Effects of prediabetes on long-term clinical outcomes of patients with acute myocardial infarction who underwent PCI using new-generation drug-eluting stents

Journal Pre-proofs Effects of prediabetes on long-term clinical outcomes of patients with acute myocardial infarction who underwent PCI using new-generation drug-eluting stents Yong Hoon Kim, Ae-Young Her, Myung Ho Jeong, Byeong-Keuk Kim, Sung-Jin Hong, Seunghwan Kim, Chul-Min Ahn, Jung-Sun Kim, Young-Guk Ko, Donghoon Choi, Myeong-Ki Hong, Yangsoo Jang PII: DOI: Reference:

S0168-8227(19)31526-8 https://doi.org/10.1016/j.diabres.2019.107994 DIAB 107994

To appear in:

Diabetes Research and Clinical Practice

Received Date: Revised Date: Accepted Date:

22 October 2019 28 November 2019 20 December 2019

Please cite this article as: Y. Hoon Kim, A-Y. Her, M. Ho Jeong, B-K. Kim, S-J. Hong, S. Kim, C-M. Ahn, J-S. Kim, Y-G. Ko, D. Choi, M-K. Hong, Y. Jang, Effects of prediabetes on long-term clinical outcomes of patients with acute myocardial infarction who underwent PCI using new-generation drug-eluting stents, Diabetes Research and Clinical Practice (2019), doi: https://doi.org/10.1016/j.diabres.2019.107994

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Effects of prediabetes on long-term clinical outcomes of patients with acute myocardial infarction who underwent PCI using new-generation drugeluting stents Running title: Long-term outcome of prediabetes in AMI

Yong Hoon Kim a,*,1, Ae-Young Her a,1, Myung Ho Jeong b, Byeong-Keuk Kim c, Sung-Jin Hong c, Seunghwan Kim d, Chul-Min Ahn c, Jung-Sun Kim c, Young-Guk Ko c, Donghoon Choi c, Myeong-Ki Hong c, Yangsoo Jang c

a

Division of Cardiology, Department of Internal Medicine, Kangwon National University

School of Medicine, Chuncheon, Republic of Korea b Department

of Cardiology, Cardiovascular Center, Chonnam National University Hospital,

Gwangju, Republic of Korea c

Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University College of

Medicine, Republic of Korea d Division of Cardiology, Inje University College of Medicine, Haeundae Paik Hospital, Busan,

Republic of Korea

1Yong

Hoon Kim and Ae-Young Her are equally contributed to this work as first authors

* Corresponding author: Division of Cardiology, Department of Internal Medicine, Kangwon 1

National University School of Medicine, 24289, 156 Baengnyeong Road, Chuncheon City, Gangwon Province, South Korea E-mail address: [email protected] (Y.H. Kim)

E-mail addresses: [email protected] (Y.H. Kim), [email protected] (A.-Y. Her), [email protected] (M.H. Jeong), [email protected] (B.-K. Kim), [email protected] (S.-J. Hong), [email protected] (S. Kim), [email protected] (C.-M. Ahn), [email protected] (J.-S. Kim), [email protected] (Y.-G. Ko), [email protected] (D. Choi), [email protected] (M.K. Hong), [email protected] (Y. Jang).

2

ABSTRACT Aims: We investigated the 2-year clinical outcomes of patients with acute myocardial infarction (AMI) and prediabetes after new-generation drug-eluting stents implantation. Methods: A total of 11,962 patients with AMI were classified into normoglycemia (group A; 3,080), prediabetes (group B; 3,709), and diabetes (group C; 5,173) groups. The primary outcomes were the patient-oriented composite outcomes (POCOs) defined as all-cause death, recurrent myocardial infarction (Re-MI), and any repeat revascularization. Secondary outcomes were the individual components of POCOs and stent thrombosis (ST). Results: POCOs in groups B and C were significantly higher than those in group A. Cardiac death (adjusted hazard ratio [aHR]: 1.957, 95% confidence interval [CI]: 1.126–3.402; p = 0.017) and any repeat revascularization (aHR: 1.597, 95% CI: 1.052–2.424; p = 0.028) rates were significantly higher in group B than in group A. Re-MI (aHR: 1.884, 95% CI: 1.201– 2.954; p = 0.006) and death or MI (aHR: 1.438, 95% CI: 1.098–1.884; p = 0.008) were significantly higher in group C than in group B. Conclusions: In this study, prediabetes showed bad clinical outcomes post AMI. However, larger randomized controlled studies including ethnically diverse population are needed to confirm these harmful cardiovascular effects of prediabetes in the future. Key words: Prediabetes Myocardial infarction Outcomes 3

1.

Introduction

Hyperglycemia is related to adverse clinical outcomes and increased mortality in patients with acute myocardial infarction (AMI) [1-3]. Diabetes mellitus (diabetes) and prediabetes are observed in almost two-thirds of patients with AMI, who have a 2-fold higher long-term mortality rate than those with normoglycemia [4]. Patients with prediabetes are at an increased risk of cardiovascular disease (CVD), and prediabetes is associated with an increased incidence of coronary artery disease (CAD) [5-8]. However, early and long-term (up to 15 years) appropriate sustained diabetes prevention interventions (e.g., lifestyle modification or metformin use) can reduce the incidence of diabetes compared with standard care and/or placebos [9]. Furthermore, if patients can avoid diabetes, they may have a reduced risk of CVD [10-12]. One hypothesis is that strict glycemic control would attenuate the progression of coronary atherosclerosis [13]. However, there have been conflicting [14-16] and limited data concerning outcomes among patients with prediabetes after AMI. Herein we investigated the long-term clinical outcomes of prediabetes in patients with AMI who underwent percutaneous coronary intervention (PCI) with the implantation of contemporary new-generation drugeluting stents (DESs) during a 2-year follow-up period.

2.

Materials and methods

2.1.

Study Population

This was a non-randomized multicenter observational retrospective cohort study. A total of 21343 patients with AMI aged ≥ 30 years of age at the onset of diabetes who underwent successful PCI with new-generation DESs from November 2005 to June 2015 in the Korea 4

AMI Registry (KAMIR) were evaluated. Therefore, the patients who were participated in this study as a diabetes group were solely composed of type 2 diabetes. Detailed information and characteristics of the KAMIR were previously published [17]. Patients who met either of the following conditions were excluded: (1) incomplete laboratory results (n = 8,314; 39.0%); or (2) lost to follow-up (n = 1,067; 5.0%). After exclusion, a total of 11,962 AMI patients who underwent successful new-generation DESs were included. The patients were classified into normoglycemia (group A: 3,080; 25.7%), prediabetes (group B: 3,709; 31.0%), and diabetes (group C: 5,173; 43.3%) groups (Fig. 1). The study protocol was approved by the institutional review board of each participating center and the study was conducted under the 1975 Declaration of Helsinki. In this retrospective study, we evaluated patients who had provided written informed consent prior to participation in the KAMIR study. Therefore, any information concerning adverse events of these 11,962 participants with AMI including the time intervals and the types of events after the index PCI, which occurred during the follow-up period, were monitored at the outpatient clinic, by phone calls, or by reviewing their charts at each participating center in those days.

2.2.

PCI Procedures and Medical Treatment

Diagnostic coronary angiographies and PCI were performed using standard techniques [18]. Before PCI, all patients were given loading doses of aspirin 200–300 mg and clopidogrel 300– 600 mg; alternatively, ticagrelor 180 mg or prasugrel 60 mg was administered instead of clopidogrel. The total duration of dual antiplatelet therapy (DAPT; combination of aspirin 100 mg/day with clopidogrel 75 mg/day or ticagrelor 90 mg twice-daily or prasugrel 5–10 mg/day) recommended was >12 months for patients who underwent PCI. Triple antiplatelet therapy 5

(cilostazol 100 mg twice-daily added to DAPT) was left to the discretion of the individual operators. Moreover, at the time of this study, there were no operator restrictions for performing PCI 2.3

Study Definitions and Clinical Outcomes

Glycemic categories were determined based on glycosylated hemoglobin (HbA1c), fasting plasma glucose (FPG), and random plasma glucose (RPG) levels or random plasma glucose of the patients at the index hospitalization as well as their medical history. Diabetes was defined as either known diabetes for which patients received medical treatment (insulin or antidiabetics), or newly diagnosed diabetes defined as an HbA1c level ≥ 6.5%, FPG ≥ 126 mg/dL (7.0 mmol/L), and/or RPG ≥ 200 mg/dL (11.1 mmol/L) according to the American Diabetes Association clinical practice recommendations [19]. Prediabetes was defined as an HbA1c of 5.7–6.4% and an FPG of 100–125 mg/dL (5.6–6.9 mmol/L) [19]. ST-elevation myocardial infarction (STEMI) and non-ST-elevation myocardial infarction (NSTEMI) were defined according to current guidelines [20, 21]. In cases of NSTEMI, an early invasive treatment strategy was defined as a PCI within 24 hours after admission [21]. The primary clinical outcome of this study was the occurrence of patient-oriented composite outcome (POCOs) defined as all-cause death, recurrent myocardial infarction (Re-MI), or any coronary repeat revascularization. Secondary outcomes were the individual components of POCOs and definite or probable stent thrombosis (ST) during a 2-year follow-up period. All-cause death was classified as cardiac death (CD) or non-CD. Any repeat revascularization was composed of target lesion revascularization (TLR), target vessel revascularization (TVR), and non-TVR. The definitions of Re-MI, TLR, TVR, and non-TVR were previously published [22]. 2.4.

Statistical Analysis 6

For continuous variables, differences among the three groups were evaluated using analysis of variance or the Jonckheere-Terpstra test, while a post-hoc analysis of the two groups was performed using the Hochberg test or the Dunnett T3 test; the data are expressed as mean ± standard deviation. For categorical variables, intergroup differences were analyzed using the χ2 test or Fisher’s exact test as appropriate. Data are expressed as counts and percentages. Various clinical outcomes were estimated using the Kaplan-Meier method, and intergroup differences were compared using the log-rank test. We included meaningful confounding covariates (p < 0.001 or having predictive values) during the multivariate Cox regression analysis (Table 2). For all analyses, two-sided values of p < 0.05 were considered statistically significant. All statistical analyses were performed using SPSS version 20 (IBM; Armonk, NY, USA) [23].

3.

Results

3.1.

Baseline Characteristics

Table 1 shows the baseline characteristics of this retrospective study population, which consisted of patients who had a relatively well-preserved left ventricular ejection fraction (LVEF) (mean, 52.1 ± 11.3%). Group A included the most men. Group C had the oldest mean patient age of all groups. Group B included the most patients with STEMI, while group C included the most patients with NSTEMI. The three groups included similar numbers of patients with primary PCI and patients with cardiogenic shock and cardiopulmonary resuscitations (CPR). As expected, group C included the most patients with hypertension, dyslipidemia, or a previous history of heart disease (myocardial infarction [MI], PCI, coronary 7

artery bypass grafts, and heart failures) and the lowest mean estimated glomerular filtration rates (eGFR) calculated using the Modification of Diet in Renal Disease (MDRD) study equation [24]. The prescription rates of ticagrelor, prasugrel, and lipid-lowering agents were the highest in group A. The American College of Cardiology/American Heart Association lesion types, use of optical coherence tomography, and fractional flow reserve were similar among the three groups. 3.2.

Clinical Outcomes

The cumulative incidences of major clinical outcomes during the 2-year follow-up period are summarized in Table 2 and Fig. 2. The cumulative incidences of POCOs were significantly higher in group B (adjusted HR [aHR]: 1.501, 95% confidence interval [CI]: 1.136–1.984; p = 0.04) and in group C (aHR: 1.608, 95% CI: 1.245–2.077; p < 0.001) than in group A (Table 2, Fig. 2A). This higher cumulative incidence of POCOs was mainly related to increased incidences of CD (aHR: 1.957, 95% CI: 1.126–3.402; p < 0.001) and any repeat revascularization (aHR: 1.597, 95% CI: 1.052–2.424; p = 0.028). The cumulative incidence of POCOs between groups B and C was similar (aHR: 1.165, 95% CI: 0.942–1.441; p = 0.159). However, the cumulative incidences of Re-MI (aHR: 1.884, 95% CI: 1.201–2.954; p = 0.006) and death or MI (aHR: 1.438, 95% CI: 1.098–1.884; p = 0.008, Fig. 2B) were significantly higher in group C than in group B. The cumulative incidences of all-cause death (Fig. 2C), CD (Fig. 2D), Re-MI (Fig. 2E), and repeat revascularization (Fig. 2F) were significantly higher in group C than in group A. In addition, the cumulative incidence of ST was not significantly different among the three groups after adjustment (Fig. 2G). Table 3 shows the independent predictors for POCOs at 2 years. Old age, male sex, decreased LVEF (< 40%), STEMI, decreased eGFR (< 60 mL/min/1.73 m2), multivessel disease, cardiogenic shock, CPR on 8

admission, and the use of intravascular ultrasound (IVUS) were meaningful independent predictors of POCOs.

4.

Discussion

The main findings of this study are: (1) the cumulative incidences of POCOs in groups B and C were significantly higher than those in group A; (2) the cumulative incidences of POCOs were similar between groups B and C; (3) the cumulative incidences of CD and any repeat revascularization were significantly higher in group B than in group A; (4) the cumulative incidences of Re-MI and death or MI were significantly higher for group C than for group B; and (5) the cumulative incidences of all-cause death, CD, Re-MI, and repeat revascularization were significantly higher for group C than for group A. The main findings of this retrospective KAMIR study highlight the meaningful relationships between prediabetes and adverse long-term clinical outcomes after PCI using contemporary new-generation DESs. Hyperglycemia is related to alteration of inflammatory pathways, which leads to endothelial dysfunction, thrombogenesis, monocyte activation, foam cell transformation, and altered smooth muscle cell migration. Furthermore, these mechanisms increase the volume of atheromatous plaques in coronary arteries and potentiate the complexity of CAD [12, 25, 26]. In addition, Logstrup et al. [27] showed that abnormal glucose metabolism was associated with poor recovery of microvascular integrity after AMI and showed the prognostic interaction between glucometabolic states and abnormal coronary flow reserves (HR, 2.9; 95% CI, 1.1–7.6; p = 0.003). Prior studies demonstrated that higher fasting glucose levels on admission were related with worse clinical outcomes regardless of the presence or 9

absence of diabetes [28, 29]. Another study showed that prediabetes was a causative factor for arrhythmias and sudden cardiac death [30]. Data concerning the outcomes in patients with prediabetes after AMI have shown conflicting results [14-16]. Possible causes for such inconsistencies are related to the number and composition of study populations, diagnostic tests used (e.g., oral glucose tolerance test [OGTT], HbA1c, FPG), the definition of prediabetes (e.g., cut-off value of HbA1c or FPG) and follow-up durations of these studies. In the Arnold et al. study [14], the morality rate between patients with prediabetes and normoglycemia (10.6% vs. 8.6%) was statistically insignificant during the 3-year follow-up period. However, their study population was not confined to patients with AMI receiving new-generation DESs. In the Kok et al. study [15], a sub-study of the multicenter BIO-RESORT trial, prediabetes was associated with a twofold higher event risk than normoglycemia (aHR: 2.0, 95% CI: 1.4–3.0) based on HbA1c values. Additionally, comparative clinical outcomes were similar between prediabetes and diabetes (11.1% vs. 10.5%) in that study. In the Kok et al. study [15], approximately 50% of the total study population had AMI (STEMI and NSTEMI), and their follow-up duration was 1 year compared to our retrospective study in which all participants had AMI and their 2year major clinical outcomes were evaluated. In the Giraldez et al. study [16], the patients with prediabetes did not show worse clinical outcomes than those with normoglycemia. However, the study population of Giraldez et al. [16] consisted of only NSTEMI patients. More recently, von Birgelen et al. [31] reported the results of the BIO-RESORT Silent Diabetes Study. In their study, the cumulative incidence of major adverse cardiac events was different between patients with prediabetes (5.5%) and normoglycemia (3.0%) (log-rank, p = 0.07) based on HbA1c levels. Similar to the Kok et al. study [15], approximately 50% of the patients had AMI and a 1 year follow-up duration. Furthermore, studies by Kok et al. [15] and von Birgelen et al. [30] used 10

stricter guidelines [32, 33] to define prediabetes (HbA1c: 6.0–6.4%; FPG: 6.1–6.9 mmol/L) than our study. In this study, the cumulative incidences of CD and any repeat revascularization of the patients with prediabetes were significantly higher than those of the patients with normoglycemia. Although many previous studies examined the relationship between HbA1c levels and clinical outcomes, their studies were not performed in this era of new-generation DESs [34-36]. Cueva-Recalde et al. [37] suggested that prediabetes was not associated with long-term adverse cardiovascular outcomes in patients with CAD and PCI based on HbA1c levels during a mean follow-up period of 42.3 ± 3.6 months. In contrast, one meta-analysis [38] demonstrated that prediabetes defined by HbA1c was associated with an increased risk of composite cardiovascular events (relative risk: 1.21, 95% CI; 1.01–1.44). Therefore, the result of our study may be similar to those of that meta-analysis. Choi et al. [39] suggested that patients with prediabetes tended to show higher incidences of binary restenosis (15.6% vs. 9.8%, p = 0.066) and late loss (0.71 ± 0.70 mm vs. 0.59 ± 0.62 mm; p = 0.076) than patients with normoglycemia during their 2-year follow-up period. Therefore, a possible cause of the higher cumulative incidence of revascularization in our study in patients with prediabetes compared to those with normoglycemia could reflect the results of the Choi et al. study [39]. Another possible cause of higher revascularization rate may be related to the increased use of intravascular ultrasound (IVUS) during the procedure in the prediabetes group than in the normoglycemic group (23.8% vs. 21.5%, p = 0.025). In this study, the use of IVUS was an independent predictor of POCOs (aHR: 1.190, 95% CI; 1.026–1.379; p = 0.021; Table 3). In the Hoorn study [40], the risk of a recurrent cardiovascular event was similar between the normoglycemia and prediabetes groups. However, individuals with diabetes had an increased 11

risk of recurrent cardiovascular events compared to individuals with normoglycemia during a median 4.1 years of follow-up after the first event. Also, the cumulative incidence of Re-MI was similar between the patients with normoglycemia and prediabetes. However, the cumulative incidence of Re-MI was significantly higher in the patients with diabetes than in patients with prediabetes in this study. HbA1c is a useful monitoring tool for achieving optimal blood glucose control in diabetes and is considered a screening test to identify subjects at high risk of developing diabetes [33]. Every 1% increase in HbA1c is correlated with a higher risk of cardiovascular outcomes with a relative risk of 1.07 [41]. HbA1c values reflect the mean blood level over the previous 2–3 months [42]. Although the OGTT is considered more sensitive than HbA1c for defining diabetes, one of main advantages of measuring HbA1c is that it can be performed at any time since it does not require fasting. This is especially in circumstances in which there may be some difficulty performing and interpreting such testing in the milieu of an acute illness such as AMI [15, 43]. While HbA1c may not be ideal, it can be used as alternative diagnostic tool for making these important assessments [15]. In this study, the proportion of prediabetes was approximately 31% (3709/11962), a value that is comparable with that (31%) reported by Arnold et al. [14] and lower than that of a European study [44]. In the China Heart Study, the prevalence of prediabetes was about 24% [45]. Although these differences were related to the diagnostic tools for defining prediabetes, a higher proportion of AMI occurred in individuals with prediabetes. Prediabetes creates the potential for higher long-term mortality and higher revascularization rates than normoglycemia. More than 50 high-volume university or community hospitals in South Korea participated in this study, but the study population was insufficient to provide meaningful results. Furthermore, 12

even though prediabetes showed bad clinical outcomes post AMI in this study; larger randomized controlled studies including ethnically diverse population are needed to confirm these harmful cardiovascular effects of prediabetes in the future. Finally, previous studies demonstrated that diabetes is a well-established independent but modifiable risk factor for stroke. [47, 48] However, in this retrospective study, the cumulative incidence of stroke during a 2-year follow-up period was very low (normoglycemia: 14/3080 [0.5%], prediabetes: 25/3709 [0.7%], diabetes: 37/5173 [0.7%]; p = 0.332). Therefore, inevitably, the cumulative incidence of stroke could not be included as major clinical endpoint in this study. There were several limitations in this study. First, there may have been some underreporting and/or missed data due to the non-randomized nature of this study. Secondly, it is likely that a proportion of the patients with prediabetes (based on HbA1c levels) may be diagnosed with overt diabetes if retested using a more sensitive diagnostic test (e.g., OGTT). Therefore, any diabetes diagnostic tests (e.g., OGTT, HbA1c) must be performed for patients after discharge [46]. However, detailed information regarding these variables was not included in the KAMIR. Therefore, the results of this study can be altered based on FPG or OGTT after the acute illness has subsided. Additionally, several reports suggested that HbA1c values are not available or justifiable in rural areas of low-mid income countries. [49, 50]. Thirdly, this study was based on discharge medications since we could not confirm the participants’ adherence or non-adherence to their antidiabetic drugs. Therefore, we could not discern the degree of glycemic control of the participants during the follow-up period which might constitute an additional bias of this study. Fourthly, the 2-year follow-up period of this study was relatively short for determining the long-term major clinical outcomes and longer follow13

up period data are required. Fifthly, we performed a multivariable analysis to strengthen our results, but variables not included in the KAMIR may have affected the study outcomes. In this retrospective study, patients with prediabetes showed higher CD and any repeat revascularization rates than the normoglycemia, although they had comparable cumulative incidence of major clinical outcomes with the exception of Re-MI and death or MI. However, larger randomized controlled studies including ethnically diverse population are needed to confirm these harmful cardiovascular effects of prediabetes in the future.

Funding This research was supported by a fund (2016-ER6304-02) by Research of Korea Centers for Disease Control and Prevention.

14

Conflicts of interest None.

Acknowledgements Korea Acute Myocardial infarction Registry (KAMIR) investigators Myung Ho Jeong, MD, Youngkeun Ahn, MD, Sung Chul Chae, MD, Jong Hyun Kim, MD, Seung-Ho Hur, MD, Young Jo Kim, MD, In Whan Seong, MD, Donghoon Choi, MD, Jei Keon Chae, MD, Taek Jong Hong, MD, Jae Young Rhew, MD, Doo-Il Kim, MD, In-Ho Chae, MD, Jung Han Yoon, MD, Bon-Kwon Koo, MD, Byung-Ok Kim, MD, Myoung Yong Lee, MD, Kee-Sik Kim, MD, Jin-Yong Hwang, MD, Myeong Chan Cho, MD, Seok Kyu Oh, MD, NaeHee Lee, MD, Kyoung Tae Jeong, MD, Seung-Jea Tahk, MD, Jang-Ho Bae, MD, Seung-Woon Rha, MD, Keum-Soo Park, MD, Chong Jin Kim, MD, Kyoo-Rok Han, MD, Tae Hoon Ahn, MD, Moo-Hyun Kim, MD, Ki Bae Seung, MD, Wook Sung Chung, MD, Ju-Young Yang, MD, Chong Yun Rhim, MD, Hyeon-Cheol Gwon, MD, Seong-Wook Park, MD, Young-Youp Koh, MD, Seung Jae Joo, MD, Soo-Joong Kim, MD, Dong Kyu Jin, MD, Jin Man Cho, MD, Sang-Wook Kim, MD, Jeong Kyung Kim, MD, Tae Ik Kim, MD, Deug Young Nah, MD, Si Hoon Park, MD, Sang Hyun Lee, MD, Seung Uk Lee, MD, Hang-Jae Chung, MD, Jang-Hyun Cho, MD, Seung Won Jin, MD, Myeong-Ki Hong, MD, Yangsoo Jang, MD, Jeong Gwan Cho, MD, Hyo-Soo Kim, MD and Seung Jung Park, MD.

15

Contributors Y.H.K. and A.-Y.H. researched data and wrote the manuscript. Y.H.K., A.-Y.H., M.H.J., B.K.K., J.-S.K., and M.-K.H. contributed to study design. M.H.J., S.-J.H., S.K., C.-M.A., J.-S.K., Y.-G.K., D.C., M.-K.H., and Y.J. contributed to the collection research data. M.H.J., B.-.KK., J.-S.K., Y.-G.K., D.C., M.-K.H., and Y.J. contributed to provide intellectual inputs for the discussion. Y.H.K., A.-Y.H., S.-J.H., S.K. contributed to data analysis and edited the manuscript. Y.H.K., M.H.J., D.C., M.-K.H., and Y.J. contributed to provide supervisor role during the full processes of manuscript submitting and editing. All authors take full responsibility for this work.

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Table and figure legends Table 1 - Baseline clinical, laboratory, and procedural characteristics of patients Table 2 - Comparison of clinical outcomes at 2 years. Table 3 - Multivariable Cox-proportional regression analysis for independent predictors of POCOs

23

Fig. 1 - Flow chart. Fig. 2 - Kaplan-Meier analysis for POCOs (A), death or MI (B), all-cause death (C), cardiac death (D), re-MI (E), any repeat revascularization (F), and stent thrombosis (G).

24

Fig. 1 - Flow chart Abbreviations: AMI, acute myocardial infarction; PCI, percutaneous coronary intervention; DESs, drug-eluting stents; KAMIR, Korea AMI Registry.

25

26

Fig. 2 - Kaplan-Meier curved analysis for POCOs (A), death or MI (B), allcause death (C), cardiac death (D), Re-MI (E), any repeat revascularization (F), and stent thrombosis (G). Abbreviations: POCO, patient-oriented composite outcome; MI, myocardial infarction. 27

Table 1 - Baseline clinical, laboratory, and procedural characteristics of patients

Variables

Age (years) Men, n (%) LVEF (%) BMI (kg/m2) SBP (mmHg) DBP (mmHg) STEMI, n (%) Primary PCI, n (%) NSTEMI, n (%) PCI within 24 hours Cardiogenic shock CPR on admission Hypertension, n (%) Dyslipidemia, n (%) Previous MI, n (%) Previous PCI, n (%) Previous CABG, n (%) Previous CVA, n (%) Previous HF, n (%) Current smokers, n (%) Peak CK-MB (mg/dL) Peak troponin-I (ng/mL) NT-ProBNP (pg/mL)

Group A Normoglyce mia (n = 3,080)

p value Group B Prediabetes (n = 3,709)

Group C Diabetes (n = 5,713)

Group A Group Group Group vs. Group A vs. A vs. B vs. B vs. B C C Group C <0.00 <0.00 61.1 ± 13.1 63.3 ± 12.5 64.2 ± 11.6 0.001 <0.001 1 1 <0.00 <0.00 <0.00 2488 (80.7) 2800 (75.5) 3628 (70.1) <0.001 1 1 1 <0.00 <0.00 53.0 ± 10.7 52.7 ± 11.0 51.1 ± 11.7 0.260 <0.001 1 1 <0.00 <0.00 23.8 ± 3.1 24.2 ± 3.3 24.4 ± 3.2 0.008 <0.001 1 1 131.2 ± 27.9 129.8 ± 27.4 131.0 ± 28.1 0.034 0.785 0.035 0.055 <0.00 <0.00 80.7 ± 16.7 79.1 ± 16.3 78.7 ± 16.3 0.321 <0.001 1 1 <0.00 <0.00 1840 (59.7) 2227 (60.0) 2739 (52.9) 0.800 <0.001 1 1 1773 (96.4) 2137 (96.0) 2624 (95.8) 0.510 0.344 0.782 0.635 <0.00 <0.00 1240 (40.3) 1482 (40.0) 2434 (47.1) 0.800 <0.001 1 1 1094 (88.2) 1271 (85.8) 2051 (84.3) 0.058 0.001 0.205 0.005 122 (4.0) 159 (4.3) 244 (4.7) 0.502 0.107 0.337 0.251 152 (4.9) 177 (4.8) 210 (4.1) 0.756 0.060 0.105 0.115 <0.00 <0.00 1239 (40.2) 1624 (43.8) 3123 (60.4) 0.003 <0.001 1 1 <0.00 <0.00 <0.00 254 (8.2) 425 (11.5) 744 (14.4) <0.001 1 1 1 <0.00 <0.00 89 (2.9) 96 (2.6) 248 (4.8) 0.448 <0.001 1 1 <0.00 <0.00 121 (3.9) 174 (4.7) 396 (7.7) 0.125 <0.001 1 1 <0.00 7 (0.2) 5 (0.1) 40 (0.8) 0.367 0.001 <0.001 1 <0.00 <0.00 142 (4.6) 185 (5.0) 410 (7.9) 0.470 <0.001 1 1 <0.00 14 (0.5) 36 (1.0) 80 (1.5) 0.013 0.018 <0.001 1 <0.00 <0.00 1416 (46.0) 1740 (46.9) 2005 (38.8) 0.440 <0.001 1 1 105.4 ± <0.00 <0.00 140.6 ± 205.8 147.3 ± 207.4 0.183 <0.001 141.3 1 1 48.7 ± 84.6 48.5 ± 124.4 47.4 ± 148.5 0.957 0.645 0.721 0.896 1419.8 ± 1280.1 ± 2888.9 ± <0.00 <0.00 0.238 <0.001 4087.7 3123.8 7310.9 1 1 28

Hs-CRP (mg/dL)

6.67 ± 34.00

9.61 ± 54.31

11.61 ± 50.77

0.017

Serum creatinine (mg/L)

1.00 ± 0.95

1.05 ± 1.47

1.22 ± 1.64

0.165

eGFR (mL/min/1.73m2)

91.4 ± 37.9

89.2 ± 38.9

84.1 ± 43.5

0.018

Total cholesterol (mg/dL)

181.2 ± 40.7

190.0 ± 43.9

178.6 ± 48.4

Triglyceride (mg/L)

118.0 ± 87.5

133.8 ± 105.6

150.9 ± 132.2

<0.00 1 <0.00 1

HDL cholesterol (mg/L)

44.5 ± 15.3

43.8 ± 15.6

41.7 ± 14.2

0.072

LDL cholesterol (mg/L)

115.2 ± 36.7

122.4 ± 47.5

110.1 ± 39.5

<0.00 1

Discharge medications Aspirin, n (%)

2981 (96.8)

3572 (96.3)

4973 (96.1)

Clopidogrel, n (%)

2480 (80.5)

3184 (85.8)

4435 (85.7)

Ticagrelor, n (%)

374 (12.1)

317 (8.5)

403 (7.8)

Prasugrel, n (%)

190 (6.2)

173 (4.7)

242 (4.7)

Cilostazole, n (%)

434 (14.1)

704 (19.0)

1008 (19.5)

BBs, n (%)

2558 (83.1)

3060 (82.5)

4305 (83.2)

0.283 <0.00 1 <0.00 1 0.006 <0.00 1 0.550

ACEIs, n (%)

1789 (58.1)

2071 (55.8)

2608 (50.4)

0.063

ARBs, n (%)

725 (23.5)

885 (23.9)

1553 (30.0)

0.756

CCBs, n (%)

170 (5.5)

200 (5.4)

384 (7.4)

0.818

0.001

3201 (86.3)

4334 (83.8)

0.048

56 (1.5)

102 (2.0)

0.372

1567 (50.9)

1856 (50.0)

2389 (46.2)

0.596

490 (15.9) 968 (31.4)

605 (16.4) 1192 (32.1)

869 (16.8) 1813 (35.0)

0.902 0.532

84 (2.7) 1824 (59.2) 753 (24.0)

103 (2.8) 2188 (59.0) 945 (25.5)

159 (3.1) 3010 (58.2) 1437 (27.8)

0.901 0.862 0.329

1133 (36.8)

1423 (38.4)

2206 (42.6)

0.181

405 (13.1) 1022 (33.2)

505 (13.6) 1165 (31.4)

662 (12.8) 1683 (32.5)

0.575 0.120

Lipid lowering agents, n 2708 (87.9) (%) Infarct-related artery Left main, n (%) 55 (1.8) LAD, n (%) LCx, n (%) RCA, n (%) Treated vessel Left main, n (%) LAD, n (%) LCx, n (%) RCA, n (%) ACC/AHA lesion type Type B1, n (%) Type B2, n (%)

29

<0.00 1 <0.00 1 <0.00 1 0.009 <0.00 1 <0.00 1 <0.00 1 0.125 <0.00 1 <0.00 1 0.003 <0.00 1 0.843 <0.00 1 <0.00 1

0.123 <0.00 1 <0.00 1 <0.00 1 <0.00 1 <0.00 1 <0.00 1

0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001

0.675

0.305

0.882

<0.001

0.198

<0.001

0.976

0.005

0.552

<0.001

0.375 <0.00 1 <0.00 1 <0.00 1

0.665

<0.00 1

0.001

<0.001

0.550 <0.00 1 0.480 0.001

0.104 <0.00 1 0.543 0.004

0.268

0.368 0.356 0.001 <0.00 1

0.415 0.448 0.016 <0.00 1

0.583 0.595 0.002

0.645 0.544

0.260 0.263

0.531 0.279

<0.001 <0.001 <0.001

<0.001 0.730 0.001

<0.001

Type C, n (%) Extent of CAD

1379 (44.8)

1630 (43.9)

2345 (45.3)

0.495

1-vessel, n (%)

1695 (55.0)

1937 (52.2)

2221 (42.9)

0.021

2-vessel, n (%)

916 (29.8)

1137 (30.7)

1707 (33.0)

0.424

≥ 3-vessel, n (%)

469 (15.2)

635 (17.1)

1245 (24.1)

0.035

IVUS OCT FFR Drug-eluting stents ZES, n (%) EES, n (%)

661 (21.5) 23 (1.3) 29 (1.7)

881 (23.8) 30 (1.8) 45 (2.7)

1099 (21.2) 36 (1.5) 62 (2.6)

0.025 0.246 0.035

983 (31.9) 1583 (51.4)

1292 (34.8) 1921 (51.8)

1797 (34.7) 2669 (51.6)

509 (16.5)

490 (13.2)

672 (13.0)

0.011 0.889 <0.00 1

Stent diameter (mm)

3.16 ± 0.43

3.14 ± 0.42

3.10 ± 0.42

0.056

Stent length (mm)

27.1 ± 11.4

26.8 ± 11.2

27.4 ± 11.8

0.178

Number of stent

1.42 ± 0.75

1.47 ± 0.80

1.55 ± 0.83

0.008

BES, n (%)

0.622

0.196

<0.00 1 0.002 <0.00 1 0.817 0.674 0.055

<0.00 1 0.020 <0.00 1 0.005 0.399 0.724

0.009 0.980 <0.00 1 <0.00 1 0.263 <0.00 1

0.925 0.854

0.015 0.982

0.761

<0.001

<0.00 1 0.007 <0.00 1

Values are means ± SD or numbers and percentages. The p values for categorical data were obtained from the chisquare or Fisher’s exact test. For continuous variables, differences among the three groups were evaluated using the analysis of variance or the Jonckheere-Terpstra test, and post-hoc analysis between the two groups was carried out using the Hochberg test or Dunnett-T3 test. Abbreviations: LVEF, left ventricular ejection fraction; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; STEMI, ST-segment elevation myocardial infarction; NSTEMI, non-ST-segment elevation myocardial infarction; PCI, percutaneous coronary intervention; CPR, cardiopulmonary resuscitation; MI, myocardial infarction; CABG, coronary artery bypass graft; CVA, cerebrovascular events; HF, heart failure; CK-MB, creatine kinase myocardial band; NT-ProBNP, N-terminal pro-brain natriuretic peptide; hs-CRP, highsensitivity C-reactive protein; eGFR, estimated glomerular filtration rate; HDL, high-density lipoprotein; LDL, low-density lipoprotein; ACEIs, angiotensin converting enzyme inhibitors; ARBs, angiotensin receptor blockers; CCBs, calcium channel blockers; LAD, left anterior descending coronary artery; LCx, left circumflex coronary artery; RCA, right coronary artery; ACC/AHA, American College of Cardiology/American Heart Association; CAD, coronary artery disease; IVUS, intravascular ultrasound; OCT, optical coherence tomography; FFR, fractional flow reserve; ZES, zotarolimus-eluting stent; EES, everolimus-eluting stent; BES, biolimus-eluting stent.

30

0.433 <0.001 0.004 <0.001 0.012 0.485 0.083

<0.001 0.028 <0.001

Table 2 - Comparison of clinical outcomes at 2 years. Outcomes

POCOs

Group A Group B Normoglycemia Prediabetes

LogRank

180 (6.4)

285 (8.1)

0.008

All-cause death

71 (2.5)

128 (3.6)

0.008

Cardiac death

52 (1.8)

102 (2.8)

0.005

Re-MI

43 (1.6)

62 (1.8)

0.420

Death or MI

108 (3.8)

186 (5.2)

0.004

Any repeat revascularization

80 (3.0)

113 (3.4)

0.388

Stent thrombosis (probable or definite)

15 (0.5)

22 (0.6)

0.553

Outcomes

Group A Group C Normoglycemia Diabetes

LogRank

180 (6.4)

511 (10.6)

<0.001

All-cause death

71 (2.5)

257 (5.2)

<0.001

Cardiac death

52 (1.8)

190 (3.8)

<0.001

Re-MI

43 (1.6)

123 (2.7)

0.004

Death or MI

108 (3.8)

367 (7.6)

<0.001

Any repeat revascularization

80 (3.0)

197 (4.3)

0.006

Stent thrombosis (probable or definite)

15 (0.5)

50 (1.0)

0.017

Outcomes

Group B

Group C

POCOs

31

Log-

Unadjusted HR (95% CI) 1.289 (1.0691.553) 1.474 (1.1031.970) 1.613 (1.1552.253) 1.173 (0.7951.731) 1.408 (1.1101.784) 1.134 (0.8521.511) 1.219 (0.6332.351) Unadjusted HR (95% CI) 1.668 (1.4071.976) 2.131 (1.6382.771) 2.159 (1.5892.934) 1.662 (1.1752.353) 1.995 (1.6092.472) 1.436 (1.1071.862) 1.989 (1.1173.541) Unadjusted

Adjusteda p value

HR (95% CI)

p value

0.008

1.501 (1.1361.984)

0.004

0.009

1.528 (0.9722.402)

0.066

0.005

1.957 (1.1263.402)

0.017

0.421

1.010 (0.5721.782)

0.973

0.005

1.408 (0.9802.023)

0.064

0.388

1.597 (1.0522.424)

0.028

0.553

1.286 (0.5013.302)

0.601

Adjusteda p value

HR (95% CI)

p value

<0.001

1.608 (1.2452.077)

<0.001

<0.001

1.768 (1.1712.670)

0.007

<0.001

1.887 (1.1223.175)

0.016

0.004

1.752 (1.0872.823)

0.021

<0.001

1.895 (1.3722.617)

<0.001

0.006

1.498 (1.0142.213)

0.043

0.020

2.070 (0.9034.743)

0.085

Adjusteda

Prediabetes

Diabetes

285 (8.1)

511 (10.6)

All-cause death

128 (3.6)

257 (5.2)

Cardiac death

102 (2.8)

190 (3.8)

Re-MI

62 (1.8)

123 (2.7)

Death or MI

186 (5.2)

367 (7.6)

Any repeat revascularization

113 (3.4)

197 (4.3)

Stent thrombosis (probable or definite)

22 (0.6)

50 (1.0)

POCOs

aAdjusted

Rank

HR (95% CI) 1.298 <0.001 (1.1231.500) 1.449 0.001 (1.1721.791) 1.342 0.016 (1.0551.707) 1.437 0.019 (1.0591.950) 1.425 <0.001 (1.1951.700) 1.268 0.044 (1.0061.598) 1.631 0.054 (0.9882.693)

p value

HR (95% CI)

p value

<0.001

1.165 (0.9421.441)

0.159

0.001

1.220 (0.8741.703)

0.242

0.016

1.035 (0.7061.519)

0.859

0.020

1.884 (1.2012.954)

0.006

<0.001

1.438 (1.0981.884)

0.008

0.044

1.033 (0.7481.419)

0.855

0.056

2.026 (0.9894.148)

0.054

by age, men, LVEF, BMI, DBP, STEMI, NSTEMI, hypertension, dyslipidemia, previous MI, PCI, CABG CVA, and HF, current smoker, CK-MB, NT-ProBNP, serum creatinine, eGFR, total cholesterol, triglyceride, HDL-cholesterol, LDL-cholesterol, clopidogrel, ticagrelor, cilostazole, ACEIs, ARBs, CCBs, lipid lowering agents, LDA-IRA, RCA-treated vessel, 1-vessel disease, ≥ 3-vessel disease, BES, stent diameter, number of stent. Abbreviations: POCOs, patient-oriented composite outcome defined as a composite of allcause deaths, Re-MI, or any repeat revascularization; Re-MI, recurrent myocardial infarction; LVEF, left ventricular ejection fraction; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; STEMI, ST-segment elevation myocardial infarction; NSTEMI, non-ST-segment elevation myocardial infarction; PCI, percutaneous coronary intervention; MI, myocardial infarction; CABG, coronary artery bypass graft; CVA, cerebrovascular events; HF, heart failure; CK-MB, creatine kinase myocardial band; NT-ProBNP, N-terminal pro-brain natriuretic peptide; eGFR, estimated glomerular filtration rate; HDL, high-density lipoprotein; LDL, low-density lipoprotein; ACEIs, angiotensin converting enzyme inhibitors; ARBs, angiotensin receptor blockers; CCBs, calcium channel blockers; LAD, left anterior descending coronary artery; RCA, right coronary artery; BES, biolimus-eluting stent.

32

Table 3 - Multivariable Cox-proportional regression analysis for independent predictors of POCOs Variables

Unadjusted HR (95% CI)

p value

Adjusted HR (95% CI)

p value

Group 1.207 (1.000 0.048 1.456) 1.362 (1.141 Group A vs. Group C 1.668 (1.407 - 1.976) <0.001 0.001 1.625) 1.115 (0.959 Group B vs. Group C 1.298 (1.123 - 1.500) <0.001 0.157 1.295) 1.588 (1.399 1.224 (1.064 Age ≥ 65 years <0.001 0.005 1.802) 1.408) 1.249 (1.079 Male 1.451 (1.270 - 1.659) <0.001 0.003 1.446) 2.132 (1.838 <0.00 LVEF <40% 2.657 (2.304 - 3.065) <0.001 2.437) 1 1.205 (1.057 STEMI 1.179 (1.040 - 1.337) 0.010 0.005 1.373) 1.037 (0.907 Hypertension 1.271 (1.120 - 1.442) <0.001 0.593 1.186) 1.080 (0.894 Dyslipidemia 1.108 (0.919 - 1.336) 0.282 0.424 1.305) 1.526 (1.319 <0.00 eGFR < 60mL/min/1.73m2 2.048 (1.787 - 2.347) <0.001 1.766) 1 1.434 (1.254 Multivessel disease 1.640 (1.439 - 1.869) <0.001 <0.001 1.640) 1.326 (1.037 Cardiogenic shock 1.876 (1.480 - 2.377) <0.001 0.025 1.695) 3.409 (2.818 <0.00 CPR on admission 4.043 (3.371 - 4.849) <0.001 4.124) 1 1.132 (0.966 ACC/AHA type B2/C 1.211 (1.037 - 1.414) 0.015 0.125 1.326) 1.066 (0.931 Stent diameter < 3.0mm 1.182 (1.036 - 1.349) 0.013 0.353 1.221) 1.007 (0.884 Stent length ≥ 28mm 1.168 (1.030 - 1.325) 0.016 0.917 1.146) 1.190 (1.026 IVUS 1.159 (1.001 - 1.341) 0.049 0.021 1.379) Abbreviations: HR, hazard ratio; CI, confidence interval; Group A, normoglycemia; Group B, prediabetes; Group C, diabetes; LVEF, left ventricular ejection fraction; STEMI, ST-segment elevation myocardial infarction; eGFR, estimated glomerular filtration rate; CPR, cardiopulmonary resuscitation; ACC/AHA, American College of Cardiology/American Heart Association; IVUS, intravascular ultrasound. Group A vs. Group B

1.289 (1.069 - 1.553)

33

0.008

Highlights

Hyperglycemia is related with adverse clinical outcomes in acute myocardial infarction Prediabetes had higher cardiac death and repeat revascularization rates than normoglycemia Diabetes had higher recurrent myocardial infarction rates than prediabetes.

34