Risks of Recurrent Cardiovascular Events and Mortality in 1-Year Survivors of Acute Myocardial Infarction Implanted with Newer-Generation Drug-Eluting Stents

Current treatments for acute myocardial infarction (AMI) have dramatically improved clinical outcomes during the first year after AMI. Less is known, however, about the subsequent risks of recurrent cardiovascular events and mortality in patients who survive 1 year after AMI. The purpose of the present study is to evaluate long-term clinical outcomes in 1-year AMI survivors who were implanted with newer-generation drug-eluting stents (DESs) since 2010. The COREA-AMI (CardiOvascular Risk and idEntificAtion of potential high-risk population in AMI) registry consecutively enrolled AMI patients who underwent percutaneous coronary intervention (PCI), and patients who received newer-generation DESs since 2010 were analyzed. The primary endpoint was major adverse cardiovascular events (MACEs), and secondary endpoint was all-cause mortality. Of 6242 AMI patients, 5397 were alive 1 year after the index procedure. The cumulative incidence of MACEs and all-cause death 1 to 7 years after AMI were 28.4% (annually 4–6%) and 20.2% (annually 3–4%), respectively. Multivariate analysis showed that uncontrolled systolic blood pressure (SBP) and serum low-density lipoprotein cholesterol (LDL-C) concentration, as well as traditional risk factors, were associated with MACEs and all-cause death. Recurrent non-fatal myocardial infarction, ischemic stroke, and bleeding events within 1 year were significantly associated with all-cause death. The risks of adverse cardiovascular events and death remain high in AMI patients more than 1 year after the index PCI with newer-generation DESs. Traditional risk factors, uncontrolled SBP and LDL-C, and non-fatal adverse events within 1 year after the index procedure strongly influence long-term clinical outcomes.


Introduction
Acute myocardial infarction (AMI) is a common and fatal manifestation of ischemic heart disease. Although deaths from cardiovascular disease are increasing as a result of population growth and aging of the population [1,2], the age-standardized death rate from AMI has been declining in most developed countries [3]. These improvements have been attributed to many potential reasons, including the early diagnosis and treatment of AMI, the widespread use of cardiac catheterization and revascularization, the appropriate use of antithrombotics, secondary preventive therapies, development of the coronary care unit, and advances in critical care, as well as a decline in the prevalence of smoking and modifications in physical activities [3,4].
Despite these advances in diagnosis and management, AMI remains a major public health concern worldwide. Although current treatment guidelines have been updated and effective therapies recommended [5][6][7], many recommendations have focused on patient management during hospitalization or the first year after diagnosis, as most clinical trials have assessed the efficacy of beneficial strategies during the acute phase or the mid-term period, usually within 1 or 2 years [8][9][10]. However, the improved rates of short-term survival after AMI have led to evaluations of the rates of and risk factors for adverse events occurring over longer periods of time. Although several studies have demonstrated improved long-term prognosis in short-term survivors, most of these trials were conducted in the 2000s and included patients who did not undergo revascularization or received older-generation stents [11][12][13]. At present, most AMI patients are implanted with newergeneration drug-eluting stents (DESs) and take guideline-directed medical therapy [14,15]. Therefore, the purpose of the present study was to evaluate long-term clinical outcomes, for up to 7 years, in 1-year AMI survivors who were implanted with newer-generation DESs since 2010.

Study Population
The COREA-AMI (CardiOvascular Risk and idEntificAtion of potential high-risk population in Acute Myocardial Infarction) registry was designed to evaluate the real-world, long-term clinical outcomes of all consecutive patients with AMI who were evaluated at nine major university cardiac centers located throughout South Korea. These nine hospitals have shared, web-based registries enrolling AMI patients. The COREA-AMI I registry included AMI patients who underwent percutaneous coronary intervention (PCI) from January 2004 to December 2009. The COREA-AMI II registry extended the follow-up period and included additional patients from January 2010 to August 2014. Factors recorded in this large observational registry include demographic, clinical, and procedural data, and short-term and long-term clinical outcomes as long as possible by 2019. All of the included patients were over 20 years old and were treated with PCI. Patients managed with a conservative strategy were excluded. The study protocol conformed with the Declaration of Helsinki regarding investigations in humans and was approved by the Institutional Review Board of each participating center. This registry has been registered on www.ClinicalTrials.gov as NCT02806102 (accessed on 20 June 2016).
Patients were diagnosed with AMI if their concentrations of cardiac biomarkers were at least one unit above the 99th percentile with temporal variations and at least one of the following indications: symptoms of ischemia, new or apparently new significant STsegment-T wave changes or new left bundle branch block, electrocardiographic indications of pathological Q waves, imaging evidence of new loss of viable myocardium or new regional wall motion abnormality, or an angiographically detected intracoronary thrombus [16]. Patients were divided into two groups based on electrocardiography findings: those with ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI). Patients assigned to the STEMI group including those with typical ST-segment elevation in two contiguous leads and atypical electrocardiographic presentations, such as bundle branch block, isolated posterior wall myocardial infarction (MI), or ST-segment elevation in lead aVR, with appropriate clinical and angiographic findings; all other patients were assigned to the NSTEMI group. Figure 1 depicts the study flow. Between January 2004 and August 2014, 10,719 patients were diagnosed with AMI and underwent PCI. Until 2009, most were implanted with first-generation DESs. The present study evaluated patients who received newergeneration DESs from January 2010 to August 2014. Patients implanted with a bare-metal stent or first-generation DES, even if also implanted with a newer-generation DES, were excluded. Of the 6242 AMI patients who were implanted a with newer-generation DES, 593 died, and 252 were lost to follow-up within 1 year after the index procedure. Therefore, this study analyzed 5397 patients who survived for 1 year after implantation of newer-generation DESs.  AMI if their concentrations of cardiac biomarkers were  at least one unit above the 99th percentile with temporal variations and at least one of the  following indications: symptoms of ischemia, new or apparently new significant ST-segment-T wave changes or new left bundle branch block, electrocardiographic indications of pathological Q waves, imaging evidence of new loss of viable myocardium or new regional wall motion abnormality, or an angiographically detected intracoronary thrombus [16]. Patients were divided into two groups based on electrocardiography findings: those with ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI). Patients assigned to the STEMI group including those with typical ST-segment elevation in two contiguous leads and atypical electrocardiographic presentations, such as bundle branch block, isolated posterior wall myocardial infarction (MI), or ST-segment elevation in lead aVR, with appropriate clinical and angiographic findings; all other patients were assigned to the NSTEMI group. Figure 1 depicts the study flow. Between January 2004 and August 2014, 10,719 patients were diagnosed with AMI and underwent PCI. Until 2009, most were implanted with first-generation DESs. The present study evaluated patients who received newergeneration DESs from January 2010 to August 2014. Patients implanted with a bare-metal stent or first-generation DES, even if also implanted with a newer-generation DES, were excluded. Of the 6242 AMI patients who were implanted a with newer-generation DES, 593 died, and 252 were lost to follow-up within 1 year after the index procedure. Therefore, this study analyzed 5397 patients who survived for 1 year after implantation of newer-generation DESs.

Treatment and Data Collection
Coronary angiography and interventions were performed according to standard guidelines [17][18][19][20]. Patients naïve to aspirin and P2Y12 inhibitor were administered loading doses of 250-500 mg aspirin and 300-600 mg clopidogrel, 180 mg ticagrelor, or 60 mg prasugrel. The revascularization strategy, techniques, selection of devices, and adjunctive antithrombotic therapy were at the discretion of the operators. Treatments recommended after PCI included maintenance doses of aspirin (usually 100 mg once daily) and P2Y12 inhibitors (clopidogrel 75 mg once daily, ticagrelor 90 mg twice daily, or prasugrel 10 mg once daily), with the intensity and duration of dual antiplatelet therapy at the discretion

Treatment and Data Collection
Coronary angiography and interventions were performed according to standard guidelines [17][18][19][20]. Patients naïve to aspirin and P2Y12 inhibitor were administered loading doses of 250-500 mg aspirin and 300-600 mg clopidogrel, 180 mg ticagrelor, or 60 mg prasugrel. The revascularization strategy, techniques, selection of devices, and adjunctive antithrombotic therapy were at the discretion of the operators. Treatments recommended after PCI included maintenance doses of aspirin (usually 100 mg once daily) and P2Y12 inhibitors (clopidogrel 75 mg once daily, ticagrelor 90 mg twice daily, or prasugrel 10 mg once daily), with the intensity and duration of dual antiplatelet therapy at the discretion of the physician. Optimal pharmacological therapy, including statins, beta-blockers, or reninangiotensin system inhibitors, was recommended after the intervention, according to standard guidelines. Doses were titrated and medications changed at the index admission and during follow-up according to each patient's condition.
All data were collected on a web-based system after eliminating personal information. Independent research personnel collected baseline clinical, laboratory, and medication data, and independent trained reviewers and interventional cardiologists assessed angiographic and procedural data. Vital signs were obtained from chart reviews at hospital admission and discharge and at each visit to the outpatient clinic. Follow-up laboratory data were determined at the discretion of each physician. Blood pressure and lipid profiles were obtained by reviewing patients' charts. Clinical events and outcomes were obtained from electrical medical records and telephone conversations. All the adverse clinical events of interest were determined by source documents and were confirmed centrally by the committee of the Cardiovascular Center of Seoul St. Mary's Hospital, Seoul, Republic of Korea. Mortality was verified by determining whether the patient had been removed from the National Health Insurance Service, the single government-managed insurance program in Korea that includes almost the entire population of the country. The final dataset was managed by independent statisticians of the Clinical Research Coordinating Center and sealed with a code by a Clinical Research Associate.

Endpoints and Definitions
Clinical outcomes from 1 to 7 years after the index PCI were analyzed in 1-year survivors of AMI who underwent newer-generation DES implantation. The primary endpoint of this study was the incidence of major adverse cardiovascular events (MACEs), defined as cardiovascular death, non-fatal MI, non-fatal ischemic stroke, and any revascularization. The secondary endpoints were all-cause death; individual components of MACEs, including cardiovascular death, non-fatal MI, non-fatal ischemic stroke, and revascularization; and bleeding events, defined as Bleeding Academic Research Consortium (BARC) 2, 3, and 5 [21].
Cardiovascular death was defined as death resulting from AMI, sudden cardiac death, heart failure, stroke, or other vascular cause. Deaths without definite non-cardiovascular causes were considered cardiovascular deaths. Recurrent MI was defined as elevated cardiac marker(s) with evidence of ischemia, such as a typical symptom, electrocardiographic changes, or appropriate anatomical or functional results. Stroke was defined as an episode of focal or global neurologic dysfunction related to the brain, spinal cord, or retinal vascular injury as a result of infarction or hemorrhage. Any revascularization was defined as any unscheduled repeat PCI to any coronary lesions or unplanned coronary artery bypass surgery. Uncontrolled systolic blood pressure (SBP) was defined as mean office SBP ≥ 130 mmHg within 1 year after index PCI during follow-up, whereas uncontrolled low-density lipoprotein cholesterol (LDL-C) was defined as LDL-C ≥ 100 mg/dL at 1 year after index PCI.

Statistical Analysis
Continuous variables were reported as the mean ± standard deviation (SD) or median (interquartile range (IQR)) and analyzed by independent sample t-tests or Mann-Whitney U-tests, according to their distribution. Categorical variables were reported as a number (percent or rate) and were analyzed by the chi-square test or Fisher's exact test, as appropriate. The cumulative yearly incidence of primary and secondary endpoints was evaluated by the Kaplan-Meier method and compared by log-rank tests. Landmark analyses for events that occurred within the time points were performed. A Cox proportional hazard model was applied to analyze hazard ratios (HRs) and 95% confidence interval (CI) of covariates for endpoints. Univariate analyses included all variables in the table of baseline characteristics. To adjust for confounding factors, multivariate analyses were performed using variables significantly (p < 0.1) associated with clinical events in univariate analyses. Age cutoffs were at 55 and 65 years, based on approximate quartiles. The clinical impact of non-fatal events (MI, ischemic stroke, any revascularization, and bleeding) within 1 year after the index procedure on all-cause death beyond 1 year was analyzed by adjusting for all covariates with p < 0.1 on univariate analysis. All analyses were two-tailed, with clinical significance defined as p < 0.05. All statistical analyses were performed using SAS version 9.8 (SAS Institute Inc., Cary, NC, USA), SPSS version 20.0 (SPSS Inc., Chicago, IL, USA), and R version 3.6.1 (R Foundation for Statistical Computing, Vienna, Austria) statistical software.

Clinical Outcomes beyond 1 Year
The median follow-up duration was 1575 days (interquartile range 1102 to 2097 days). Table 2 shows the numbers of events and Kaplan-Meier estimates of events in the study population. The cumulative incidence of MACEs and all-cause mortality 1 to 7 years after index PCI were 28.5% (928 events/5061 patients) and 20.2% (684 deaths/5397 patients), respectively ( Figure 2). The annual risk of MACEs more than 1 year after index PCI was about 4-6% and the annual risk of all-cause mortality after 1 year was about 3-4%. Nonfatal MI, non-fatal stroke, any revascularization, and bleeding events were observed even in patients who did not experience events during the first year after index PCI. Although the annual risk of events during the first year was higher than those in subsequent years, the steady occurrence of events resulted in a higher overall incidence over time.
Clinical outcomes were also analyzed in patients subgrouped by age. The numbers of events and Kaplan-Meier estimates are shown in Supplementary Materials Table S2. The annual risks of MACEs more than 1 year after index PCI in patients aged <55, 55-64, 65-74, and ≥75 years were about 2.2-4.0%, 3.3-6.0%, 4.0-7.0%, and 7.5-11.8%, respectively, whereas the annual risks of all-cause death in these four subgroups were 0.6-0.9%, 1.3-3.8%, 3.5-4.7%, and 7.8-11.9%, respectively. The incidence of MACEs, all-cause and cardiovascular deaths, ischemic stroke, and bleeding increased with increasing age, whereas the incidence of MI and any revascularization did not. Kaplan-Meier analyses of MACEs and all-cause death in patients subgrouped by age showed that the log-rank p value for all age categories was <0.001 for both more than 1 year after the index procedure (Supplementary Materials Figure S1).      Clinical outcomes were also analyzed in patients subgrouped by age. The numbers of events and Kaplan-Meier estimates are shown in Supplementary Materials Table S2. The annual risks of MACEs more than 1 year after index PCI in patients aged <55, 55-64, 65-74, and ≥75 years were about 2.2-4.0%, 3.3-6.0%, 4.0-7.0%, and 7.5-11.8%, respectively, whereas the annual risks of all-cause death in these four subgroups were 0.6-0.9%, 1.3-3.8%, 3.5-4.7%, and 7.8-11.9%, respectively. The incidence of MACEs, all-cause and cardiovascular deaths, ischemic stroke, and bleeding increased with increasing age, whereas the incidence of MI and any revascularization did not. Kaplan-Meier analyses of MACEs and all-cause death in patients subgrouped by age showed that the log-rank p value for all age categories was <0.001 for both more than 1 year after the index procedure (Supplementary Materials Figure S1).
Multivariate analyses were also performed to identify predictors of MACEs and all-cause death (Supplementary Materials Table S4) more than 1 year after index PCI as a function of patient age. Anemia, renal insufficiency, multivessel CAD, and uncontrolled LDL-C were found to be significantly associated with MACEs in patients aged <65 years, whereas age, Killip classification III~IV, reduced LVEF, multivessel CAD, multivessel intervention, uncontrolled SBP, and uncontrolled LDL-C were associated with MACEs in patients aged ≥65 years. By contrast, lower body mass index, diabetes mellitus, reduced LVEF, anemia, renal insufficiency, and uncontrolled SBP were associated with all-cause death in patients aged <65 years, whereas age, male sex, Killip classification III or IV, reduced LVEF, renal insufficiency, uncontrolled SBP, and uncontrolled LDL-C were significant predictors of all-cause death in patients aged ≥65 years. Kaplan-Meier analysis of all-cause death in men and women according to age found that the cumulative unadjusted risk of all-cause death in patients aged <65 years was significantly lower in men than in women (unadjusted HR 0.63, 95% CI 0.40-0.99, p = 0.044), but this difference was not statistically significant after multivariate adjustment (adjusted HR 1.50, 95% CI 0.84-2.69, p = 0.172) (Supplementary Materials Figure S2). By contrast, the risk of all-cause death was significantly higher in men than in women aged ≥65 years (unadjusted HR 1.24, 95% CI 1.04-1.47, p = 0.014; unadjusted p for interaction = 0.006), a difference that remained statistically significant after multivariate adjustment (adjusted HR 1.82, 95% CI 1.38-2.42, p < 0.001; adjusted p for interaction = 0.114). Abbreviations: CI, confidence interval; HR, hazard ratio; LDL, low-density lipoprotein; * Adjusted by all covariates in Table 1 with p values < 0.1 on univariate analysis.

Discussion
This real-world AMI registry described the long-term clinical outcomes and their predictors in 1-year AMI survivors who underwent PCI with newer-generation DESs and received guideline-directed medical therapy. The annual risk of MACEs and all-cause death more than 1 year after index PCI were 4-6% and 3-4%, respectively, and the cumulative incidence from 1 to 7 years was 28.4% and 20.2%, respectively. Uncontrolled SBP and serum LDL-C concentration, as well as traditional risk factors, were found to be associated with higher risks of MACEs and all-cause death after 1 year. In addition, 1-year survivors who experienced non-fatal MI, ischemic stroke, or bleeding within 1 year were found to be at increased risk of all-cause death beyond 1 year.
Previous registry data and randomized controlled trials have reported long-term cardiovascular risks in patients with AMI. Table 5 lists the long-term clinical outcomes of representative studies and of the present registry [13,[22][23][24][25][26][27][28][29][30]. The long-term risks of combined endpoints, cardiovascular death, and all-cause death in our registry were similar to those in some Western registries or in Asian registries [22,26], whereas the risks in our registry were lower than those in several Western national health records that included all MI patients [23][24][25]. Later national health records studies included very older patients and more females, with fewer than two-thirds being treated with PCI or bypass surgery. The cumulative rates of combined endpoints, cardiovascular death, and all-cause death in the present study were higher than those in randomized controlled trials [13,[27][28][29][30]. Although the risks of MI and stroke were lower in the present study than in Western national health records studies and one randomized trial that included high-risk patients without history of PCI [13,23,25], the rates in our study were similar to those in Asian registry studies and other randomized trials that included only patients implanted with DES [26][27][28][29][30]. Our real-world registry included all consecutive AMI patients who underwent PCI, with the present study showing real-world clinical outcomes in 1-year survivors of AMI who received newer-generation DESs since 2010. Although direct statistical comparisons could not be performed, our findings demonstrate that, compared with previous various observational and randomized studies, the rates of cardiovascular and all-cause mortality were similar or higher, while the rates of MI and stroke were similar to studies that included only patients implanted with DES. Moreover, our study found that longterm cardiovascular risks persist in AMI patients who survive 1 year after an index PCI, even when implanted with newer-generation DESs.  Multivariate analyses demonstrated two important findings in patients who survived 1 year after AMI: First, in addition to traditional important risk factors, such as age, reduced LVEF, renal insufficiency, and multivessel CAD, two controllable risk factors, uncontrolled SBP and LDL-C, were significantly associated with poorer clinical outcomes and higher rates of all-cause death. Second, non-fatal MI, ischemic stroke, and bleeding events within 1 year from an index PCI were significantly associated with all-cause death more than 1 year after AMI. Control of BP and lipids has been shown to be important in patients with cardiovascular disease [31,32], and early adverse events were found to be associated with poorer long-term clinical outcomes [33,34]. The present findings emphasize the importance of controlling BP and LDL more than 1 year after AMI, even in patients implanted with the newer-generation DESs. Large randomized trials and/or other largescale registry studies are needed to confirm the importance of BP and LDL-C control in AMI survivors 1 year after index PCI involving the implantation of newer-generation DESs.
Sex differences in long-term mortality after AMI have been reported. For example, unadjusted analyses showed higher mortality rates in women than in men. However, mixed results have been reported after adjustment for confounding factors [35]. Although the present study found that long-term unadjusted risk of MACEs was lower in men than in women who survived 1-year after newer-generation DES implantation, this risk was similar in men and women after multivariate adjustment. By contrast, the long-term unadjusted risk of all-cause death was lower in men than in women, whereas multivariate analysis showed a higher risk in men. These results were apparently related to the increased unadjusted and adjusted HRs in men aged ≥65 years. These patterns are similar to a study showing that the adjusted HR for 20-year mortality was higher in men than in women [36]. In addition, 2018 data from the Korean Statistical Information Service (http://kosis.kr (accessed on 14 October 2020)) on persons aged ≥65 years in the general population found that the crude mortality rate was significantly higher in men than in women (3551.9 per 100,000 vs. 2779.8 per 100,000, risk ratio 1.28, 95% CI 1.22-1.34, p < 0.001). These findings were in good agreement with the difference we observed in the long-term incidence of all-cause death between men and women aged ≥65 years. Nevertheless, additional studies are required to assess differences in mortality between male and female AMI patients following PCI with newer-generation DESs.
This study had several limitations. First, this study was a registry-based observational study, with its inherent limitations and inability to adjust for unmeasurable confounders. In addition, the frequencies of missing values in registry studies differ among variables, such that inclusion of these missing values may have affected the study results. Second, despite intensive chart review and telephone interviews, some adverse clinical events may have been underestimated and some patients were lost to follow-up. However, the rate of all-cause death was quite accurate, as almost all deaths could be validated by the removal of patients from the National Health Insurance Service. Third, uncontrolled diabetes mellitus could not be evaluated because more than half were missing the value of Hb A1c. Forth, this study only patients who underwent implantation of newer-generation DESs were included. Thus, these results should be interpreted with caution in patients managed with other treatment options.

Conclusions
The risks of adverse cardiovascular events and all-cause death persist for several years in AMI patients who survive 1 year after PCI with newer-generation DESs. Several traditional risk factors were found to be predictors of adverse events. In addition, uncontrolled risk factors and non-fatal adverse events within 1 year were also associated with MACEs and mortality more than 1 year after index PCI. Physicians should be concerned with assessing and controlling risk factors and preventing non-fatal adverse events in patients with AMI.