Different Statin Effects of ST-elevation Versus Non-ST-Elevation Acute Myocardial Infarction After Stent Implantation

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Different statin effects of ST-elevation versus non-ST-elevation acute myocardial infarction in Korean after stent implantation Yong Hoon Kim MD, PhD , Ae-Young Her MD, PhD , Myung Ho Jeong MD, PhD , Byeong-Keuk Kim MD., PhD , Sung-Jin Hong MD , Seunghwan Kim MD , Chul-Min Ahn MD, PhD , Jung-Sun Kim MD, PhD , Young-Guk Ko MD, PhD , Donghoon Choi MD, PhD , Myeong-Ki Hong MD, PhD , Yangsoo Jang MD, PhD PII: DOI: Reference:

S0002-9629(19)30428-8 https://doi.org/10.1016/j.amjms.2019.12.004 AMJMS 964

To appear in:

The American Journal of the Medical Sciences

Received date: Accepted date:

26 July 2019 5 December 2019

Please cite this article as: Yong Hoon Kim MD, PhD , Ae-Young Her MD, PhD , Myung Ho Jeong MD, PhD , Byeong-Keuk Kim MD., PhD , Sung-Jin Hong MD , Seunghwan Kim MD , Chul-Min Ahn MD, PhD , Jung-Sun Kim MD, PhD , Young-Guk Ko MD, PhD , Donghoon Choi MD, PhD , Myeong-Ki Hong MD, PhD , Yangsoo Jang MD, PhD , Different statin effects of ST-elevation versus non-ST-elevation acute myocardial infarction in Korean after stent implantation, The American Journal of the Medical Sciences (2019), doi: https://doi.org/10.1016/j.amjms.2019.12.004

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc. on behalf of Southern Society for Clinical Investigation.

Different statin effects of ST-elevation versus non-ST-elevation acute myocardial infarction in Korean after stent implantation Running title: Statin therapy of STEMI vs. NSTEMI

Yong Hoon Kim, MD, PhD1, Ae-Young Her, MD, PhD1, Myung Ho Jeong, MD, PhD2, Byeong-Keuk Kim, MD., PhD3, Sung-Jin Hong, MD3, Seunghwan Kim, MD4, Chul-Min Ahn, MD, PhD3, Jung-Sun Kim, MD, PhD3, Young-Guk Ko, MD, PhD3, Donghoon Choi, MD, PhD3, Myeong-Ki Hong, MD, PhD3, and Yangsoo Jang, MD, PhD3

1

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

School of Medicine, Chuncheon, Republic of Korea;

2

Department of Cardiology,

Cardiovascular Center, Chonnam National University Hospital, Gwangju, Republic of Korea; 3

Division of Cardiology Severance Cardiovascular Hospital, Yonsei University College of

Medicine, Republic of Korea; 4Division of Cardiology, Inje University College of Medicine, Haeundae Paik Hospital, Busan, Republic of Korea.

The first two authors (Yong Hoon Kim and Ae-Young Her) contributed equally to this work.

Address for Correspondence: Yong Hoon Kim, MD, PhD.

Division of Cardiology, Department of Internal Medicine, Kangwon National University School of Medicine, 24289, 156 Baengnyeong Road, Chuncheon City, Gangwon Province, Republic of Korea. Tel: +82-33-258-9455, Fax: +82-33-258-2455, E-mail: [email protected]

Conflict of Interest Statement The authors have no financial or other conflicts of interest to disclose.

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

ABSTRACT Background: Intensive statin therapy reduces cardiovascular events in acute coronary syndrome. The data concerning the long-term clinical impacts of statin therapy between STsegment elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI) after drugeluting stents (DES) implantation are limited. We compared the 2-year clinical outcomes between these two groups after statin therapy.

Methods: A total of 30616 Korean acute myocardial infarction (AMI) patients were enrolled. Among them, 13686 patients were classified as the group A (STEMI statin user), 3824 patients were as the group B (STEMI statin non-user), 10398 patients were as the group C (NSTEMI statin user), and 2708 patients were as the group D (NSTEMI statin non-user). The major clinical endpoint was the occurrence of major adverse cardiac events (MACE) defined as all-cause death, recurrent myocardial infarction (re-MI), and any repeat revascularization during a 2-year follow-up period. Results: After adjustment, the cumulative risks of MACE (adjusted hazard ratio [aHR] = 1.112 [1.002-1.235]; P = 0.047), all-cause death (aHR = 1.271 [1.054-1.532]; P = 0.012), and target vessel revascularization (TVR, aHR = 1.262 [1.049-1.518]; P = 0.014) in the group C were significantly higher than group A. The cumulative risks of MACE, all-cause death, and cardiac death of the statin non-user group (group B and D) were significantly higher compared with statin user group (group A and C). Conclusions: Statin therapy was more effective in reducing the cumulative risks of MACE, all-cause death, and TVR in the STEMI group than NSTEMI group in Korean AMI patients after successful DES implantation. Key Indexing Terms Cardiovascular outcomes; Non-ST-Segment elevation myocardial infarction; Statins; STSegment elevation myocardial infarction

INTRODUCTION Early and intensive statin therapy reduced the cumulative incidences of mortality1-3 and reduced atherosclerotic plaque progression and new plaque development in patients with acute coronary syndrome (ACS).4,5 The European and American guidelines recommended that statin therapy should be initiated or continued in all acute myocardial infarction (AMI) patients if there is no contraindication to its use regardless of ST-segment elevation myocardial infarction (STEMI) or non-STEMI (NSTEMI) (Class 1A or 1B).6-10 Despite the beneficial effects of statin in AMI patients, the data concerning the long-term clinical effects of statin therapy between STEMI and NSTEMI after percutaneous coronary intervention (PCI) are limited. Therefore, we compared the clinical impact of statin therapy on 2-year major clinical outcomes between STEMI and NSTEMI patients who underwent successful PCI with drug-eluting stents (DES).

METHODS Study Population A total of 45863 AMI patients who underwent successful PCI with DES in the Korea Myocardial Infarction Registry (KAMIR) from November 2005 to June 2015 were evaluated. The characteristics and detailed information of this registry (KAMIR) were already published.11 This study protocol was approved by the ethics committee at each participating center and informed consents were obtained from all individual participants included in the study prior to enrollment. These processes were conducted according to the ethical guidelines of the 2013 Declaration of Helsinki. This study was a non-randomized, multicenter, observational, retrospective study. We applied the following exclusion criteria: (1) patients whose laboratory results were incomplete (n = 11282, 24.6%), (2) patients who were lost to follow-up (n = 2029, 4.4%), and (3) patients who received bare-metal stents (BMSs) (n = 2030, 4.4%). Finally, a total of 30616 acute myocardial infarction (AMI) patients who underwent successful PCI with DES were enrolled. Among these patients, 13686 patients (44.7%) were classified as the group A (STEMI with statin user), 3824 patients (12.5%) were as the group B (STEMI with statin non-user), 10398 patients (34.0%) were as the group C (NSTEMI with statin user), and the remaining 2708 patients (8.8%) were as the group D (NSTEMI with statin non-user) (Figure 1). The detailed reasons for not using statins in groups B and D were as follows: (1) Expected risk was higher than benefit due to several factors such as end-stage renal failure, advanced age ≥ 75 years, or severe heart failure (group

B, n = 1526, 39.9%; group D, n = 1001, 37.0%), (2) abnormal liver function (aspartate aminotransferase or alanine aminotransferase was higher than 3-fold than upper normal limit) (group B, n = 765, 20.0%; group D, n = 506, 18.7%), (3) multi-organ failure (group B, n = 191, 5.0%; group D, n = 108, 4.0%), (4) statin-induced myopathy or arthralgia (group B, n = 118, 3.1 %; group D, n = 136, 5.0%), or (5) unknown (group B, n = 1224, 32.0 %; group D, n = 957, n = 35.3%). In this study, all 30616 patients completed a 2-year clinical follow up by face-to-face interviews, phone calls, or chart review. Percutaneous Coronary Intervention Procedure and Medical Treatment A diagnostic coronary angiography and PCI were performed after an administration of unfractionated heparin (50–100 IU/kg) according to standard technique.12 All patients were treated with loading doses of 200 to 300 mg aspirin and 300 to 600 mg clopidogrel, when available or, alternatively, 180 mg ticagrelor or 60 mg prasugrel was given before PCI. After discharge, the dual antiplatelet therapy (DAPT, 100 to 200 mg/day of aspirin and 75 mg/day of clopidogrel) was maintained for ≥ 12 months.13 Triple antiplatelet therapy (TAPT) (100mg cilostazol twice a day were added on to DAPT) was left to the discretion of the individual operators. The kinds and doses of statin as the discharge medications were as follows, 10-80 mg of atorvastatin, 5-20 mg of rosuvastatin, 2-4 mg of pitavastatin, 10-40 mg of simvastatin, 10-40 mg of pravastatin, 80 mg fluvastatin, and 50-100 mg lovastatin per day. The choice of the kinds of statin and the dose of statin were left by the physicians’ discretion. Study Definitions and Clinical Outcomes STEMI and NSTEMI were defined according to current guidelines.10,14 In case of NSTEMI, an early invasive treatment strategy was defined as performing PCI within 24

hours after admission. The major clinical endpoint was the occurrence of major adverse cardiac events (MACE) defined as all-cause death, recurrent myocardial infarction (re-MI), any coronary repeat revascularization including target lesion revascularization (TLR), target vessel revascularization (TVR), and non-TVR during the 2-year follow-up period. All-cause death classified as cardiac death (CD) or non-CD. Re-MI was defined as the presence of clinical symptoms, electrocardiographic changes, or abnormal imaging findings of MI, combined with an increase in the creatine kinase myocardial band fraction above the upper normal limits or an increase in troponin-T/troponin-I to greater than the 99th percentile of the upper normal limit after the index PCI.14 The definition TLR, TVR, and non-TVR was previously published.15 Statistical Analysis For continuous variables, differences between two groups were evaluated with the unpaired t-test and data are expressed as mean ± standard deviations. For categorical variables, the differences between two groups were analyzed with the Chi-square test or, if not applicable, Fisher’s exact test and data are expressed as counts and percentages. To adjust for any potential confounders, multivariable Cox-regression analysis, which includes baseline confounding factors, was used for assessing independent impact factors. We tested all available variables including baseline clinical, laboratory, angiographic and procedural characteristics listed in Table 1 that could be of potential relevance. During the multivariable Cox regression analysis, the baseline confounding covariates were selected if they were significantly different (P < 0.001) or had predictive values as seen in Table 2. Various clinical outcomes were estimated with Kaplan-Meier curve analysis, and differences between groups were compared with the log-rank test. For all analyses, a two-sided P < 0.05 was considered

statistically significant. All statistical analyses were performed using SPSS software, version 20 (IBM; Armonk, NY, USA).16

RESULTS Baseline clinical, laboratory, and procedural characteristics Baseline laboratory and clinical characteristics of this study population are summarized in Table 1. In both groups, the STEMI group and the NSTEMI, the mean value of left ventricular ejection fraction (LVEF) was higher in the statin user group than statin nonuser group (STEMI group, 51.3 ± 10.9% vs. 49.1 ± 12.0%, P <0.001; NSTEMI group, 54.6 ± 11.1% vs. 52.8 ± 12.5%, P <0.001). In addition, the mean values of body mass index, systolic blood pressure, and diastolic blood pressure, the numbers of dyslipidemia, the prescription rates of aspirin, ticagrelor, prasugrel, cilostazole, beta-blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers as the discharge medications, PCI within 24 hours, the American College of Cardiology/American Heart Association lesion type B2 and C, the use of intravascular ultrasound and fractional flow reserve, one-vessel disease, the frequencies of second-generation DES (everolimus-eluting stent, biolimus-eluting stents) deployments, the numbers of deployed stents, the serum levels of total cholesterol and lowdensity lipoprotein (LDL)-cholesterol were higher in the statin user group than statin nonuser group. The mean lengths of deployed stents were longer in the statin user group than the statin non-user group. The mean age of the statin non-user group was older than the statin user group (STEMI group, 63.5 ± 12.9 years vs. 61.8 ± 12.5, P <0.001, NSTEMI group, 65.0 ± 12.0 years vs. 64.1 ± 12.0, P <0.001). The numbers of cardiogenic shock, cardiopulmonary resuscitation (CPR) on admission, diabetes mellitus (DM), previous heart failure, the

ACC/AHA lesion type B1, multivessel disease, the frequency of first-generation DES (sirolimus-eluting stent and paclitaxel-eluting stent) deployments, the serum levels of creatine kinase myocardial band, glucose, hemoglobin A1c, N-terminal pro-brain natriuretic peptide, creatinine were higher in the statin non-user group than statin user group. Clinical Outcomes Statin user vs. Statin non-user After adjustment, the cumulative risks of MACE (STEMI group, adjusted HR [aHR], 1.189; 95% confidence interval [CI], 1.041-1.358; P = 0.011; NSTEMI group, aHR, 1.389; 95% CI, 1.200–1.608; P < 0.001), all-cause death (STEMI group, aHR, 1.510; 95% CI, 1.216–1.875; P < 0.001; NSTEMI group, aHR, 1.636; 95% CI, 1.307–2.048; P < 0.001), and CD (STEMI group, aHR, 1.550; 95% CI, 1.208–1.988; P = 0.001, NSTEMI group, aHR, 1.767; 95% CI, 1.356–2.301; P < 0.001) were significantly higher in the statin non-user group than statin user group (Table 2). In addition, in the NSTEMI group, the cumulative risks of any repeat revascularization (aHR, 1.277; 95% CI, 1.035–1.576; P = 0.022) and nonTVR (aHR, 1.432; 95% CI, 1.045–1.962; P = 0.026) were also higher in the statin non-user group than the statin user group. However, the cumulative risks of Re-MI, TLR, and TVR were similar between the two groups. STEMI vs. NSTEMI After adjustment, the cumulative risks of MACE (aHR, 1.112; 95% CI, 1.002–1.235; P = 0.047), all-cause death (aHR, 1.271; 95% CI, 1.054–1.532; P = 0.012), and TVR (aHR, 1.262; 95% CI, 1.049–1.518; P = 0.014) in the NSTEMI group were significantly higher than STEMI group (Table 2). In case of statin non-user, the cumulative incidences of MACE, all-

cause death, CD, re-MI, any revascularization, TLR, TVR, and non-TVR were similar between the two groups. Figure 3 shows subgroup analysis for MACE at 2years. The group A patients who had decreased LVEF (<50%, HR, 1.32; 95% CI, 1.14-1.52; P <0.01) and who received large diameter stent (≥ 3.0mm, HR, 1.14; 95% CI, 1.01-1.28; P = 0.028) showed a more beneficial effect on MACE than the group C.

DISCUSSION As far as we know, head-to-head comparisons of the statin effect on long-term clinical outcomes in STEMI versus NSTEMI patients with AMI after successful PCI with DES are limited. Many previous studies concerning the beneficial effect of statin in patients with AMI were confined to STEMI5,6,8,14 or NSTEMI2,9,10 separately or as a whole.1,3 Therefore, we believe this may be the first report focused on the major clinical impact of statin therapy in patients with AMI with or without ST-elevation. Moreover, the present study confirms the MACE and mortality reduction capacity of statin therapy compared with statin non-use, including being more effective in patients with STEMI compared with NSTEMI. The main findings of this study are as follows: First, the cumulative risks of the MACE, all-cause death, and TVR were significantly higher in the group C compared with group A. Second, the cumulative risks MACE, all-cause death, and CD were significantly higher in the statin non-user group compared with statin user group. Third, the cumulative risks of all clinical outcomes between the group B and group D were similar. AMI is caused by thrombotic occlusion of epicardial coronary artery combined with

rupture of atherosclerotic plaques.17 Characteristically, ruptured plaques have thin and inflamed fibrous cap encircling lipid-rich necrotic core.18 These specific lesions are classified as vulnerable plaques or thin-cap fibroatheromas.17 Continuous accumulation of cytotoxic lipids in the plaque tissue lead to vicious cycle of cell death, inflammation, degradation of the fibrous tissue, and plaque rupture finally.19 NSTEMI can be caused by a thrombus formation on the surface of the plaques having thick fibrous cap without apparent plaque rupture compared with the STEMI.20,21 Fundamentally, all statins reduce serum LDL-cholesterol in a non-linear and dose-dependent fasion.22 Moreover, statin is involved in plaque regression; removal of lipid and necrotic core, restoration of endothelial function, and cessation of intravascular smooth muscle cell proliferation.23 According to the results of the ASTEROID study,24 the regimen of 40 mg/day rosuvastatin decreased 63.6% percent atheroma volume in 507 patients with stable or ACS after 24 months of treatment. In the SATURN trial,25 high dose statin therapy (atorvastatin 80 mg or rosuvastatin 40 mg) in ACS versus on-ACS patients, those with ACS had higher rates of plaque regression (−1.46 ±0.14 versus −0.89 ±0.13; P = 0.003). Statin treatment contributes to plaque stabilization by alteration of atheroma composition. Statin increases the proportion of dense calcified plaque and decreases non- calcified plaque while increasing fibrous cap thickness additionally.26 These beneficial effects of statin lead to a reduction in the frequency of major coronary events.27,28 After adjustment, the cumulative risks of MACE, all-cause death, and TVR of the NSTEMI were significantly higher than the STEMI group in this study. Some proportions of these differences were related with the poorer baseline profiles of the group C compared to the group A, such as higher numbers of cardiovascular risk factors (age, hypertension, DM, dyslipidemia, previous MI, previous PCI, previous CABG, previous CVA, previous heart

failure, and multivessel disease) (Table 1) and these characteristics were comparable with previous reports.29,30 However, it has been reported that patients with STEMI showed a greater infarct size as assessed by the serum CK-MB levels31 and cardiac magnetic resonance studies than patients with NSTEMI.32 Left anterior descending coronary artery (LAD) supplies 40-60% of the left ventricular myocardium; therefore, LAD as a IRA could result in ischemia of a large area of the myocardium.33 In the present study, the proportion of LAD as the IRA was significantly higher in group A than in group C (52.8% vs. 43.0%, P <0.001). Additionally, the mean value of LVEF in group C was significantly higher than those in group A. (54.6 ± 11.1% vs. 51.3 ± 10.9%, P <0.001). The numbers of cardiogenic shock (5.2% vs. 1.7%, p < 0.001) and CPR on admission (3.6% vs. 1.5%, p < 0.001) were also higher in group A compared with group C. Furthermore, major clinical outcomes may be influenced by differences in culprit lesion morphology between patients with STEMI and NSTEMI.34 One optical coherence tomography study34 demonstrated that plaque rupture (70% vs 47%), thincap fibroatheroma (78% vs. 49%), and red thrombi (78% vs. 27%) are more common in STEMI patients than NSTEMI patients. However, the total numbers of intravascular ultrasound users and optical coherence tomography users were relatively low and the detailed information regarding above plaque characteristics was not included in this registry, we could not provide the comparative results between the STEMI and NSTEI according to the plaque characteristics. The number of patients who underwent PCI within 24 hours between the two groups (92.8% vs 78.0%, P <0.001) may represent another important factor explaining the better clinical outcomes observed in patients with STEMI. Previous studies emphasized35-37 that the early use of statin in AMI is associated with a lower rate of early complication. In present study, the 2-year cumulative risk of all-cause

death was similar between groups B and D (aHR, 1.174; 95% CI, 1.958–1.440; P = 0.122) (Table 2). However, the early 6 months cumulative risk of all-cause death was significantly higher in group B than group D (8.7% [332/3824] vs. 6.9% [187/2708], Log-rank P = 0.004) (Fig. 2b). This pattern of cumulative risk of all-cause death may reflect early phase beneficial effect of statin after the occurrence of AMI. For the same reason, the cumulative risk of allcause death during the first 6 months after index PCI was similar between the statin-users groups (group A and group C) due to early phase beneficial effect of statin. However, the 2year cumulative risk of all-cause death was significantly higher in group C than group A (aHR, 1.271; 95% CI, 1.054-1.532; P = 0.012). These results also reflect the necessity and the importance of the early phase statin therapy after index PCI in patients with STEMI compared with those with NSTEMI. Therefore, considering the pattern of the Kaplan-Meier curves among these four groups, we could predict statin’s beneficial effect on all-cause death in the STEMI patients was much higher than the NSTEMI patients (Fig. 2b). In the statin user group, the cumulative risk of TVR in the NSTEMI group was significantly higher than the STEMI group. Previous studies demonstrated a potential benefit of statin therapy on restenosis38,39 and reported that statin use significantly slowed plaque growth compared with usual treatment.40 Although we could not precisely explain the causes of higher TVR rate in the NSTEMI group, we think that the difference in culprit lesion morphology between the two groups was related to this result. The KAMIR is a nationwide, prospective, observational on-line registry in South Korea since November 2005 and more than fifty high-volume University or community hospitals with facilities for primary PCI and onsite cardiac surgery participated in this study. Therefore, the study population of this study is large. In addition, the results of this

comparative study may provide meaningful information to interventional cardiologists concerning the important role of statin in reducing MACE, all-cause death, and TVR in STEMI patients compared with NSTEMI after PCI. Hence, despite the fact that the beneficial effects of statins in AMI are well known, the present study confirms the MACE and mortality reduction capacities of statin therapy compared with statin non-use, including being more effective in patients with STEMI compared with NSTEMI. Finally, racial differences in the cholesterol-lowering effect of statin have been suggested.41 Naito et al. reported that the differences in response to statins between Westerners

and

Asians

might

relate

to

the

pharmacokinetics

rather

than

the

pharmacodynamics of the drug.41 Others suggested the factors responsible for those differences are genetic factors, which might be related to statin-induced side effects.42 However, the detailed mechanisms of these differences in response to statins between Asians and Westerners are not fully elucidated. Therefore, in this study, only Korean AMI patients alone were enrolled; some cautions are needed to interpret the present results especially among other ethnicities in different parts of the world. In our study, there were several limitations.13,15,37 First, because this study was a nonrandomized retrospective study, there may be some under-reporting and/or missed data. Second, even though we have done multivariate analysis to strengthen our results; variables not included in this registry may have affected the study outcomes. Third, despite blood cholesterol level, especially LDL-cholesterol, is very important during the follow-up period, we could not provide the follow-up laboratory results of these parameters due to limitations of this registry data. Fourth, in both groups (STEMI and NSTEMI), the numbers of statin non-user were relatively higher considering AMI. This distribution may be related to

selection bias during the exclusion process. Fifth, because the choices of certain type of statin and specific dose of statin were left to the discretion of the individual provider, this provider’s preference for certain drugs and dose may represent another bias. Sixth, one of the most important factors that may have affected study outcomes is medication history during the follow-up period. Because this study was based on discharge medications and the registry data did not include the full data concerning long-term drug compliance and drug-related adverse events, we could not precisely estimate these factors. Seventh, as mentioned above, the total numbers of IVUS users and OCT users were relatively low and many parts of the results before and after PCI by using both devices were missed in this registry. Hence, we could not provide the proper comparative results among the four groups.

CONCLUSION The MACE, all-cause death, and TVR reduction capability of statin therapy was more prominent in the STEMI group compared with the NSTEMI group in Korean AMI patients after successful DES implantation. As predicted, the cumulative risks of MACE, allcause death, and CD in the statin non-user group were significantly higher compared with statin user group. Moreover, in the statin non-user group, the cumulative risks of all clinical outcomes were not significantly different.

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, Nae-Hee Lee, MD, Kyoung Tae Jeong, MD, Seung-Jea Tahk, MD, Jang-Ho Bae, MD, SeungWoon 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.

AUTHOR CONTRIBUTIONS Conceptualization: Y.H.K., A.-Y.H, M.H.J., B.-K.K., J.-S.K., D.C., M.-K.H., Y.J. Data curation: Y.H.K., A.-Y.H, S.-J.H., C.-M.A., S.K., J.-S.K., Y.-G.K., M.-K.H., Y.J. Formal analysis: Y.H.K., A.-Y.H, S.-J.H., S.K., C.-M.A., M.-K.H., Y.J. Investigation: Y.H.K., A.-Y.H, M.H.J., B.-K.K., J.-S.K., Y.-G.K., M.-K.H., Y.J. Methodology: Y.H.K., A.-Y.H, M.H.J., B.-K.K., S.K., J.-S.K., Y.-G.K., D.C., M.-K.H., Y.J. Project administration: Y.H.K., A.-Y.H, M.H.J., M.-K.H. Resources: M.H.J., B.-K.K., S.-J.H., B.-K.K., C.-M.A., J.-S.K., Y.-G.K., D.C., M.-K.H., Y.J. Software: Y.H.K., A.-Y.H, M.-K.H.. Supervision: Y.H.K., M.H.J., D.C., M.-K.H., Y.J. Validation: Y.H.K., A.-Y.H, M.H.J., B.-K.K., S.-J.H., S.K., C.-M.A., J.-S.K., Y.-G.K., D.C., M.-K.H., Y.J. Visualization: Y.H.K., A.-Y.H, S.-J.H., M.-K.H. Writing ± original draft: Y.H.K., A.-Y.H. Writing ± review & editing: Y.H.K., A.-Y.H, M.-K.H.

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Figure legends FIGURE 1. Flow chart. Abbreviations: AMI, acute myocardial infarction; DESs, drug-eluting stents; KAMIR, Korea AMI Registry; NSTEMI, non-ST-segment elevation myocardial infarction; PCI, percutaneous coronary intervention; STEMI, ST-segment elevation myocardial infarction.

FIGURE 2. Kaplan-Meier curve analysis for major adverse cardiac events (A), all-cause death (B), cardiac death (C), recurrent myocardial infarction (D), any repeat revascularization (E), target lesion revascularization (F), target vessel revascularization (G), and non-target vessel revascularization (H) during 2-year follow-up period. Abbreviations: CI, confidence interval; Group A, STEMI statin users; Group B, STEMI statin non-users; Group C, NSTEMI statin users; Group D, NSTEMI statin nonusers; HR, hazard ratio; MACE, major adverse cardiac events; Re-MI, recurrent myocardial infarction; TLR, target lesion revascularization; TVR, target vessel revascularization.

FIGURE 3. Subgroup analysis for major adverse cardiac events. Abbreviations: CI, confidence interval; Group A, STEMI statin users; Group C, NSTEMI statin users; HR, hazard ratio; MACE, major adverse cardiac events.

TABLE 1. Baseline clinical, laboratory, and procedural characteristics STEMI (n = 17510) Variables Men, n (%) Age (years) LVEF (%) BMI (kg/m2) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Cardiogenic shock, n (%) CPR on admission, n (%) Hypertension, n (%) Diabetes mellitus, n (%) Dyslipidemia, n (%) Previous MI, n (%) Previous PCI, n (%) Previous CABG, n (%) Previous CVA, n (%) Previous heart failure, n (%) Current smokers, n (%) CK-MB (mg/dL) Troponin-I (ng/mL) Serum glucose (mg/dL) Hemoglobin A1c (%) NT-ProBNP (pg/mL) High-sensitivity CRP (mg/dL) Serum creatinine (mg/L) Total cholesterol (mg/dL)

Statin (+) (n = 13686) 10514 (76.8) 61.8 ± 12.5 51.3 ± 10.9 24.1 ± 3.2 128.1 ± 27.2 78.8 ± 16.6 708 (5.2) 489 (3.6) 6180 (45.2) 3246 (23.7) 1502 (11.0) 347 (2.5) 545 (4.0) 46 (0.3) 684 (5.0) 82 (0.6) 6638 (48.5) 175.0 ± 226.9 61.9 ± 263.5 171.8 ± 73.8 6.54 ± 2.01 1703.4 ± 2965.5 10.7 ± 48.5 1.06 ± 1.19 186.6 ± 43.9

Statin (-) (n = 3824) 2843 (74.3) 63.5 ± 12.9 49.1 ± 12.0 23.8 ± 3.2 124.6 ± 28.7 76.7 ± 16.9 299 (7.8) 200 (5.2) 1757 (45.9) 1036 (27.1) 269 (7.0) 98 (2.6) 154 (4.0) 7 (0.2) 206 (5.4) 48 (1.3) 1761 (46.1) 195.7 ± 293.0 59.6 ± 106.7 181.6 ± 84.3 6.77 ± 2.92 2224.0 ± 4411.2 12.2 ± 62.8 1.15 ± 1.05 177.4 ± 44.6

NSTEMI (n = 13106) P value 0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.385 <0.001 <0.001 0.924 0.900 0.128 0.333 <0.001 0.007 <0.001 0.418 <0.001 0.004 <0.001 0.173 <0.001 <0.001

Statin (+) (n = 10398) 7336 (70.6) 64.1 ± 12.0 54.6 ± 11.1 24.2 ± 3.1 134.2 ± 26.0 80.6 ± 15.3 180 (1.7) 159 (1.5) 5543 (53.3) 3059 (29.4) 1385 (13.3) 485 (4.7) 743 (7.1) 68 (0.7) 728 (7.0) 152 (1.5) 3949 (38.0) 67.7 ± 162.2 24.7 ± 65.5 159.2 ± 77.8 6.60 ± 2.09 2267.4 ± 4674.9 11.5 ± 52.3 1.12 ± 1.42 185.1 ± 46.0

Statin (-) (n = 2708) 1904 (70.3) 65.0 ± 12.0 52.8 ± 12.5 23.9 ± 3.3 132.9 ± 27.1 79.6 ± 15.5 79 (2.9) 69 (2.5) 1449 (53.5) 919 (33.9) 276 (10.2) 113 (4.2) 238 (8.8) 21 (0.8) 247 (9.1) 69 (2.5) 965 (35.6) 76.5 ± 169.2 26.7 ± 41.1 165.9 ± 83.7 6.77 ± 2.21 3011.1 ± 5880.2 11.6 ± 37.8 1.42 ± 2.51 176.4 ± 45.0

P value 0.806 <0.001 <0.001 <0.001 0.025 0.002 <0.001 <0.001 0.853 <0.001 <0.001 0.275 0.004 0.493 <0.001 <0.001 0.025 0.015 0.046 <0.001 0.021 <0.001 0.980 <0.001 <0.001

Triglyceride (mg/L) 134.6 ± 108.9 HDL cholesterol (mg/L) 44.3 ± 19.3 LDL cholesterol (mg/L) 118.6 ± 39.4 Discharge medications, n (%) Aspirin, n (%) 13589 (99.3) Clopidogrel, n (%) 12315 (90.0) Ticagrelor, n (%) 722 (5.3) Prasugrel, n (%) 500 (3.7) Cilostazole, n (%) 3484 (25.5) Beta-blockers, n (%) 11402 (83.3) ACEIs, n (%) 8424 (61.6) ARBs, n (%) 3056 (22.3) CCBs, n (%) 660 (4.8) Statins, n (%) 13686 (100.0) Atorvastatin, n (%) 7184 (52.5) Rosuvastatin, n (%) 4392 (32.1) Pitavastatin, n (%) 1245 (9.1) Simvastatin, n (%) 616 (4.5) Pravastatin, n (%) 192 (1.4) Fluvastatin, n (%) 55 (0.4) Lovastatin, n (%) 2 (0.0) Angiographic & procedural characteristics PCI within 24 hours 12697 (92.8) Infarct-related artery Left main, n (%) 156 (1.1) Left anterior descending, n (%) 7229 (52.8) Left circumflex, n (%) 1260 (9.2) Right coronary artery, n (%) 5041 (36.8) Treated vessel Left main, n (%) 237 (1.7)

128.2 ± 104.1 43.8 ± 15.0 111.7 ± 39.6

0.001 0.092 <0.001

135.0 ± 106.2 43.7 ± 16.8 117.5 ± 38.4

137.4 ± 111.6 43.1 ± 16.4 110.7 ± 44.5

0.312 0.097 <0.001

3145 (82.2) 3473 (90.8) 168 (4.4) 49 (1.3) 763 (20.0) 2548 (66.6) 1951 (51.0) 640 (16.7) 159 (4.2)

<0.001 0.124 0.028 <0.001 <0.001 <0.001 <0.001 <0.001 0.085

10305 (99.1) 9258 (89.0) 644 (6.2) 368 (3.5) 2501 (24.1) 8615 (82.9) 5695 (54.8) 3046 (29.3) 994 (9.6) 10398 (100.0) 5688 (54.7) 3182 (30.6) 873 (8.4) 447 (4.3) 156 (1.5) 42 (0.4) 10 (0.1)

2227 (82.2) 2416 (89.2) 92 (3.4) 30 (1.1) 567 (20.9) 1765 (65.2) 1202 (44.4) 586 (21.6) 286 (10.6)

<0.001 0.788 <0.001 <0.001 0.001 <0.001 <0.001 <0.001 0.118

3504 (91.6)

0.018

8107 (78.0)

1855(68.5)

<0.001

71 (1.9) 2053 (53.7) 352 (9.2) 1348 (35.3)

0.001 0.342 0.998 0.072

258 (2.5) 4468 (43.0) 2798 (26.9) 2874 (27.6)

74 (2.7) 1148 (42.4) 703 (26.0) 783 (28.9)

0.458 0.589 0.320 0.188

94 (2.5)

0.004

417 (4.0)

111 (4.1)

0.835

Left anterior descending, n (%) Left circumflex, n (%) Right coronary artery, n (%) Pre-PCI TIMI grade TIMI 0, n (%) TIMI 1, n (%) TIMI 2, n (%) TIMI 3, n (%) ACC/AHA lesion type Type B1, n (%) Type B2, n (%) Type C, n (%) IVUS, n (%) OCT, n (%) FFR, n (%) Extent of coronary artery disease 1-vessel, n (%) 2-vessel, n (%) ≥ 3-vessel, n (%) Multi-vessel disease, n (%) Drug-eluting stents SES, n (%) PES, n (%) ZES, n (%) EES, n (%) BES, n (%) Others, n (%) Stent diameter (mm) Stent length (mm) Numbers of stents

8169 (59.7) 2230 (16.3) 5680 (41.5)

2256 (59.0) 561 (14.7) 1508 (39.4)

0.440 0.015 0.022

5779 (55.6) 4041 (38.9) 3801 (36.6)

1424 (52.6) 1022 (37.7) 996 (36.8)

0.005 0.285 0.829

8507 (62.2) 1493 (10.9) 1617 (11.8) 2069 (15.1)

2356 (61.6) 415 (10.9) 436 (11.4) 617 (16.1)

0.202 0.921 0.482 0.123

2859 (27.5) 1321 (12.7) 1856 (17.8) 4362 (42.0)

768 (28.4) 381 (14.1) 488 (18.0) 1071 (40.0)

0.370 0.062 0.836 0.054

1974 (14.4) 3899 (28.5) 6519 (47.6) 1987 (14.5) 28 (0.2) 91 (0.7)

620 (16.2) 1022 (26.7) 1660 (43.4) 468 (12.2) 3 (0.1) 9 (0.2)

0.006 0.032 <0.001 <0.001 0.101 0.002

1608 (15.5) 3559 (34.2) 4253 (40.9) 1912 (18.4) 80 (0.8) 106 (1.0)

464 (17.1) 856 (31.6) 1019 (37.6) 405 (15.0) 13 (0.5) 13 (0.5)

0.034 0.010 0.002 <0.001 0.110 0.008

7215 (52.7) 4064 (29.7) 2407 (17.6) 6471 (47.3)

1901 (49.7) 1164 (30.4) 759 (19.8) 1923 (50.3)

0.001 0.374 0.001 0.001

4539 (43.7) 3494 (33.6) 2365 (22.7) 5859 (56.3)

1085 (40.1) 882 (32.6) 741 (27.4) 1623 (59.9)

0.001 0.310 <0.001 0.001

2322 (17.0) 1983 (14.5) 3284 (24.0) 4062 (29.7) 1180 (8.6) 855 (6.2) 3.18 ± 0.40 26.2 ± 9.1 1.41 ± 0.72

843 (22.0) 697 (18.2) 871 (22.8) 932 (24.4) 212 (5.5) 269 (7.0) 3.18 ± 0.41 25.5 ± 7.8 1.38 ± 0.70

<0.001 <0.001 0.117 <0.001 <0.001 0.030 0.346 <0.001 0.038

1476 (14.2) 1318 (12.7) 2405 (23.1) 3591 (34.5) 1140 (11.0) 468 (4.5) 3.08 ± 0.41 26.9 ± 11.3 1.62 ± 0.89

562 (20.8) 510 (18.8) 550 (20.3) 735 (27.1) 205 (7.6) 146 (5.3) 3.09 ± 0.41 25.5 ± 9.56 1.57 ± 0.87

<0.001 <0.001 0.002 <0.001 <0.001 <0.001 0.675 <0.001 0.010

Values are means ± SD or numbers and percentages. The P values for continuous data were obtained from the unpaired t-test. The P values for categorical data were from the chi-square or Fisher’s exact test. Abbreviations: ACC/AHA, American College of Cardiology/American Heart Association; ACEIs, angiotensin converting enzyme inhibitors; ARBs, angiotensin receptor blockers; BES, biolimus-eluting stent; BMI, body mass index; CABG, coronary artery bypass graft; CCBs, calcium channel blockers; CK-MB, creatine kinase myocardial band; CPR, cardiopulmonary resuscitation; CRP, C-reactive protein; EES, everolimus-eluting stent; FFR, fractional flow reserve; HDL, high-density lipoprotein; IVUS, intravascular ultrasound; LDL, low-density lipoprotein; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NT-ProBNP, N-terminal pro-brain natriuretic peptide; OCT, optical coherence tomography; PCI, percutaneous coronary intervention; PES, paclitaxel-eluting stent; SES, sirolimus-eluting stent; ZES, zotarolimus-eluting stent.

TABLE 2. Comparison of clinical outcomes at 2 years. Outcomes STEMI MACE All-cause death Cardiac death Re-MI Any repeat revascularization TLR TVR Non-TVR NSTEMI MACE All-cause death Cardiac death Re-MI Any repeat revascularization TLR TVR Non-TVR Outcomes Statin (+) MACE All-cause death Cardiac death Re-MI Any repeat revascularization TLR TVR

Log-Rank

Unadjusted HR (95% CI)

P value

Adjusteda H1R (95% CI)

P value

<0.001 <0.001 <0.001 0.947 0.562 0.218 0.540 0.893

2.154 (1.937-2.396) 4.981 (4.251-5.836) 5.957 (4.985-7.119) 0.990 (0.733-1.336) 1.055 (0.880-1.267) 1.217 (0.890-1.663) 1.079 (0.846-1.378) 1.019 (0.778-1.334)

<0.001 <0.001 <0.001 0.947 0.562 0.219 0.540 0.893

1.189 (1.041-1.358) 1.510 (1.216-1.875) 1.550 (1.208-1.988) 0.854 (0.610-1.195) 1.082 (0.893-1.312) 1.232 (0.887-1.710) 1.102 (0.851-1.428) 1.063 (0.802-1.409)

0.011 <0.001 0.001 0.854 0.420 0.214 0.461 0.669

<0.001 <0.001 <0.001 0.200 0.114 0.927 0.463 0.109

1.935 (1.709-2.190) 3.447 (2.891-4.112) 4.378 (3.564-5.377) 1.236 (0.893-1.711) 1.176 (0.962-1.437) 0.982 (0.667-1.447) 1.104 (0.848-1.436) 1.282 (0.945-1.738) Unadjusted HR (95% CI)

<0.001 <0.001 <0.001 0.200 0.114 0.927 0.463 0.110

<0.001 <0.001 <0.001 0.201 0.022 0.935 0.290 0.026

P value

1.389 (1.200-1.608) 1.636 (1.307-2.048) 1.767 (1.356-2.301) 1.260 (0.884-1.769) 1.277 (1.035-1.576) 1.017 (0.675-1.534) 1.162 (0.880-1.535) 1.432 (1.045-1.962) Adjusteda HR (95% CI)

1.090 (0.990-1.199) 1.320 (1.114-1.565) 1.168 (0.952-1.433) 0.996 (0.807-1.230) 1.055 (0.927-1.199) 1.067 (0.846-1.346) 1.176 (0.993-1.393)

0.080 0.001 0.137 0.973 0.418 0.582 0.060

1.112 (1.002-1.235) 1.271 (1.054-1.532) 1.203 (0.962-1.506) 1.002 (0.799-1.257) 1.120 (0.973-1.289) 1.107 (0.856-1.430) 1.262 (1.049-1.518)

0.047 0.012 0.105 0.984 0.115 0.439 0.014

Statin (+)

Statin (-)

Group A (n = 13686) 931 (7.1) 267 (2.0) 196 (1.5) 203 (1.6) 528 (4.1) 161 (1.3) 289 (2.3) 248 (1.9) Group C (n = 10398) 758 (7.8) 264 (2.7) 172 (1.7) 151 (1.6) 414 (4.4) 128 (1.3) 252 (2.7) 168 (1.8)

Group B (n = 3824) 537 (14.2) 359 (9.4) 316 (8.3) 54 (1.5) 148 (4.3) 52 (1.5) 83 (2.4) 67 (2.0) Group D (n = 2708) 374 (14.2) 233 (8.8) 193 (7.3) 48 (2.0) 124 (5.1) 32 (1.3) 71 (2.9) 55 (2.3)

STEMI

NSTEMI

Log-Rank

Group A (n = 13686) 931 (7.1) 267 (2.0) 196 (1.5) 203 (1.6) 528 (4.1) 161 (1.3) 289 (2.3)

Group C (n = 10398) 758 (7.8) 264 (2.7) 172 (1.7) 151 (1.6) 414 (4.4) 128 (1.3) 252 (2.7)

0.079 0.001 0.136 0.973 0.418 0.582 0.059

P value

Non-TVR Statin (-) MACE All-cause death Cardiac death Re-MI Any repeat revascularization TLR TVR Non-TVR a

248 (1.9) Group B (n = 3824) 537 (14.2) 359 (9.4) 316 (8.3) 54 (1.5) 148 (4.3) 52 (1.5) 83 (2.4) 67 (2.0)

168 (1.8) Group D (n = 2708) 374 (14.2) 233 (8.8) 193 (7.3) 48 (2.0) 124 (5.1) 32 (1.3) 71 (2.9) 55 (2.3)

0.344

0.910 (0.748-1.107)

0.344

0.954 (0.771-1.182)

0.669

0.704 0.252 0.085 0.270 0.184 0.505 0.257 0.445

0.975 (0.854-1.112) 0.908 (0.770-1.071) 0.855 (0.715-1.022) 1.244 (0.843-1.835) 1.175 (0.926-1.492) 0.861 (0.554-1.337) 1.201 (0.875-1.648) 1.149 (0.804-1.641)

0.704 0.252 0.086 0.271 0.185 0.505 0.258 0.445

1.033 (1.841-1.269) 1.174 (0.958-1.440) 1.114 (0.890-1.393) 1.313 (0.851-2.027) 1.243 (0.954-1.618) 0.824 (0.506-1.343) 1.233 (0.867-1.752) 1.287 (0.868-1.907)

0.756 0.122 0.346 0.218 0.107 0.438 0.244 0.209

Adjusted by the age, male gender, LVEF, BMI, cardiogenic shock, CPR on admission, DM, dyslipidemia, previous HF, CK-MB, troponin-I, serum glucose, serum creatinine, NT-BNP, total cholesterol, LDL-cholesterol, aspirin, clopidogrel, cilostazole, ACEIs, ARBs, BBs, PCI within 24 hours, IVUS, MVD, SES, PES, EES, BES, stent length. Abbreviation: ACEIs, angiotensin converting enzyme inhibitors; ARBs, angiotensin receptor blockers; BBs, beta-blockers; BES, biolimuseluting stent; BMI, body mass index; CI, confidence interval; CK-MB, creatine kinase myocardial band; CPR, cardiopulmonary resuscitation; DM, diabetes mellitus; EES, everolimus-eluting stent; Group A, STEMI statin user; Group B, STEMI statin non-user; Group C, NSTEMI statin user; Group D, NSTEMI statin non-user; HF, heart failure; LDL, IVUS, intravascular ultrasound; low-density lipoprotein; LVEF, left ventricular ejection fraction; MACE, major adverse cardiac events; MVD, multivessel disease; NSTEMI, non-ST-segment elevation myocardial infarction; NT-BNP, N-terminal pro-brain natriuretic peptide; PCI, percutaneous coronary intervention; PES, paclitaxel-eluting stent; Re-MI, recurrent myocardial infarction; SES, sirolimus-eluting stent; STEMI, ST-segment elevation myocardial infarction; TLR, target lesion revascularization; TVR, target vessel revascularization.

TABLE 3. Cumulative clinical events at 2 years Variables, n (%)

Total (n = 30616)

Group A (n = 13686)

Group B (n = 3824)

Group C (n = 10398)

Group D (n = 2708)

P value

MACE 2600 (8.5) 931 (6.8) 537 (14.0) 758 (7.3) 374 (13.8) <0.001 All-cause death 1123 (3.7) 267 (2.0) 359 (9.4) 264 (2.5) 233 (8.6) <0.001 Cardiac death 877 (2.9) 196 (1.4) 316 (8.3) 172 (1.7) 193 (7.1) <0.001 Re-MI 456 (1.5) 203 (1.5) 54 (1.4) 151 (1.5) 48 (1.8) 0.629 Any repeat revascularization 1214 (4.0) 528 (3.9) 148 (3.9) 414 (4.0) 124 (4.6) 0.363 TLR 373 (1.2) 161 (1.2) 52 (1.4) 128 (1.2) 32 (1.2) 0.830 TVR 695 (2.3) 289 (2.1) 83 (2.2) 252 (2.4) 71 (2.6) 0.228 Non-TVR 538 (1.8) 248 (1.8) 67 (1.8) 168 (1.6) 55 (2.0) 0.454 Values are numbers and percentages. Abbreviations: Group A, STEMI statin user; Group B, STEMI statin non-user; Group C, NSTEMI statin user; Group D, MACEs, major adverse cardiac events; NSTEMI statin non-user; NSTEMI, non-ST-segment elevation myocardial infarction; Re-MI, recurrent myocardial infarction; STEMI, ST-segment elevation myocardial infarction; TLR, target lesion revascularization; TVR, target vessel revascularization.