data collection study designed to investigate acute and long-term antithrombotic management patterns (AMPs) in ACS survivors. The aim of this analysis was to evaluate long-term use of DAPT, and baseline patient characteristics associated with earlier DAPT discontinuation vs >12 months of DAPT, in patients with NSTEMI. were excluded from the study. Baseline and in-hospital data were collected retrospectively for the index event up to hospital discharge, and prospectively by means of telephone interviews at 6 weeks then every 3 months up to 2 years.
All patients provided written informed consent to participate in the study and agreed to follow-up interviews. The study was conducted in accordance with ethical principles that are consistent with the Declaration of Helsinki revision, International Conference on Harmonization Good Clinical Practice guidelines, and the applicable legislation on non-interventional studies, and written approval was obtained from the relevant local Ethics Committees and/or Regulatory Authorities.

| Objectives
The primary objective of EPICOR Asia was to describe acute and long-term AMPs in ACS survivors across a range of clinical settings in the eight different countries/regions in Asia. The objectives of the present post hoc analysis were to evaluate reported use of AMPs at discharge and during follow-up in the sub-population of patients with NSTEMI and to investigate possible differences in baseline characteristics according to DAPT duration ≤12 months vs >12 months up to the final follow-up at 2 years in patients discharged on DAPT who survived ≥12 months post-discharge. The incidence of major adverse CV events (composite of death, MI, and ischemic stroke; and death as an individual outcome) and major bleeding events during the second year post-discharge by DAPT duration ≤12 vs >12 months is also described. In practice, final interviews were conducted within Includes all patients discharged on two or more antiplatelets (ie, including triple antiplatelet therapy) from the index hospitalization. DAPT duration is defined as the time from discharge to the last use of two or more antiplatelets not accounting for interruptions. b Number affected/number with data available. F I G U R E 1 Cumulative incidence of, A, the composite endpoint and, B, mortality over the following 12 months in NSTEMI patients who survived ≥12 months and received DAPT for ≤12 months or >12 months post-discharge.* The incidence of the composite endpoint, death, MI, and stroke, over the second 12 months was 10.6% with DAPT ≤12 months and 3.1% with DAPT >12 months, and the mortality rate was 8.4% and 1.6%, respectively differences in in-hospital CV complications, degree of dependence at discharge, or EuroQol-5 Dimensions score between those who stopped DAPT early or continued beyond 12 months.

| DAPT duration and outcomes
In the NSTEMI population who survived at least 12 months post-discharge, the median (interquartile range) duration of DAPT in patients who received it for ≤12 months and > 12 months was 219 (80-347) and 718 (589-725) days, respectively. The incidence of the composite endpoint, death, MI, and stroke, over the next 12 months was 10.6% with DAPT ≤12 months and 3.1% with DAPT >12 months, and the mortality rate was 8.4% and 1.6%, respectively (Table 4 and Figure 1).
There were only four patients with major bleeding, all in the DAPT >12 months group.

| DISCUSSION
The results of this analysis of NSTEMI patients included in the EPI-COR Asia study showed that the majority (90.8%) were discharged on DAPT, 78.8% continued it for over 12 months, and 60.0% remained on DAPT at the final 2-year follow-up visit. Patients who discontinued DAPT within the first year appeared to be a higher-risk population, as they were older, and more likely to have a history of CVD or renal dysfunction. Conversely, patients treated with DAPT beyond 1 year appeared to be at lower CV risk. This reflects the observed paradox that higher-risk patients post-MI are less likely to persist with prescribed medication. 18 A recent Canadian observational study in 2034 acute MI patients (NSTEMI or STEMI) who had undergone PCI also reported higher baseline risk among patients who discontinued DAPT early compared with at least 12 months of treatment. 19 In that study, significant differences in baseline characteristics with shorter vs longer DAPT duration included older age, history of MI, heart failure, or atrial fibrillation, and a higher Global Registry of Acute Coronary Events (GRACE) score (all P < .001 for trend). The authors also reported a higher incidence of a composite primary outcome (nonfatal acute MI, unplanned coronary revascularization, stent thrombosis, new or worsening heart failure, cardiogenic shock, or stroke) in patients who discontinued DAPT in less than 6 weeks (P < .0001), and 6 weeks to <6 months (P = .02), but not for 6 months to <12 months (P = .06) compared with DAPT ≥12 months, indicating that the highest risk of events is in the earliest stages following an acute MI. This appears to be reflected in the EPICOR Asia data, since most of the sig-  Here, more than 80% of patients were managed medically following hospitalization with 48% discharged on DAPT; this declined to 32% and 16% at 3 and 12 months, respectively. 21 Although the authors did not report on CV outcomes, this was a younger population than in EPICOR Asia and a high-risk population with only 3% having no identifiable CV risk factor.
In fact, the high-risk population should be given longer duration of DAPT than others, which was verified in THEMIS (The Effect of Ticagrelor on Health Outcomes in diabetes Mellitus patients Intervention Study). 22 The results showed that patients aged 50 years or older with stable CAD and diabetes, even without a history of MI or stroke, had a lower incidence of ischemic CV events with long-term DAPT (median duration 39.9 months) vs single aspirin therapy. The THEMIS-PCI substudy showed that in the prespecified subgroup of patients with diabetes, stable CAD, and previous PCI, long-term DAPT (median duration 3.3 years) provided a favorable net clinical benefit, more so than in patients without a history of PCI. 23 In EPICOR Asia, the "real-world" trial, the incidence of major adverse CV events, including mortality, during the second year of follow-up among patients who survived at least the first year was higher with ≤12 months of DAPT compared with >12 months of DAPT. Furthermore, the higher incidence of the composite endpoint in patients who received DAPT for up to 12 months appeared largely driven by cumulative mortality. As stated earlier, however, a causal relationship cannot be inferred between earlier DAPT discontinuation and increased risk of subsequent events. In the "real-world" setting, the reasons contributing to DAPT use and duration will be multifarious. It is possible that at least some cases of early DAPT discontinuation are driven by bleeding events, and patients at increased risk of bleeding are also often at increased risk of ischemic events, and vice versa. 24 The results of other studies referred to above also suggest that ACS patients who stop DAPT earlier, for any reason, are a potentially high-risk group requiring careful monitoring and management.

| Limitations
Limitations of the present analysis include those usually applicable to observational studies, such as the nonrandomized nature of the study population. There is also the risk of immortal time bias; that is, bias introduced by the study design in which an outcome cannot occur during the specified period of follow-up. 25 In this study, for example, patients had to survive until the 12-month follow-up visit in order to be included in the prolonged DAPT group, necessarily inferring an advantage for these patients. Such potential bias may be evident in the somewhat counter-intuitive observation that NSTEMI patients with a prior history of CVD in EPICOR Asia were more likely to discontinue DAPT early. This could be explained by the possibility that their overall health was worse and they were more likely to have died during the first 12 months and therefore had no opportunity to continue on DAPT for >12 months. Our analysis of baseline risk factors did show that many of the significant differences between shorter vs longer overall DAPT duration populations became less or nonsignificant when we focused on patients who survived the first 12 months.
It should also be noted that most patients were enrolled at wellequipped centers, perhaps fostering greater uptake of evidence-based guidelines, specifically, the use of DAPT.
Finally, while the reasons for DAPT discontinuation were not reported, some may be suggested. For example, baseline data showed that patients who were older, female, with low body mass index (BMI), previous CVD, or renal insufficiency tended to stop DAPT treatment soon after discharge. The early cessation of DAPT in the older, low-BMI patients may be associated with bleeding, such as epistaxis and gingival bleeding. Although such bleeding is usually mild, the patient may be very nervous and likely to stop DAPT as soon as possible. Early discontinuation of drugs in women may be related to lack of awareness of ACS disease, low family and social status, and insufficient attention. In patients with previous CVD or renal insufficiency, early withdrawal of medication may be associated with too many concomitant drugs or treatment with DAPT for a period prior to study enrollment. Furthermore, in some cases, taking too much medicine can cause stomach discomfort or ulcers. Sometimes, for example, aspirin therapy may be stopped, either under the guidance of a doctor or by the patient him/herself. As premature cessation of DAPT can increase the risk of CV events, additional attention should be paid to these groups, including patient education, increased follow-up frequency, and close guidance on antiplatelet therapy and other treatments.

| CONCLUSIONS
In summary, the majority of NSTEMI patients in EPICOR Asia were discharged on DAPT, and nearly two-thirds remained on it at 2 years.
NSTEMI patients in whom DAPT treatment is stopped earlier than 12 months post-discharge appear to represent a vulnerable group in terms of baseline risk factors and may benefit from more intensive monitoring during long-term follow-up.