Clinical outcome of statin plus ezetimibe versus high-intensity statin therapy in patients with acute myocardial infarction propensity-score matching analysis

International Journal of Cardiology 225 (2016) 50–59

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Clinical outcome of statin plus ezetimibe versus high-intensity statin therapy in patients with acute myocardial infarction propensity-score matching analysis☆ Mi Seon Ji a, Myung Ho Jeong a,⁎, Young keun Ahn a, Sang Hyung Kim a, Young Jo Kim b, Shung Chull Chae c, Taek Jong Hong d, In Whan Seong e, Jei Keon Chae f, Chong Jin Kim g, Myeong Chan Cho h, Seung-Woon Rha i, Jang Ho Bae j, Ki Bae Seung k, Seung Jung Park l, other Korea Acute Myocardial Infarction Registry Investigators: a

Chonnam National University Hospital, Gwangju, Republic of Korea Yeungnam Univ. Hosp., Daegu, Republic of Korea c Kyungpuk National Univ. Hosp., Daegu, Republic of Korea d Busan National Univ. Hosp., Busan, Republic of Korea e Chungnam National Univ. Hosp., Daejon, Republic of Korea f Chunbuk National Univ. Hosp., Jeonju, Republic of Korea g KyungHee Univ. Hosp., Seoul, Republic of Korea h Chungbuk National University Hospital, Cheongju, Republic of Korea i Korea University Guro Hospital, Seoul, Republic of Korea j Konyang University, Daejon, Republic of Korea k Catholic Univ. Hosp., Seoul, Republic of Korea l Asan Medical Center, Seoul, Republic of Korea b

a r t i c l e

i n f o

Article history: Received 27 June 2016 Received in revised form 22 September 2016 Accepted 23 September 2016 Available online 28 September 2016 Keywords: Ezetimibe simvastatin combination Statins Myocardial infarction

a b s t r a c t Background: It is unclear whether simvastatin–ezetimibe could be an alternative therapy to high-intensity statin therapy in high-risk patients. The aim of this study was to compare the clinical outcomes of simvastatin– ezetimibe and high-intensity statin therapy in patients with acute myocardial infarction (AMI), and especially in those with high-risk factor. Methods: A total of 3520 AMI patients in the KAMIR (Korea Acute Myocardial Infarction Registry) were classified into simvastatin–ezetimibe group (n = 1249) and high-intensity statin group (n = 2271). Multivariate analysis and propensity-score matching analysis were performed. The primary endpoint was major adverse cardiac events (MACE) at 12-months follow-up. Results: In overall AMI patients, MACE occurred in 116 patients (9.3%) in simvastatin–ezetimibe group and 116 patients (5.1%) in high-intensity statin group. The difference in MACE between groups was driven by repeat revascularization (5.9% vs. 2.2%). After propensity matching analysis, simvastatin–ezetimibe was associated with a higher incidence of MACE than high-intensity statin therapy (adjusted hazard ratio: 3.090, 95% confidence interval: 1.715 to 5.566, p b 0.001). However, in patients with high-risk factors, such as diabetes, old age, or heart failure, simvastatin-ezetimibe had similar incidence of MACE compared with high-intensity statin therapy in further adjusted analysis. Conclusions: In overall AMI patients, high-intensity statin therapy had better clinical outcomes than simvastatin– ezetimibe. However, in patients with high-risk factor, simvastatin–ezetimibe had comparable clinical outcomes to high-intensity statin therapy. Therefore, simvastatin–ezetimibe could be used as an alternative to highintensity statin therapy in such patients. © 2016 Elsevier Ireland Ltd. All rights reserved.

1. Introduction

☆ This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. ⁎ Corresponding author at: Chonnam National University Hospital, 42 Jaebong-ro, Dong-gu, Gwangju 501-757, South Republic of Korea. E-mail address: [email protected] (M.H. Jeong).

http://dx.doi.org/10.1016/j.ijcard.2016.09.082 0167-5273/© 2016 Elsevier Ireland Ltd. All rights reserved.

Current guidelines have recommended high-intensity statin therapy for patients with acute coronary syndrome (ACS), which is known to be superior to moderate-intensity statin therapy in reducing cardiovascular events in them [1–3]. However, despite high-intensity statin therapy, there are unresolved issues such as residual risk or statin-associated muscle symptoms [4], which cause statin intolerance in susceptible

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high-risk patients. Based on current guidelines, moderate-intensity statin therapy is recommended to those patients. Recently, combination therapy with simvastatin and ezetimibe was demonstrated to be more effective compared with statin therapy not only in LDL lowering, but also in improving long-term clinical outcomes in the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) [5,6]. Thus, simvastatin–ezetimibe has been suggested as an alternative to statin therapy. However, there are insufficient clinical evidences to support the suggestion that simvastatin–ezetimibe could be an alternative to highintensity statin therapy in patients with acute myocardial infarction (AMI), especially in high-risk patients. Pauriah et al. indirectly reported that high-intensity statin was superior to simvastatin–ezetimibe in improving clinical outcome in survivors after AMI, but data on highrisk patients and other clinical outcomes except mortality were not provided [7]. In contrast, Chang et al. reported benefit of simvastatin– ezetimibe than high-potency statin in diabetic patients [8], but studied population was not ACS patients and there was a limitation in the definition of high-intensity statin therapy. Therefore, we performed this study to investigate the effect of simvastatin–ezetimibe compared with high-intensity statin therapy on the clinical outcomes in AMI patients, especially in patients with high-risk factor.

high-intensity statin group (N = 2271). The present study was conducted according to the Declaration of Helsinki. The study protocol was approved by the institutional review board of all centers, and the approval number was 05–49 of Chonnam National University Hospital. Written informed consent was obtained from all patients.

2. Methods

2.3.1. Cox multivariate analysis The risks of adverse cardiac events were estimated by multivariate Cox proportional hazard model, which included covariates that were clinically relevant or significant on univariate analysis. Covariates included in multivariate analysis were age, gender, prior ischemic heart disease, diabetes, smoking history, low ejection fraction (EF), chronic kidney disease, multi-vessel involvement, left anterior descending artery or left main artery, lowdensity lipoprotein-cholesterol (LDL), hs-CRP (high-sensitivity C-reactive protein), highdensity lipoprotein-cholesterol (HDL), obesity, and use of drug-eluting stent.

2.1. Study population The Korea Acute Myocardial Infarction Registry (KAMIR) is the first and largest nationwide multicenter registry, including 51 hospitals in Korea, designed to evaluate characteristics and clinical outcomes in AMI patients [9]. The patient flow is shown in Fig. 1. Among 43,286 patients enrolled in the KAMIR between November 2005 and January 2014, we selected a total of 3520 AMI patients, who underwent successful percutaneous coronary intervention (PCI) and were treated with simvastatin–ezetimibe or high-intensity statin therapy during administration or upon discharge. In our study, high-intensity statin therapy was defined as atorvastatin 40–80 mg daily or rosuvastatin 20–40 mg daily according to guidelines [1]. They were classified into simvastatin-ezetimibe group (N = 1249) and

2.2. Study endpoints, definitions, and interventional procedures The primary endpoint was major adverse cardiac events (MACE), defined as a composite of all-cause death, recurrent nonfatal myocardial infarction (MI), and repeat coronary revascularization during 12-month follow-up [10]. The secondary endpoints were a composite of cardiac death, recurrent MI, and repeat percutaneous coronary intervention (PCI); and individual components of MACE, including all-cause death, recurrent MI, and repeat revascularization. AMI was defined as elevation of cardiac biomarkers (troponin T, troponin I, or creatine kinase-MB) and specific changes on the electrocardiogram or symptoms. All-cause mortality was defined as death due to any cause. Repeat revascularization was defined as repeat PCI or coronary artery bypass graft surgery after the index procedure. Medications were prescribed during hospitalization and discharge. Coronary artery angiography and PCI were performed by standard methods, and decision for detailed treatment was left to the physician's discretion. Clinical follow-up was performed at 1, 6, and 12 months after enrollment. 2.3. Statistical analysis We used student-t tests or Mann–Whitney U tests for comparisons of continuous variables and chi-square test for categorical variables, when applicable. Survival curves were estimated by the Kaplan–Meier method and compared with the log-rank test. To reduce potential bias, we performed both multivariate analysis and propensity score-matching analysis.

2.3.2. Propensity score-matching analysis Propensity scores were estimated by logistic-regression analysis that included covariates such as age, gender, diabetes, low EF, chronic kidney disease, LDL, HDL, hs-CRP, STsegment elevation myocardial infarction (STEMI), complex lesion type, drug-eluting

Fig. 1. Patient flow chart. KAMIR = Korea Acute Myocardial Infarction Registry, AMI = acute myocardial infarction, MI = myocardial infarction, PCI = percutaneous coronary intervention.

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stent, and multi-vessel disease. A 1:1 matching was done with the greedy algorithm and we used the nearest neighbor method in patients with an individual propensity score. The C-statistic for the propensity score model was 0.604, indicating good discrimination (Hosmer–Lemeshow goodness of fit, p = 0.955). In propensity score-matched population, continuous variables were compared using the paired t test or Wilcoxon signed rank test and categorical variables using McNemar test, as appropriate. In matched population, we used conditional logistic regression analysis which adjusted for potential confounders, including clopidogrel, ACEI/ARB, and beta-blockers to reduce the potential bias and to compare the risks of adverse cardiac events between simvastatin–ezetimibe and highintensity statin therapy. 2.3.3. Subgroup analysis To investigate whether the effect is consistent across various subgroups, we calculated unadjusted hazard ratio (HR) and 95% confidence interval (CI) for MACE in these subpopulations. Moreover, we performed multivariate Cox analysis and calculated adjusted HR for MACE. Furthermore, we conducted propensity matching analysis in each subpopulation. The C-statistic was 0.636 in diabetic patients, 0.603 in old patients, and 0.640 in heart failure patients, indicating good discrimination (Hosmer–Lemeshow goodness-offit test p-value = 0.371 in diabetic patients, 0.251 in old patients, and 0.907 in heart failure patients). In the matched subpopulations, we conducted conditional logistic regression analysis which adjusted for potential confounders to reduce the potential bias and calculated adjusted incidences of primary endpoint. Statistical analyses were performed with SPSS version 18.0 (SPSS Institute Inc., Cary, North Carolina). All tests were 2-tailed and p b 0.05 was considered significant.

3. Results 3.1. Baseline characteristics and angiographic findings Among 3520 AMI patients, 2271 patients (64.5%) were treated with high-intensity statin, and 1249 patients (35.5%) with simvastatin– ezetimibe (Fig. 1). Baseline clinical characteristics and angiographic findings were shown in Table 1.

The mean age of the patients was 61.2 years and 785 were women (22.3%). Overall, patients in simvastatin–ezetimibe group had relatively high risk factors. Compared with the high-intensity statin group, the simvastatin–ezetimibe group had a higher prevalence of previous ischemic heart disease, STEMI, chronic kidney disease, and multi-vessel involvement, but had a lower prevalence of complex lesion type and lower hs-CRP level. Angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers (ACEI/ARB) and beta-blockers were less frequently prescribed to simvastatin–ezetimibe group, but drug-eluting stent was more frequently used in them. After 1:1 propensity-score matching, 1342 patients were matched (Tables 1). In the propensity-matched population, there were no significant differences in baseline characteristics between the 2 groups except for clopidogrel, ACEI/ARB, and beta-blockers. 3.2. Clinical outcomes 3.2.1. Clinical outcomes in the overall population The clinical outcomes were shown in Table 2. During 12-months follow-up, MACE occurred in 116 patients in simvastatin–zetimibe group and 116 patients in high-intensity statin group. Kaplan–Meier estimates showed that MACE rates were significantly higher in the simvastatin–ezetimibe group than in the high-intensity statin group (9.3% vs. 5.1%, p b 0.001) (Fig. 2). Similarly, the composite of cardiac death, recurrent MI, and repeat PCI was higher in the simvastatin– ezetimibe group. There were no differences in the rates of cardiac death, all-cause death, MI, or the composite of cardiac death or MI between the two groups. However, repeat revascularization rate was higher in the simvastatin–ezetimibe group than in high-intensity statin group (5.9% vs. 2.2%, p b 0.001).

Table 1 Baseline and procedural characteristics in overall and propensity-matched populations. Variables n (%)

Overall population

Propensity-matched population

HI-statin (N = 2271)

Simva-EZ (N = 1249)

p

HI-statin (N = 671)

Simva-EZ (N = 671)

p

Age (years) Male gender

61.3 ± 12.90 1778(78.5)

61.2 ± 13.19 945(76.0)

0.902 0.081

61.8 ± 12.98 509(75.9)

60.7 ± 13.34 513(76.5)

0.133 0.847

Medical history Hypertension Dyslipidemia Ischemic heart disease Diabetes mellitus Smoking history Ejection fraction (%) ST-elevation MI Non-ST-elevation MI

1036(46.3) 281(12.8) 279(23.3) 690(30.4) 1488(66.1) 52.0 ± 11.83 1347(59.3) 924(40.7)

589(47.7) 132(12.1) 154(29.7) 357(28.6) 836(67.4) 52.0 ± 11.53 799(64.0) 450(36.0)

0.421 0.573 0.005 0.264 0.460 0.206 0.007 0.007

294(44.7) 79(13.6) 29(4.3) 185(27.6) 437(65.7) 51.6 ± 11.76 424(63.2) 247(36.8)

288(43.8) 63(10.8) 41(6.1) 178(26.5) 443(66.6) 51.1 ± 11.95 434(64.7) 237(35.3)

0.784 0.178 0.111 0.710 0.772 0.375 0.542 0.542

Laboratory finding Blood sugar Hemoglobin A1C (%) LDL (mg/dL) Triglyceride (mg/dL) HDL (mg/dL) Chronic kidney disease hs-CRP (mg/L)

163.9 ± 75.14 6.5 ± 1.50 121.9 ± 39.80 143.0 ± 120.76 42.6 ± 11.28 530(26.9) 3.0(0.9,9.5)

165.9 ± 73.23 6.5 ± 1.54 125.2 ± 38.56 140.8 ± 103.00 44.1 ± 11.28 358(32.7) 2.1(0.5,9.6)

0.458 0.948 0.025 0.609 b0.001 0.001 b0.001

164.3 ± 74.40 6.5 ± 1.58 127.2 ± 38.86 138.2 ± 103.37 43.7 ± 11.01 213(31.7) 2.5(0.8,7.5)

164.3 ± 72.06 6.5 ± 1.48 126.4 ± 40.04 139.4 ± 112.06 44.0 ± 11.47 210(31.3) 2.4(0.6,9.8)

0.999 0.795 0.692 0.838 0.634 0.899 0.418

Medication Aspirin Clopidogrel ACEI/ARB Beta-blocker

2268(99.9) 2090(92.3) 1951(95.0) 2060(97.6)

1248(99.9) 1173(93.9) 1056(87.3) 1115(92.0)

0.938 0.077 b0.001 b0.001

671(100.0) 603(89.9) 554(82.6) 586(87.3)

671(100.0) 648(96.6) 516(76.9) 557(83.0)

– b0.001 b0.001 b0.001

Angiographic finding Multi-vessel involvement Left main or LAD Lesion type B2C Pre-PCI TIMI flow grade 0/I Drug-eluting stent

1195(52.8) 1152(50.8) 1684(82.4) 1403(65.1) 1998(88.0)

704(56.6) 623(50.0) 838(76.1) 748(63.0) 1110(88.9)

0.028 0.653 b0.001 0.223 0.001

370(55.1) 353(52.6) 516(76.9) 395(60.8) 647(96.4)

373(55.6) 339(50.5) 497(74.1) 391(60.2) 638(95.1)

0.905 0.482 0.132 0.864 0.272

HI-statin, high-intensity statins therapy; Simva-EZ, simvastatin–ezetimibe; MI, myocardial infarction; LDL, low-density lipoprotein-cholesterol; HDL, high-density lipoprotein-cholesterol; hs-CRP, high-sensitivity C-reactive protein; ACEI/ARB, angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers; LAD, left anterior descending artery.

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Table 2 Twelve-months clinical outcomes in overall and propensity-matched population. Simvastatin–ezetimibe (N = 1249)

High-intensity statin (N = 2271)

Unadjusted

Adjusted

HR (95% CI)

p

HR (95% CI)

p

A. Overall population (N = 3520) Primary endpoint All-MACE

116 (9.3)

116 (5.1)

1.585 (1.223–2.054)

b0.001

1.739 (1.064–2.841)

0.027

Secondary endpoints Cardiac death, MI, or Re-PCI Cardiac death or MI All-cause mortality Cardiac death Recurrent MI Repeat revascularization

98 (7.8) 29 (2.3) 39 (3.1) 22 (1.8) 7 (0.6) 74 (5.9)

93 (4.1) 60 (2.6) 59 (2.6) 37 (1.6) 23 (1.0) 49 (2.2)

1.657 (1.245–2.250) 0.782 (0.501–1.221) 1.083 (0.722–1.627) 0.994 (0.585–1.688) 0.461 (0.196–1.082) 2.313 (1.607–3.328)

b0.001 0.279 0.699 0.982 0.069 b0.001

2.194 (1.452–3.316) 0.891 (0.416–1.908) 1.225 (0.648–2.315) 0.950 (0.434–2.081) 0.515 (0.203–1.307) 3.117 (1.837–5.288)

b0.001 0.767 0.532 0.899 0.163 b0.001

Simvastatin–ezetimibe (N = 671 )

High- intensity statin (N = 671)

Unadjusted HR (95% CI )

p

HR (95% CI)

p

Adjusted

B. Propensity-matched population (N = 1342) Primary endpoint All-MACE

70(10.4)

27(4.0)

2.311 (1.478–3.613)

b0.001

3.090 (1.715–5.566)

b0.001

Secondary endpoints Cardiac death, MI, or Re-PCI Cardiac death or MI All-cause mortality Cardiac death Recurrent MI Repeat revascularization

59(8.8) 13(1.9) 20(3.0) 10(1.5) 3(0.4) 51(7.6)

25(3.7) 16(2.4) 14(2.1) 12(1.8) 4(0.6) 12(1.8)

2.053(1.280–3.291) 0.717(0.343–1.501) 1.321(0.666–2.620) 0.758(0.326–1.764) 0.601(0.131–2.768) 3.654(1.940–6.883)

0.002 0.376 0.425 0.519 0.510 b0.001

2.661 (1.480–4.785) 0.819 (0.382–1.756) 1.860 (0.625–5.538) 0.855 (0.338–2.158) 0.750 (0.168–3.351) 3.935 (2.043–7.582)

0.001 0.607 0.265 0.739 0.706 b0.001

HR, hazard ratio; CI, confidential interval; MACE, major adverse cardiac events; MI, myocardial infarction; Re-PCI, repeat percutaneous coronary intervention.

Fig. 2. Clinical outcomes in the overall population. Compared with high-intensity statin, simvastatin-ezetimibe had higher MACE rate (A), mainly driven by repeat revascularization (D), but not by all-cause death (B) or myocardial infarction (C). Simva-EZ = simvastatin–ezetimibe, HI-statin = high-intensity statin, MACE = major adverse cardiac events, HR = hazard ratio.

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Fig. 3. Clinical outcomes in the propensity-matched population. Similar results were observed in the propensity-matched patients. (A) MACE, (B) all-cause death, (C) myocardial infarction, (D) repeat revascularization. Abbreviations as in Fig. 2.

Multivariate Cox analysis showed that simvastatin–ezetimibe was associated with higher risk of MACE (HR 1.739, 1.064 to 2.841; p = 0.027) and repeat revascularization (HR 3.117, 1.837 to 5.288; p b 0.001) at 12 months than high-intensity statin therapy. Similar results were observed at 6 months in further analysis.

3.2.2. Clinical outcomes in propensity matched population After adjustment for potential confounders, including clopidogrel, ACEI/ARB, and beta-blockers in propensity matched population, simvastatin–ezetimibe was associated with higher rates of MACE (adjusted HR: 3.090, 1.715 to 5.566, p b 0.001) and repeat revascularization (adjusted HR: 3.935, 2.043 to 7.582, p b 0.001) (Table 2, Fig. 3).

However, there were no significant differences between the 2 groups in the rates of cardiac death, all-cause deaths, or MI.

3.3. LDL data At admission, the mean LDL level was 123.1 mg/dL in the overall population. Although it was higher in simvastatin–ezetimibe group than in high-intensity statin group in the overall population, it was well balanced in both groups after propensity-score matching (Table 1). At 1 year, there was no significant difference in the mean LDL levels between the 2 groups in the overall population (p = 0.261) and the propensity-matched population (p = 0.412) (Table 3).

Table 3 Changes in the mean LDL levels. At admission

12-Months follow-up

Difference (mg/dL)

Reduction (%)

p-Value

121.9 ± 39.80 125.2 ± 38.56 3.3 0.025

70.8 ± 29.28 73.1 ± 29.76 2.3 0.261

51.1 52.1

41.9 41.6

b0.01 b0.01

B. Propensity-score matched population High-intensity statin 127.2 ± 38.90 Simvastatin-EZ 126.4 ± 40.04 Difference (mg/dL) −0.8 p-Value 0.692

72.8 ± 26.15 76.2 ± 23.40 3.4 0.412

54.4 50.2

42.8 39.7

b0.01 b0.01

A. Overall population High-intensity statin Simvastatin–EZ Difference (mg/dL) p-Value

M.S. Ji et al. / International Journal of Cardiology 225 (2016) 50–59

3.4. Subgroup analysis As shown in Fig. 4, significant interactions were observed between diabetes, old age, or low EF and treatment strategies on the primary endpoint (p value for interaction = 0.014, 0.035, 0.047, respectively). In particular, hemoglobin A1c had the strongest interaction (Pinteraction = 0.001). Moreover, in multivariate Cox analysis (Fig. 5), simvastatin–ezetimibe was comparable to high-intensity statin in the 12-month MACE in diabetic patients (adjusted HR: 1.185, 0.689 to 2.036, p = 0.540), in older patients (adjusted HR: 1.486, 0.888 to 2.485, p = 0.132), and in those with low EF (adjusted HR: 1.417, 0.650 to 3.090, p = 0.380). Furthermore, as shown in Table 4, after propensity matching analysis, baseline characteristics were almost similar between the 2 groups in the matched subpopulations, except for clopidogrel, ACEI/ARB, or beta-blockers. Of note, even after adjustment for potential confounders, including clopidogrel, ACEI/ARB, or beta-blockers in matched population, there were no significant differences in the incidences of 12-month MACE between simvastatine–ezetimibe and high-intensity statin therapy in diabetic patients (adjusted p = 0.162), in older patients (adjusted p = 0.120), and in heart failure patients (adjusted p = 0.107). 4. Discussion This is the first nationwide, multi-center study and currently the largest observational study in Korea, investigating clinical outcomes of AMI patients who were treated with simvastatin–ezetimibe or highintensity statin. Main findings of the present study were as follows. (1) In overall AMI population, high-intensity statin therapy was superior to simvastatin-ezetimibe in 12-month MACE, despite similar LDL-lowering effect.

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(2) Significant reduction was observed in repeat revascularization, although there were no differences in cardiac mortality or allcause mortality or MI between simvastatin-ezetimibe and highintensity statin. Similar results were observed in propensity score-matching analysis. (3) Significant interactions were observed between treatment strategies and diabetes, old age, or low EF on the primary endpoint, and simvastatin-ezetimibe was comparable to high-intensity statin in patients with these high-risk factors in further adjusted analysis.

4.1. Overall AMI patients Simvastatin–ezetimibe has been suggested as an alternative to highintensity statin therapy, which is recommended in ACS patients in current guidelines but has unresolved problems. However, so far there are only a few studies comparing simvastatin–ezetimibe with highintensity statin therapy in terms of clinical outcomes [7,8]. Our finding of better clinical outcomes in high-intensity statin therapy than in simvastatin–ezetimibe group in overall AMI population, was in agreement with those of the study by Pauriah et al., which indirectly showed superiority of high-intensity statin to simvastatin–ezetimibe in the clinical outcome [7]. However, there were discrepancies in the improved clinical outcomes between the 2 studies. Pauriah et al., showed superiority of high-intensity statin in reducing all-cause mortality rate, while data for other clinical outcomes was not provided. In contrast, our study showed superiority of high-intensity statin in reducing MACE, which was mainly driven by repeat revascularization, but not by death or MI between simvastatin–ezetimibe and high-intensity statin, in agreement with a previous study [11]. These inconsistent findings might be attributed to differences in the follow–up duration and the study population between the study by Pauriah et al. and our study.

Fig. 4. Subgroup analysis in the overall population. Significant interactions were present between treatment strategies and diabetes, old age, or low EF on the primary endpoint. HbA1c = hemoglobin A1c, LVEF = left ventricular ejection fraction, LDL = low-density lipoprotein–cholesterol.

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finding was in accordance with previous studies which demonstrated early clinical benefit of high-intensity statin therapy attributed to the pleiotropic effect independent of LDL-lowering effect [3,12,13]. In contrast to this finding, the IMPROVE-IT demonstrated no significant differences between simvastatin–ezetimibe and simvastatin in terms of 1-year clinical outcomes, although there were significant differences between them in long-term clinical outcomes with a median follow-up of 6 years in stable ACS patients [6]. This discrepancy in results might be attributed to differences in statin intensity between our study and IMPROVE-IT, in which moderate-intensity statin therapy was compared with simvastatin–ezetimibe in contrast to our study. Therefore, we could speculate that pleiotropic effect of highintensity statin might explain the lower revascularization rate in highintensity statin group than in simvastatin–ezetimibe group in overall AMI patients. 4.2. High-risk AMI patients

Fig. 5. Multivariate-adjusted analysis in high-risk AMI patients. In adjusted analysis, simvastatin-ezetimibe had similar MACE rate to high-intensity statin therapy in diabetic patients (A), older patients (B), and patients with systolic heart failure (C).

Interestingly, moreover, we found that differences in the clinical outcomes between high-intensity statin and simvastatin–ezetimibe occurred in early period. MACE curve and repeat revascularization curve appeared to separate from 6 months (Figs. 2, 3) and high-intensity statin had also better clinical outcomes at 6 months in further analysis. This

However, of note, subgroup analysis showed that three risk factors had significant interactions with treatment strategies on clinical outcomes (Fig. 4); diabetes, old age, and heart failure. The two former were in a similar trend to the result of IMPROVE-IT study. Furthermore, simvastatin–ezetimibe had comparable clinical outcomes to highintensity statin in each high-risk subgroup in adjusted Cox multivariate analysis (Fig. 5), suggesting attenuated effect of high-intensity statin in them. Further analysis which adjusted for potential confounders in propensity-matched subpopulations also showed that simvastatine– ezetimibe had comparable clinical outcomes to high-intensity statin therapy in those high-risk patients who had similar baseline characteristics, even after adjustment for confounding factors, making this result more reliable. First, in diabetic AMI patients, high-intensity statin had similar event rate to simvastatin–ezetimibe, in contrast to lower event rate in nondiabetic patients. In agreement with our finding, several studies showed that the effect of high-intensity statin on plaque regression was attenuated in diabetic ACS patients [14,15]. In contrast, simvastatin–ezetimibe had comparable clinical outcome to high-intensity statin in diabetic patients, and had a trend toward favorable outcomes in those with hemoglobin A1c concentrations more than 6.5%. This finding was in similar trend to study by Chang et al. [8], which suggested benefit of simvastatin–ezetimibe compared with high-intensity statin therapy in diabetic patients. However, in the study by Chang et al., studied population was not ACS patients and there was potential limitation of the definition of high-intensity statin therapy, because statin dosage was not available. Thus, our finding can be added to the study by Chang et al. [8]. A possible mechanism for the benefit of simvastatin–ezetimibe in diabetics is the difference in pharmacological action between statin monotherapy and combination therapy with simvastatin–ezetimibe. Simvastatin–ezetimibe combination therapy could not only inhibit hepatic cholesterol synthesis, but also inhibit increased intestinal cholesterol absorption in hyperglycemic condition [16,17], thus making it more effective in diabetics. Second, we found that systolic heart failure, which was not found in the IMPROVE-IT study, had significant interaction with treatment strategy. In patients with systolic heart failure, beneficial effect of high-intensity statin was attenuated, in agreement with the recent guideline and two large randomized trials (CORONA, GISSI-HF) which reported neutral benefit of statin in heart failure patients [18–20], and simvastatin–ezetimibe had comparable clinical outcomes to highintensity statin. Finally, in older patients, superiority of high-intensity statin was also attenuated and simvastatin–ezetimibe had similar clinical outcomes to high-intensity statin. According to previous randomized trials, statinassociated adverse effects were reported in older patients treated with high-dose statins [21], and thus judicious use of statin is recommended for them [22]. In contrast, combination therapy with ezetimibe and

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Table 4 Baseline characteristics of the subpopulations before and after propensity score matching. Variables n (%)

Before matching

After matching

HI-statin (N = 690)

Simva-EZ (N = 357)

p

HI-statin (N = 166)

Simva-EZ (N = 166)

p

A. DM subpopulation Age (years) Male gender Hypertension Ejection fraction (%) ST-elevation MI Chronic kidney disease Blood sugar LDL (mg/dL) Triglyceride (mg/dL) HDL (mg/dL) hs-CRP (mg/L) Multi-vessel involvement Left main or LAD Lesion type B2C Pre-PCI TIMI flow grade 0/I Drug-eluting stent

63.6 ± 12.04 507(73.8) 404(58.9) 51.0 ± 11.98 395(57.2) 205(34.5) 220.3 ± 98.04 114.2 ± 41.87 157.2 ± 136.13 41.2 ± 11.46 3.0(1.1,12.0) 428(62.2) 338(49.1) 548(87.4) 395(60.6) 612(97.3)

62.0 ± 12.06 260(72.8) 229(65.1) 51.2 ± 12.89 208(58.3) 128(40.1) 223.8 ± 91.15 117.9 ± 38.69 158.2 ± 116.13 42.3 ± 10.88 2.5(0.6,18.1) 233(65.8) 169(47.5) 241(78.5) 213(64.0) 320(96.1)

0.050 0.736 0.054 0.885 0.752 0.093 0.588 0.182 0.910 0.146 0.038 0.252 0.612 b0.001 0.302 0.308

62.3 ± 11.46 124(74.7) 93(56.0) 50.1 ± 12.64 99(59.6) 71(42.8) 228.0 ± 96.44 113.1 ± 38.05 165.79124.55 41.0 ± 9.89 3.0(1.2,12.9) 103(62.4) 91(54.8) 133(80.1) 94(56.6) 136(95.8)

61.3 ± 11.94 119(71.7) 102(61.4) 49.2 ± 12.98 100(60.2) 65(39.2) 222.5 ± 89.92 116.1 ± 40.76 160.8 ± 139.05 41.8 ± 10.52 3.2(0.6,17.3) 100(60.6) 75(45.2) 129(77.7) 96(57.8) 137(96.5)

0.416 0.597 0.374 0.463 1.000 0.567 0.580 0.506 0.742 0.499 0.485 0.830 0.101 0.672 0.910 1.000

Medication Aspirin Clopidogrel ACEI/ARB Beta-blocker

690(100.0) 645(93.6) 593(95.8) 619(97.3)

357(100.0) 334(93.6) 299(86.7) 313(90.5)

– 0.972 b0.001 b0.001

166(100.0) 150(90.4) 141(98.6) 151(99.3)

166(100.0) 158(95.2) 127(88.8) 139(91.4)

– 0.134 0.001 0.002

Variables n (%)

Before matching

After matching

HI-statin (N = 851)

Simva-EZ (N = 500)

p

HI-statin (N = 298)

Simva-EZ (N = 298)

p

B. Old age subpopulation Age (years) Male gender Hypertension Diabetes mellitus Ejection fraction (%) ST-elevation MI Chronic kidney disease Blood sugar LDL (mg/dL) Triglyceride (mg/dL) HDL (mg/dL) hs-CRP (mg/L) Multi-vessel involvement Left main or LAD Lesion type B2C Pre-PCI TIMI flow grade 0/I Drug-eluting stent

74.5 ± 5.85 516(60.7) 507(60.0) 304(35.7) 51.2 ± 11.70 465(54.6) 446(56.2) 166.9 ± 77.02 115.1 ± 38.81 116.2 ± 89.03 43.5 ± 11.91 3.0(1.0,12.0) 530(62.3) 403(47.4) 653(83.1) 506(62.4) 751(96.3)

73.9 ± 5.70 284(57.1) 296(59.8) 153(30.6) 51.2 ± 11.90 298(59.6) 303(64.5) 167.6 ± 70.03 120.1 ± 36.08 117.0 ± 72.35 44.8 ± 10.77 2.6(0.6,14.5) 314(63.1) 249(50.0) 345(78.9) 270(56.7) 443(94.5)

0.062 0.199 0.942 0.055 0.985 0.076 0.004 0.872 0.024 0.865 0.054 0.083 0.777 0.348 0.074 0.045 0.128

73.8 ± 5.75 173(58.1) 183(62.2) 85(28.5) 50.3 ± 12.15 173(58.1) 176(59.1) 164.7 ± 67.00 118.1 ± 35.24 110.0 ± 71.97 45.2 ± 10.66 2.7(0.5,12.6) 196(65.8) 143(48.1) 236(79.2) 167(56.0) 254(96.9)

73.9 ± 5.71 170(57.0) 166(56.5) 85(28.5) 50.5 ± 11.64 175(58.7) 184(61.7) 167.9 ± 78.69 117.9 ± 37.70 109.0 ± 65.45 44.9 ± 11.64 3.0(0.9,9.2) 177(59.4) 156(52.5) 230(77.2) 156(52.3) 248(94.7)

0.897 0.863 0.162 1.000 0.833 0.939 0.551 0.590 0.955 0.858 0.722 0.561 0.118 0.353 0.617 0.400 0.286

Medication Aspirin Clopidogrel ACEI/ARB Beta-blocker

850(99.9) 807(94.9) 709(94.3) 738(96.5)

500(100.0) 480(96.0) 411(86.3) 428(89.7)

0.443 0.373 b0.001 b0.001

297(99.7) 276(92.6) 226(94.4) 254(96.2)

298(100.0) 293(98.3) 217(86.8) 237(89.8)

– 0.002 0.004 0.008

Variables n (%)

C. Heart failure subpopulation Age (years) Male gender Hypertension Diabetes mellitus Ejection fraction (%) ST-elevation MI Chronic kidney disease Blood sugar LDL (mg/dL) Triglyceride (mg/dL) HDL (mg/dL) hs-CRP (mg/L) Multi-vessel involvement Left main or LAD

Before matching

After matching

HI-statin (N = 259)

Simva-EZ (N = 155)

p

HI-statin (N = 116)

Simva-EZ (N = 116)

p

63.9 ± 12.70 199 (77.1) 118(46.1) 103(39.8) 31.7 ± 6.15 168(64.9) 95(42.8) 186.3 ± 87.69 121.3 ± 45.20 117.8 ± 88.81 42.7 ± 12.03 4.0(1.1,28.7) 159(61.4) 203(78.4)

62.4 ± 14.66 124(80.0) 73(47.4) 59(38.1) 31.9 ± 6.11 116(74.8) 62(45.3) 189.1 ± 87.00 123.6 ± 42.41 145.7 ± 128.41 43.4 ± 11.71 3.0(0.4,17.4) 89(57.8) 114(74.0)

0.302 0.494 0.797 0.731 0.732 0.034 0.648 0.759 0.623 0.024 0.573 0.011 0.470 0.311

63.2 ± 13.16 92(79.3) 48(42.9) 43(37.1) 32.1 ± 6.14 90(77.6) 36(37.9) 197.4 ± 103.09 124.9 ± 41.05 121.8 ± 97.74 42.5 ± 11.12 3.0(1.0,14.1) 63(54.3) 95(81.9)

62.4 ± 15.18 93(80.2) 53(47.3) 40(34.5) 31.8 ± 6.29 89(76.7) 43(45.3) 187.6 ± 85.33 125.1 ± 43.08 139.8 ± 110.83 43.1 ± 12.28 2.7(0.4,16.9) 65(56.0) 87(75.0)

0.695 1.000 0.583 0.788 0.709 1.000 0.392 0.459 0.970 0.118 0.739 0.857 0.890 0.215

(continued on next page)

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M.S. Ji et al. / International Journal of Cardiology 225 (2016) 50–59

Table 4 (continued) Variables n (%)

Before matching HI-statin (N = 259)

Simva-EZ (N = 155)

p

After matching HI-statin (N = 116)

Simva-EZ (N = 116)

p

Lesion type B2C Pre-PCI TIMI flow grade 0/I Drug-eluting stent

201(84.5) 158(62.7) 229(96.6)

111(78.2) 104(68.9) 134(91.8)

0.122 0.208 0.039

84(88.4) 68(62.4) 111(95.7)

75(78.9) 76(69.7) 108(93.1)

0.150 0.332 0.549

Medication Aspirin Clopidogrel ACEI/ARB Beta-blocker

259(100.0) 242(93.8) 218(96.5) 225(97.0)

155(100.0) 146(94.2) 130(87.8) 128(88.3)

– 0.870 0.001 0.001

116(100.0) 108(93.1) 101(97.1) 92(96.8)

116(100.0) 113(97.4) 88(84.6) 86(90.5)

– 0.227 0.004 0.146

Abbreviations as in Table 1.

statin appeared to be safe and effective in them, but there has been lack of clinical outcome data comparing simvastatin–ezetimibe and high-intensity statin in older patients. These results, which showed comparable outcomes of simvastatin– ezetimibe to high-intensity statin in these patients, could be an evidence to support the suggestion of simvastatin–ezetimibe as an alternative of high-intensity statin in such patients. Interestingly, patients with these risk factors are susceptible to statin-associated muscle symptoms leading to statin intolerance [4], which might contribute to the attenuation of beneficial effect of high-intensity statin in them. Moreover, considering the high prevalence of these risk factors in this AMI population (old age ≥ 65 years = 38%; diabetic patients = 30%; systolic HF patients = 12%), our findings deserve to notice. Taken together, we strongly support the suggestion that simvastatin–ezetimibe could be alternative to high-intensity statin in appropriately selected high-risk patients, while we also support the current guidelines recommending high-intensity statin in ACS patients [1]. Further study is needed in this regard.

4.3. Strengths of the study Our study had several strengths. First, this is the first large nationwide study to directly compare the clinical outcomes of simvastatin– ezetimibe with high-intensity statin in AMI patients regardless of basal LDL levels, in agree with the current guideline. Thus, this might reflect “real-world” clinical practice and might complement those of the IMPROVE-IT, which compared simvastatin–ezetimibe with moderate-intensity statin therapy in patients with LDL level less than 125 mg/dL. Second, our findings provide evidence to support that simvastatin–ezetimibe can be an alternative of highintensity statin therapy in appropriately selected high-risk AMI patients, while high-intensity statin therapy could be beneficial in the other patients. Finally, our results can be used as a reference for Asian population, considering that most of the guidelines were based on Western population.

4.4. Study limitations Our study had several limitations. First, this study was retrospective study with potential for selection bias and missing values. To overcome these limitations, we performed Cox multivariate analysis and propensity-matching analysis with adjustment for potential confounders, but could not adjust for unmeasured potential confounders. Second, there was lack of data on how long the medications were taken after discharge. Finally, follow-up duration was relatively short to assess the long-term clinical outcomes. Nevertheless, this study suggests that simvastatin-ezetimibe could be an effective therapy in specific subgroups of patients. Further studies are needed to better define these observations.

5. Conclusion In overall AMI patients, high-intensity statin had better clinical outcomes than simvastatin–ezetimibe. However, in specific high-risk AMI patients, simvastatin-ezetimibe had comparable clinical outcomes to high-intensity statin. Therefore, we suggest simvastatin–ezetimibe could be an effective alternative therapy to high-intensity statin in specific subgroups of patients. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [23]. Conflicts of interest None. Acknowledgements This study was supported by a grant of the Korean Health Technology R&D Project (HI13C1527), Ministry of Health & Welfare, Republic of Korea. The authors thank all of the clinical investigators of the Korea Acute Myocardial Infarction Registry who contributed time and effort to this study. References [1] N.J. Stone, J.G. Robinson, A.H. Lichtenstein, et al., 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, J. Am. Coll. Cardiol. 63 (2014) 2889–2934. [2] C.P. Cannon, E. Braunwald, C.H. McCabe, et al., Intensive versus moderate lipid lowering with statins after acute coronary syndromes, N. Engl. J. Med. 350 (2004) 1495–1504. [3] T.R. Pedersen, O. Faergeman, J.J. Kastelein, et al., High-dose atorvastatin vs usualdose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial, JAMA 294 (2005) 2437–2445. [4] E.S. Stroes, P.D. Thompson, A. Corsini, et al., Statin-associated muscle symptoms: impact on statin therapy — European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management, Eur. Heart J. 36 (2015) 1012–1022. [5] K.A. Gudzune, A.K. Monroe, R. Sharma, P.D. Ranasinghe, Y. Chelladurai, K.A. Robinson, Effectiveness of combination therapy with statin and another lipidmodifying agent compared with intensified statin monotherapy: a systematic review, Ann. Intern. Med. 160 (2014) 468–476. [6] C.P. Cannon, M.A. Blazing, R.P. Giugliano, et al., Ezetimibe added to statin therapy after acute coronary syndromes, N. Engl. J. Med. 372 (2015) 2387–2397. [7] M. Pauriah, D.H. Elder, S. Ogston, et al., High-potency statin and ezetimibe use and mortality in survivors of an acute myocardial infarction: a population-based study, Heart 100 (2014) 867–872. [8] S.H. Chang, L.S. Wu, C.H. Lee, et al., Simvastatin-ezetimibe combination therapy is associated with a lower rate of major adverse cardiac events in type 2 diabetics than high potency statins alone: a population-based dynamic cohort study, Int. J. Cardiol. 190 (2015) 20–25. [9] D.S. Sim, J.H. Kim, M.H. Jeong, Differences in clinical outcomes between patients with ST-elevation versus non-ST-elevation acute myocardial infarction in Korea, Korean Circ. J. 39 (2009) 297–303. [10] D.E. Cutlip, S. Windecker, R. Mehran, et al., Clinical end points in coronary stent trials: a case for standardized definitions, Circulation 115 (2007) 2344–2351.

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