Vol 29, No 1 (2022)
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Published online: 2020-03-18

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Monotherapy versus combination therapy of statin and renin–angiotensin system inhibitor in ST-segment elevation myocardial infarction

Yong Hoon Kim1, Ae-Young Her1, Myung-Ho Jeong2, Byeong-Keuk Kim3, Sung-Jin Hong3, Seunghwan Kim4, Chul-Min Ahn3, Jung-Sun Kim3, Young-Guk Ko3, Donghoon Choi3, Myeong-Ki Hong3, Yangsoo Jang3
Pubmed: 32207841
Cardiol J 2022;29(1):93-104.

Abstract

Background: The beneficial effects of statin and renin–angiotensin system inhibitor (RASI) are well-known. In this retrospective cohort study, 2-year clinical outcomes were compared between monotherapy and combination therapy with statin and RASI in ST-segment elevation myocardial infarction (STEMI) patients after stent implantation.
Methods: A total of 17,414 STEMI patients were enrolled and divided into the three groups (group A: 2448 patients, statin alone; group B: 2431 patients, RASI alone; and group C: 12,535 patients, both statin and RASI). The principal clinical endpoint was the occurrence of major adverse cardiac events (MACEs) defined as all-cause death, recurrent myocardial infarction, and any repeat revascularization.
Results: After adjustment, the cumulative incidences of MACEs in group A (adjusted hazard ratio [aHR] 1.337; 95% confidence interval [CI] 1.064–1.679; p = 0.013) and in group B (aHR 1.375; 95% CI 1.149–1.646; p = 0.001) were significantly higher than in group C. The cumulative incidence of all-cause death in group A was significantly higher than that in group C (aHR 1.539; 95% CI 1.014–2.336; p = 0.043). The cumulative incidences of any repeat revascularization (aHR 1.317; 95% CI 1.031–1.681; p = 0.028), target lesion vascularization, and target vessel vascularization in group B were significantly higher than in group C.
Conclusions: A statin and RASI combination therapy significantly reduced the cumulative incidence of MACEs compared with a monotherapy of these drugs. Moreover, the combination therapy showed a reduced all-cause death rate compared with statin monotherapy, and a decreased repeat revascularization rate compared with RASI monotherapy.

clinical cardiology

original article

Cardiology Journal

2022, Vol. 29, No. 1, 93–104

DOI: 10.5603/CJ.a2020.0035

Copyright © 2022 Via Medica

ISSN 1897–5593

eISSN 1898018X

Monotherapy versus combination therapy of statin and renin–angiotensin system inhibitor in ST-segment elevation myocardial infarction

Yong Hoon Kim*1Ae-Young Her*1Myung-Ho Jeong2Byeong-Keuk Kim3Sung-Jin Hong3Seunghwan Kim4Chul-Min Ahn3Jung-Sun Kim3Young-Guk Ko3Donghoon Choi3Myeong-Ki Hong3Yangsoo Jang3
1Division of Cardiology, Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon, Republic of Korea
2Department of Cardiology, Cardiovascular Center, Chonnam National University Hospital, Gwangju, Republic of Korea
3Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
4Division of Cardiology, Inje University College of Medicine, Haeundae Paik Hospital, Busan, Republic of Korea

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: yhkim02@kangwon.ac.kr

Received: 17.09.2019 Accepted: 1.03.2020 Early publication date: 18.03.2020

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

This article is available in open access under Creative Common Attribution-Non-Commercial-No Derivatives 4.0 International (CC BY-NC-ND 4.0) license, allowing to download articles and share them with others as long as they credit the authors and the publisher, but without permission to change them in any way or use them commercially.

Abstract
Background: The beneficial effects of statin and renin–angiotensin system inhibitor (RASI) are well-known. In this retrospective cohort study, 2-year clinical outcomes were compared between monotherapy and combination therapy with statin and RASI in ST-segment elevation myocardial infarction (STEMI) patients after stent implantation.
Methods: A total of 17,414 STEMI patients were enrolled and divided into the three groups (group A: 2448 patients, statin alone; group B: 2431 patients, RASI alone; and group C: 12,535 patients, both statin and RASI). The principal clinical endpoint was the occurrence of major adverse cardiac events (MACEs) defined as all-cause death, recurrent myocardial infarction, and any repeat revascularization.
Results: After adjustment, the cumulative incidences of MACEs in group A (adjusted hazard ratio [aHR] 1.337; 95% confidence interval [CI] 1.064–1.679; p = 0.013) and in group B (aHR 1.375; 95% CI 1.149–1.646; p = 0.001) were significantly higher than in group C. The cumulative incidence of all-cause death in group A was significantly higher than that in group C (aHR 1.539; 95% CI 1.014––2.336; p = 0.043). The cumulative incidences of any repeat revascularization (aHR 1.317; 95% CI 1.031–1.681; p = 0.028), target lesion vascularization, and target vessel vascularization in group B were significantly higher than in group C.
Conclusions: A statin and RASI combination therapy significantly reduced the cumulative incidence of MACEs compared with a monotherapy of these drugs. Moreover, the combination therapy showed a reduced all-cause death rate compared with statin monotherapy, and a decreased repeat revascularization rate compared with RASI monotherapy. (Cardiol J 2022; 29, 1: 93–104)
Key words: ST-segment elevation myocardial infarction, statin, renin–angiotensin system, long-term outcome

Introduction

Through the inhibition of 3-hydroxy-3-methyl glutaryl-coenzyme A (HMG-CoA) reductase activity, statin plays essential roles in primary and secondary prevention of adverse cardiovascular events [1–3]. The European guidelines recommend starting high-intensity statin therapy as early as possible, unless contraindicated, and maintain it long-term in patients with ST-segment elevation myocardial infarction (STEMI) (Class 1A) [4]. Similarly, the American guidelines recommend the use of early high-intensity statin therapy and should be continued in all STEMI patients (Class 1B) [5]. Renin–angiotensin system inhibitors (RASI) are beneficial for reducing mortality in STEMI patients after percutaneous coronary intervention (PCI) [6], and RASI is recommended in the current guidelines as Class 1A [4, 5]. Even though the beneficial effects of statin and RASI are well-known, results focused on the comparative efficacy of combination therapy of statin and RASI, including an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) and statin, or RASI monotherapy on the occurrence of major adverse cardiac events (MACEs) during a long-term follow-up period in patients with STEMI who underwent successful stent implantation are limited. In this study, we investigated the difference in clinical outcome parameters between this combination therapy and monotherapy in STEMI patients after successful stent implantation, during a 2-year clinical follow-up period.

Methods

Study design and population

The Korea Acute Myocardial Infarction Re gistry (KAMIR) is a nationwide, prospective, multicenter registry in South Korea, established in November 2005. The KAMIR provides the public and physicians in the “real-world” clinical practice with the demographic characteristic and treatment strategies of the acute myocardial infarction (MI) in Korea [7]. The present study is a non-randomized, multicenter, observational, retrospective cohort study. A total of 24,549 STEMI patients in KAMIR from November 2005 to June 2015 were evaluated. Among them, patients who had the following conditions were excluded: (1) incomplete laboratory results (n = 4825, 19.7%), (2) lost to follow-up (n = 984, 4.0%), (3) statin or RASI had not been prescribed (n = 1384, 5.6%). After exclusion, a total of 17,414 STEMI patients who underwent successful stent implantation and who had been prescribed statin or RASI were enrolled. The patients were classified into group A (2448, 14.1%), group B (2431, 13.9%), and group C (12,535, 72.0%), and received statin alone, RASI alone, or both statin and RASI, respectively, as treatment (Fig. 1). The beneficial roles of statin and RASI in STEMI [4, 5] are well-known. For these reasons, patients who had not been prescribed these drugs in this study were excluded. The data collection was done via a web-based case report form, at each participating center; well-trained coordinators participated in data collection. The study protocol was approved by the ethics committee at each participating center and the Chonnam National University Hospital Institutional Review Board (IRB) ethics committee (CNUH-2011-172) according to the ethical guidelines of the 1975 Declaration of Helsinki. All patients provided written informed consent prior to enrollment. All the 17,414 patients completed a 2-year clinical follow-up through face-to-face interviews, phone calls, or chart review.

164059.png

Figure 1. Flow chart; KAMIR — Korea Acute myocardial Infarction Registry; STEMI — ST-segment elevation myocardial infarction; RASI — renin–angiotensin system inhibitor.

PCI procedure and medical treatment

Diagnostic coronary angiography and PCI were performed through the femoral and the radial artery approach according to the standard technique [8]. Before PCI, all patients were given loading doses of 200 to 300 mg acetylsalicylic acid (ASA) and 300 to 600 mg clopidogrel, when available; alternatively, 180 mg ticagrelor or 60 mg prasugrel was given. The recommended total duration of dual antipla-telet therapy (DAPT, the combination of ASA [100 mg/day] with clopidogrel [75 mg/day] or ticagrelor [90 mg twice a day] or prasugrel [5–10 mg/ /day]) was more than 12 months to patients who had undergone PCI. Triple antiplatelet therapy (100 mg cilostazol, twice a day added on to DAPT) was left to the discretion of the individual operators. The statins and their doses were as follows: 10–40 mg of atorvastatin, 5–10 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 RASI used and their doses were as follows: 12.5–75 mg of captopril, 2.5–10 mg of ramipril, 2–8 mg of perindopril, 1.25–5 mg of cilazapril, 5–10 mg of imidapril, 7.5–15 mg of moexipril, 2.5–10 mg of enalapril, 5–10 mg of lisinopril, 10 mg of fosinopril, 3.75–7.5 mg of zofenopril, 25–100 mg of losartan, 150–300 mg of irbesartan, 40–160 mg of valsartan, 40–80 mg of telmisartan, 10–20 mg of olmesartan, 4–32 mg of candesartan, 600 mg of eprosartan, and 30–120 mg of fimasartan per day.

Study definitions and clinical outcomes

ST-segment elevation myocardial infarction was defined as the patient who had experienced chest pain with ST-segment elevation ≥ 2 mm in ≥ 2 contiguous precordial lead, or 1 ≥ 1 mm in ≥ 2 limb leads, or new-onset left bundle branch block on the admission electrocardiogram [5]. The major clinical endpoint was the occurrence of MACEs, defined as all-cause death, recurrent myocardial infarction (Re-MI), any repeat coronary revascularization, including target lesion revascularization (TLR), target vessel revascularization (TVR), and non-TVR during the follow-up period. All-cause death was classified as cardiac or non-cardiac. 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 (CK-MB) above the upper normal limits, or an increase in troponin-T/troponin-I levels above the 99th percentile of the upper normal limit during the follow-up period [5]. TLR was defined as revascularization of the target lesion due to restenosis, or re-occlusion within the stent or 5 mm in and adjacent of the distal or proximal segment. TVR was defined as revascularization of the target vessel or any segment of the coronary artery containing the target lesion. Non-TVR was defined as revascularization of any segment of the non-target coronary artery.

Statistical analysis

All statistical analyses were performed using SPSS software, version 20 (IBM; Armonk, NY, USA). 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 two groups was carried out using the Hochberg test or Dunnett-T3 test; data are expressed as the means ± standard deviations. For discrete variables, the differences between two groups among the three groups were analyzed using the c2 test or the Fisher exact test, as appropriate; data are expressed as counts and percentages. Only meaningful confounding covariates (p < 0.001 or those having predictive values) during the multivariable Cox regression analysis, which are listed were included as follows: age, sex (men), left ventricular ejection fraction (LVEF), body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), cardiopulmonary resuscitation (CPR) on admission, primary PCI, hypertension, diabetes mellitus (DM), dyslipidemia, blood N-terminal pro-B-type natriuretic peptide (NT-proBNP), serum creatinine, total cholesterol, triglyceride, low-density lipoprotein cholesterol (LDL-C), ASA, clopidogrel, ticagrelor, prasugrel, beta-blockers (BBs), calcium channel blockers (CCBs), American College of Cardiology/ /American Heart Association (ACC/AHA) lesion type B2 and C, intravascular ultrasound (IVUS), bare-metal stents (BMS), sirolimus-eluting stent (SES), paclitaxel-eluting stent (PES), everolimus--eluting stents (EES), and biolimus-eluting stents (BES). Various clinical outcomes were estimated using the Kaplan-Meier curve analysis, and differences between groups were compared with the log-rank test. A two-tailed p value of < 0.05 indicated statistical significance.

Results

Baseline clinical, laboratory, angiographic, and procedural characteristics

Table 1 shows the baseline, laboratory, angiographic, and procedural characteristics of this cohort study. The study population is composed of patients who had relatively well preserved LVEF (mean 51.2 ± 10.9%). The number of men among the enrolled patients was the highest in group C. The mean ages of the patients enrolled in group A were older than the other groups. The frequency of primary PCI was the highest in group C. In group A, the mean blood levels of CK-MB, troponin-I, NT-proBNP; the prescription rates of more recently developed antiplatelet agents (e.g., ticagrelor, prasugrel) and CCB as the discharge medications; the number of CPR on admission; ACC/AHA type C lesion, the use of IVUS and the deployment of zotarolimus-eluting stent (ZES) were the highest. Moreover, the mean diameter of deployed stents was the lowest in group A. In group B, the number of cardiogenic shocks; the mean value of blood glucose, Hemoglobin A1c, creatinine; the number of clopidogrel as the discharge medication, left anterior descending coronary artery (LAD) as an infarct-related artery, ACC/AHA type B1; and the deployments of BMS, SES, PES, and ≥ 3-vessel disease were the highest. The mean length of the deployed stents was the shortest in group B. In group C, the mean values of BMI, SBP, DBP, total cholesterol, triglyceride, LDL-C; the prescription rate of ASA and BB as the discharge medications; the number of hypertensive patients, LAD as the treated vessel, ACC/AHA type B2 lesion, and EES were the highest. The mean number of deployed stents was not significantly different among the three groups

Table 1 (cont.). Baseline clinical, laboratory, angiographic and procedural characteristics.

Variables

Total

(n = 17,414)

Group A

Statin alone

(n = 2448)

Group B

RASI alone

(n = 2431)

Group C

Statin and RASI

(n = 12535)

P

Group A vs. B

Group A vs. C

Group B vs. C

Group A vs. B vs. C

Discharge medications:

ASA

17278 (99.2%)

2405 (98.2%)

2400 (98.7%)

12437 (99.5%)

0.169

< 0.001

< 0.001

< 0.001

Clopidogrel

15711 (90.2%)

2130 (87.0%)

2346 (96.5%)

11235 (89.6%)

< 0.001

< 0.001

< 0.001

< 0.001

Ticagrelor

931 (5.3%)

170 (6.9%)

26 (1.1%)

735 (5.9%)

< 0.001

0.040

< 0.001

< 0.001

Prasugrel

576 (3.3%)

112 (4.6%)

22 (0.9%)

442 (3.5%)

< 0.001

0.012

< 0.001

< 0.001

Cilostazole

4267 (24.5%)

584 (23.9%)

604 (24.8%)

3079 (24.6%)

0.421

0.457

0.767

0.693

BB

14594 (83.8%)

1657 (67.7%)

2064 (84.9%)

10873 (86.7%)

< 0.001

< 0.001

0.015

< 0.001

CCB

827 (4.7%)

161 (6.6%)

117 (4.8%)

549 (4.4%)

0.008

< 0.001

0.343

< 0.001

Infarct-related artery:

LM

149 (0.9%)

23 (0.9%)

14 (0.6%)

112 (0.9%)

0.143

0.825

0.117

0.265

LAD

9035 (51.9%)

1207 (49.3%)

1279 (52.6%)

6549 (52.2%)

0.021

0.008

0.741

0.021

LCx

1621 (9.3%)

242 (9.9%)

237 (9.7%)

1142 (9.1%)

0.873

0.226

0.319

0.349

RCA

6598 (37.9%)

976 (39.9%)

898 (36.9%)

4724 (37.7%)

0.035

0.042

0.486

0.073

Treated vessel:

LM

258 (1.5%)

32 (1.3%)

29 (1.2%)

197 (1.6%)

0.719

0.329

0.161

0.273

LAD

10229 (58.7%)

1371 (56.0%)

1416 (58.2%)

7442 (59.4%)

0.113

0.002

0.303

0.007

LCx

2829 (16.2%)

399 (16.3%)

392 (16.1%)

2038 (16.3%)

0.869

0.960

0.870

0.984

RCA

7417 (42.6%)

1078 (44.0%)

1014 (41.7%)

5325 (42.5%)

0.101

0.155

0.482

0.232

ACC/AHA lesion type:

Type B1

2508 (14.4%)

358 (14.6%)

405 (16.7%)

1745 (13.9%)

0.050

0.360

< 0.001

0.002

Type B2

5060 (29.1%)

615 (25.1%)

684 (28.1%)

3761 (30.0%)

0.017

< 0.001

0.065

< 0.001

Type C

8193 (47.0%)

1232 (50.3%)

1032 (42.5%)

5929 (47.3%)

< 0.001

0.006

< 0.001

< 0.001

Extent of CAD:

1-vessel

9078 (52.1%)

1287 (52.6%)

1220 (50.2%)

6571 (52.4%)

0.095

0.890

0.043

0.116

2-vessel

5201(29.9%)

753 (30.8%)

737 (30.3%)

3711 (29.6%)

0.737

0.253

0.482

0.455

≥ 3-vessel

3135 (18.0%)

408 (16.7%)

474 (19.5%)

2253 (18.0%)

0.010

0.122

0.075

0.036

IVUS

2397 (13.8%)

371 (15.2%)

278 (11.4%)

1748 (13.9%)

< 0.001

0.116

0.001

< 0.001

OCT

29 (0.2%)

2 (0.1%)

2 (0.1%)

25 (0.2%)

0.994

0.298

0.213

0.233

FFR

104 (0.6%)

16 (0.7%)

2 (0.1%)

86 (0.7%)

0.001

0.858

< 0.001

0.002

Table 1. Baseline clinical, laboratory, angiographic and procedural characteristics.

Variables

Total

(n = 17,414)

Group A

Statin alone

(n = 2448)

Group B

RASI alone

(n = 2431)

Group C

Statin and RASI

(n = 12535)

P

Group A vs. B

Group A vs. C

Group B vs. C

Group A vs. B vs. C

Men

13337 (76.6%)

1821 (74.4%)

1842 (75.8%)

9674 (77.2%)

0.264

0.003

0.132

0.007

Age [years]

62.2 ± 12.7

63.1 ± 12.8

62.8 ± 12.9

61.9 ± 12.6

0.439

< 0.001

0.001

< 0.001

LVEF [%]

51.2 ± 10.9

50.5 ± 11.1

51.5 ± 10.8

51.2 ± 10.9

0.381

< 0.001

< 0.001

< 0.001

BMI [kg/m2]

24.1 ± 3.2

23.8 ± 3.2

23.9 ± 3.3

24.2 ± 3.2

< 0.001

< 0.001

< 0.001

< 0.001

SBP [mmHg]

12.7 ± 27.7

122.7 ± 26.1

125.6 ± 28.5

129.0 ± 27.8

< 0.001

< 0.001

< 0.001

< 0.001

DBP [mmHg]

78.5 ± 16.8

76.0 ± 16.4

77.3 ± 16.9

79.2 ± 16.8

0.009

< 0.001

< 0.001

< 0.001

Cardiogenic shock

972 (5.6%)

162 (6.6%)

163 (6.7%)

647 (5.2%)

0.903

0.004

0.002

0.001

CPR on admission

561 (3.2%)

135 (5.5%)

67 (2.8%)

359 (2.9%)

< 0.001

< 0.001

0.770

< 0.001

Primary PCI

16121 (92.6%)

2256 (92.2%)

2188 (90.0%)

16677 (93.2%)

0.008

0.077

< 0.001

< 0.001

Hypertension

7974 (45.8%)

987 (40.3%)

1129 (46.4%)

5858 (46.7%)

< 0.001

< 0.001

0.792

< 0.001

Diabetes mellitus

4179 (24.0%)

583 (23.8%)

639 (26.3%)

2957 (23.6%)

0.046

0.810

0.004

0.017

Dyslipidemia

1832 (10.5%)

281 (11.5%)

172 (7.1%)

1379 (11.0%)

< 0.001

0.491

< 0.001

< 0.001

Previous MI

472 (2.7%)

79 (3.2%)

60 (2.5%)

333 (2.7%)

0.111

0.114

0.595

0.206

Previous PCI

726 (4.2%)

117 (4.8%)

93 (3.8%)

516 (4.1%)

0.101

0.136

0.506

0.214

Previous CABG

54 (0.3%)

13 (0.5%)

3 (0.1%)

38 (0.3%)

0.013

0.077

0.121

0.036

Previous CVA

887 (5.1%)

113 (4.6%)

130 (5.3%)

644 (5.1%)

0.240

0.281

0.669

0.465

Previous heart failure

121 (0.7%)

21 (0.9%)

30 (1.2%)

70 (0.6%)

0.208

0.081

< 0.001

0.001

Current smokers

8381 (48.1%)

1146 (46.8%)

1160 (47.7%)

6075 (48.5%)

0.527

0.135

0.500

0.297

CK-MB [mg/dL]

175.6 ± 238.9

190.0 ± 2736

184.1 ± 3100

171.2 ± 214.5

0.482

0.001

0.051

0.001

Troponin-I [ng/mL]

64.3 ± 260.2

76.7 ± 619.7

58.3 ± 88.7

63.1 ± 140.3

0.192

0.333

0.046

0.010

Serum glucose [mg/dL]

172.1 ± 74.3

173.1 ± 76.4

176.5 ± 77.1

171.0 ± 73.3

0.128

0.207

0.001

0.013

Hemoglobin A1c (ng/dL)

6.6 ± 2.0

6.6 ± 2.2

6.8 ± 2.9

6.5 ± 1.8

0.178

0.293

0.022

0.020

NT-proBNP [pg/mL]

1515.8 ± 5292.7

2325.2 ± 7028.4

1789.9 ± 4633.6

1324.0 ± 3638.3

0.109

0.002

< 0.001

< 0.001

Hs-CRP [mg/dL]

10.8 ± 60.9

9.8 ± 46.7

11.4 ± 80.4

10.9 ± 58.7

0.467

0.385

0.804

0.523

Serum creatinine [mg/L]

1.06 ± 1.15

1.09 ± 1.54

1.12 ± 1.06

1.05 ± 1.07

0.424

0.281

0.006

< 0.001

Total cholesterol [mg/dL]

185.0 ± 44.2

183.5 ± 44.6

176.8 ± 44.4

186.8 ± 43.8

< 0.001

0.001

< 0.001

< 0.001

Triglyceride [mg/L]

133.8 ± 111.7

128.7 ± 100.9

126.0 ± 102.9

136.3 ± 115.2

0.361

0.001

< 0.001

< 0.001

HDL cholesterol [mg/L]

44.1 ± 18.5

43.5 ± 16.2

44.0 ± 14.0

44.3 ± 19.6

0.242

0.041

0.446

0.008

LDL cholesterol [mg/L]

117.4 ± 40.0

116.0 ± 38.2

110.0 ± 38.9

119.1 ± 40.4

< 0.001

< 0.001

< 0.001

< 0.001

.

Table 1 (cont.). Baseline clinical, laboratory, angiographic and procedural characteristics.

Variables

Total

(n = 17,414)

Group A

Statin alone

(n = 2448)

Group B

RASI alone

(n = 2431)

Group C

Statin and RASI

(n = 12535)

P

Group A vs. B

Group A vs. C

Group B vs. C

Group A vs. B vs. C

Types of stent:

BMS

1127 (6.5%)

105 (4.3%)

185 (7.6%)

837 (6.7%)

< 0.001

< 0.001

0.095

< 0.001

SES

2865 (16.5%)

376 (15.4%)

558 (23.0%)

1931 (15.4%)

< 0.001

0.955

< 0.001

< 0.001

PES

2446 (14.0%)

313 (12.8%)

466 (19.2%)

1667 (13.3%)

< 0.001

0.493

< 0.001

< 0.001

ZES

3869 (22.2%)

585 (23.9%)

486 (20.0%)

2798 (22.3%)

0.001

0.088

0.011

0.004

EES

4754 (27.3%)

693 (28.3%)

480 (19.7%)

3581 (28.6%)

< 0.001

0.795

< 0.001

< 0.001

BES

1343 (7.7%)

203 (8.3%)

100 (4.1%)

1040 (8.3%)

< 0.001

0.994

< 0.001

< 0.001

Stent diameter [mm]

3.20 ± 0.42

3.18 ± 0.44

3.20 ± 0.42

3.20 ± 0.42

0.044

0.008

0.956

0.007

Stent length [mm]

25.9 ± 9.0

26.1 ± 9.4

24.8 ± 7.0

26.1 ± 9.2

< 0.001

0.973

< 0.001

0.011

Number of stent

1.40 ± 0.72

1.40 ± 0.71

1.38 ± 0.70

1.41 ± 0.73

0.511

0.430

0.100

0.222

Clinical outcomes

Table 2 shows the cumulative incidences of major clinical outcomes during the 2-year follow-up period. After adjustment, the cumulative incidences of MACEs in group A (adjusted hazard ratio [aHR]: 1.337; 95% confidence interval [CI]: 1.064–1.679; p = 0.013) and in group B (aHR: 1.375; 95% CI: 1.149–1.646; p = 0.001) were significantly higher than those in group C (Table 3, Fig. 2A). The cumulative incidence of all-cause death in group A was significantly higher than that in group C (aHR: 1.539; 95% CI: 1.014–2.336; p = 0.043; Fig. 2B). The cumulative incidences of any repeat revascularization (aHR: 1.317; 95% CI: 1.031–1.681; p = 0.028; Fig. 2D), TLR (aHR: 1.754; 95% CI: 0.193–2.580; p = 0.004; Fig. 2E), and TVR (aHR: 1.539; 95% CI: 1.138–2.082; p = 0.005; Fig. 2F) in group B were significantly higher than those in group C. However, the cumulative incidences of cardiac, Re-MI, and non-TVR were similar among the three groups before and after adjustment. Table 4 shows the independent predictors for MACEs at 2 years. LVEF < 50% (aHR: 1.146; 95% CI: 1.019–1.289; p = 0.023), DM (aHR: 1.342; 95% CI: 1.187–1.518; p < 0.001), multivessel disease (aHR: 1.774; 95% CI: 1.570–2.005; p < 0.001), cardiogenic shock (aHR: 0.998; 95% CI: 0.996–1.000; p = 0.043), and CPR on admission (aHR: 2.240; 95% CI: 1.784–2.813; p < 0.001) were significant independent predictors for MACEs.

Table 2. Cumulative clinical events at 2 years.

Variables

Total

(n = 17,414)

Group A

(n = 2448)

Group B

(n = 2431)

Group C

(n = 12,535)

P

Group A vs. B

Group A vs. C

Group B vs. C

Group A vs. B vs. C

MACEs

1262 (7.2%)

193 (7.9%)

214 (8.8%)

855 (6.8%)

0.246

0.059

0.001

0.001

All-cause death:

358 (2.1%)

67 (2.7%)

59 (2.4%)

232 (1.9%)

0.528

0.004

0.060

0.007

Cardiac death

248 (1.4%)

44 (1.8%)

39 (1.6%)

165 (1.3%)

0.602

0.063

0.262

0.133

Re-MI:

257 (1.5%)

44 (1.8%)

32 (1.3%)

181 (1.4%)

0.175

0.188

0.627

0.324

Any repeat revascularization:

737 (4.2%)

94 (3.8%)

136 (5.6%)

507 (4.0%)

0.004

0.637

0.001

0.001

TLR

246 (1.4%)

34 (1.4%)

52 (2.1%)

160 (1.3%)

0.046

0.653

0.001

0.004

TVR

426 (2.4%)

50 (2.0%)

82 (3.4%)

294 (2.3%)

0.004

0.360

0.003

0.004

Non-TVR

323 (1.9%)

44 (1.8%)

57 (2.3%)

222 (1.8%)

0.179

0.928

0.056

0.155

Table 3. Hazard ratio for 2-year major clinical outcomes by Cox-proportional hazard ratio analysis.

Hazard ratio (95% confidence interval), P

Group A vs. B

Group A vs. C

Group B vs. C

MACE:

Unadjusted

1.057 (0.870–1.285), 0.574

1.187 (1.016–1.388), 0.031

1.256 (1.081–1.459), 0.003

Adjusted*

1.093 (0.822–1.454), 0.540

1.337 (1.064–1.679), 0.013

1.375 (1.149–1.646), 0.001

All-cause death:

Unadjusted

1.185 (0.835–1.681), 0.343

1.506 (1.148–1.977), 0.003

1.275 (0.958–1.696), 0.096

Adjusted*

1.386 (0.803–2.390), 0.241

1.539 (1.014–2.336), 0.043

1.172 (0.767–1.793), 0.463

Cardiac death:

Unadjusted

1.164 (0.756–1.792), 0.490

1.386 (0.994–1.933), 0.054

1.192 (0.841–1.690), 0.323

Adjusted*

1.125 (0.528–2.394), 0.768

1.090 (0.609–1.951), 0.772

1.244 (0.726–2.131), 0.426

Re-MI:

Unadjusted

1.434 (0.910–2.262), 0.121

1.276 (0.918–1.774), 0.147

1.135 (0.779–1.652), 0.510

Adjusted

1.048 (0.528–2.081), 0.894

1.041 (0.637–1.699), 0.873

1.180 (0.725–1.921), 0.499

Any repeat revascularization:

Unadjusted

1.377 (1.059–1.791), 0.017

1.024 (0.822–1.276), 0.831

1.345 (1.113–1.625), 0.002

Adjusted*

1.038 (0.712–1.513), 0.847

1.263 (0.926–1.722), 0.141

1.317 (1.031–1.681), 0.028

TLR:

Unadjusted

1.450 (0.941–2.234), 0.092

1.119 (0.773–1.620), 0.119

1.624 (0.188–2.221), 0.002

Adjusted*

1.111 (0.618–1.998), 0.724

1.648 (0.999–2.717), 0.050

1.754 (0.193–2.580), 0.004

TVR:

Unadjusted

1.555 (1.094–2.210), 0.014

1.116 (0.827–1.506), 0.474

1.391 (1.089–1.777), 0.008

Adjusted*

1.184 (0.736–1.905), 0.487

1.286 (0.857–1.930), 0.224

1.539 (1.138–2.082), 0.005

Non-TVR:

Unadjusted

1.230 (0.830–1.823), 0.302

1.004 (0.755–1.442), 0.796

1.284 (0.960–1.718), 0.092

Adjusted*

1.067 (0.578–1.968), 0.836

1.166 (0.721–1.886), 0.531

1.074 (0.717–1.610), 0.729

164021.png

Figure 2. Kaplan-Meier curved analysis for major adverse cardiac events (MACEs; A), all-cause death (B), recurrent myocardial infarction (Re-MI; C), any repeat revascularization (D), target lesion revascularization (TLR; E), and target vessel revascularization (TVR; F) during a 2-year follow-up perioad d; aHR — adjusted hazard ratio.

Table 4. Multivariate Cox-proportional regression analysis for independent predictor of MACEs.

Variables

Unadjusted

Adjusted

HR (95% CI)

P

HR (95% CI)

P

Groups

A vs. B

1.057 (0.870–1.285)

0.574

1.063 (0.870–1.298)

0.550

A vs. C

1.187 (1.016–1.388)

0.031

1.208 (1.037–1.408)

0.019

B vs. C

1.256 (1.081–1.459)

0.003

1.217 (1.044–1.418)

0.012

Age, ≥ 65 years

1.042 (1.013–1.071)

0.004

1.034 (0.990–1.081)

0.129

Gender, men

1.208 (1.066–1.367)

0.003

1.038 (0.899–1.199)

0.281

LVEF, < 50%

1.248 (1.118–1.394)

< 0.001

1.146 (1.019–1.289)

0.023

Hypertension

1.211 (1.084–1.352)

0.001

1.082 (0.961–1.217)

0.192

Diabetes mellitus

1.481 (1.315–1.667)

< 0.001

1.342 (1.187–1.518)

< 0.001

Dyslipidemia

1.066 (0.894–1.271)

0.478

1.027 (0.857–1.232)

0.772

Previous MI

1.373 (1.020–1.849)

0.037

1.206 (0.890–1.633)

0.227

Multi-vessel disease

1.897 (1.691–2.129)

< 0.001

1.774 (1.570–2.005)

< 0.001

Current smokers

1.145 (1.025–1.279)

0.017

1.043 (0.869–1.251)

0.842

Cardiogenic shock

1.301 (1.049–1.614)

0.017

1.135 (0.908–1.419)

0.043

CPR on admission

2.385 (1.941–2.972)

< 0.001

2.240 (1.784–2.813)

< 0.001

ACC/AHA type B2/C

1.027 (0.902–1.168)

0.689

1.028 (0.900–1.174)

0.701

Stent diameter, < 3.0 mm

1.242 (1.093–1.412)

0.001

1.116 (0.978–1.273)

0.103

Stent length, ≥ 28 mm

1.149 (1.027–1.285)

0.015

1.048 (0.934–1.176)

0.421

LAD — IRA

1.002 (0.898–1.119)

0.967

1.072 (0.881–1.305)

0.541

LAD — treated vessel

1.158 (1.034–1.298)

0.011

1.190 (0.978–1.447)

0.083

IVUS

1.117 (0.956–1.307)

0.164

1.083 (0.923–1.271)

0.329

Discussion

The main findings of this study are as follows: First, the cumulative incidences of MACEs in group A and group B were significantly higher than those in group C. Second, the cumulative incidence of all-cause death in group A was significantly higher than that in group C. Third, the cumulative incidences of any repeat revascularization, TLR, and TVR in group B were significantly higher than those in group C. Finally, the cumulative incidences of cardiac, Re-MI, and non-TVR were similar among the three groups before and after adjustment.

Statins have both fundamental lipid-lowering capacity and additional pleiotropic actions [9]. In patients with STEMI, these pleiotropic activities include cardiovascular death, non-fatal MI, and coronary revascularization rate reduction capabilities [3, 10]. Even though the relative superiority on the long-term clinical outcome between ACEI and ARB in acute MI patients is still debatable [11–13], RASI is recommended in patients with STEMI after PCI [4, 5]. In this study, the cumulative incidence of MACEs, all-cause death, Re-MI, and any repeat revascularization (TLR, TVR, and non-TVR) between group A and group B were similar. It was assumed that the major causative factors for similar results between these two groups are related to a shared process, such as nitric oxide (NO) production [14]. The statins’ pleiotropic action include the upregulation and activation of endothelial NO synthase [15], and the accumulated bradykinin after ACEI treatment lead to increased stimulations of the NO production [16]. The combination therapy of statin and RASI compensate unwanted effects of statin and has additive or synergistic effects on endothelial dysfunction, inflammation, and lipid profiles [17–19]. Furthermore, the statin plus RASI combination reduced cardiovascular events more than statin alone and to a greater extent than RASI therapy alone [18, 20]. As expected, additional beneficial effects of the statin and RASI combination therapy were observed in reducing MACEs compared to that achieved with monotherapy alone in this study. Previous studies have shown that both the statin and the RASI could reduce the death rate and revascularization rate in STEMI patients [21–23]. Additionally, the relative superiority between these two abilities, according to the drugs, was suspected in this study. Figure 2B shows the Kaplan-Meier curve of all-cause death among the three groups. The cumulative incidence of all-cause death in group A was continuously higher than that in group C during the 2-year follow-up period. However, the cumulative incidence of all-cause death between group B and group C was statistically insignificant. In contrast, the cumulative incidence of total revascularization in group B was continuously higher than that in group C (Fig. 2D). The cumulative incidence between group A and group C was insignificantly different. The Kaplan-Meier curve of TLR (Fig. 2E) and TVR (Fig. 2F) also showed similar patterns among the three groups. Regarding the results of this study, it was cautiously supposed that the possibility that RASI was more likely related with mortality reduction rather than revascularization reduction, and statin was more likely related with repeat revascularization reduction rather than mortality reduction in these STEMI patients after successful stent implantation. In this study, independent predictors for MACEs at 2 years were decreased LVEF (< 50%), DM, multivessel disease, cardiogenic shock, and CPR on admission (Table 4). Therefore, in these situations, the combination therapy of statin and RASI might be helpful in reducing MACEs.

Unlike previous studies [18, 24], the present study population was composed of solely STEMI patients. While some previous studies [25, 26] were conducted before the widespread use of statin and dual antiplatelet agents, diverse kinds of statins and newly developed antiplatelet agents were used in this study. More than 50 high-volume University or community hospitals with facilities for primary PCI and onsite cardiac surgery in South Korea participated in this study. Therefore, this comparative study might provide meaningful information to interventional cardiologists regarding the importance of a statin and RASI combination therapy rather than a monotherapy of each drug, and some different clinical outcome characteristics of the statin monotherapy and RASI monotherapy compared with a combination therapy in STEMI patients, after successful stent implantation during a 2-year follow-up period.

Limitations of the study

This study had several limitations. First, there may be some under-reporting and/or missed data due to limitations of registry data. Second, this study was based on medications at discharge, and this registry data did not include a full detailed data concerning the starting times of statin and RASI therapy, change of prescription doses, long-term adherence, and discontinuation during the follow-up period; these factors might, therefore, act as substantial bias in this study. Third, the achievement of target blood cholesterol level (i.e., LDL-C) was a critical prognostic parameter after statin therapy during the follow-up period. However, the follow-up results could not presented for these lipid profiles due to a limitation of the registry data, which might act as a bias. Fourth, because this study reflectsa multicenter “real-world” clinical practice, diverse kinds and doses of statins and RASI were prescribed; all of which could not be adjusted during statistical analysis, and might be another limitation of this study. Fifth, the selection of either monotherapy or combination therapy of statin and RASI after PCI was left to physician preferences; which might act as selection bias. Sixth, a multivariate analysis was done to strengthen the present results; variables not included in this registry may have affected the study outcomes.

Conclusions

In conclusion, a statin and RASI combination therapy significantly reduced the cumulative incidence of MACEs compared with a monotherapy of these drugs. Moreover, this combination therapy showed a reduced all-cause death rate compared with statin monotherapy, and a decreased repeat revascularization rate compared with RASI monotherapy.

Funding

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

Acknowledgments

The authors thank all of the clinical investigators who contributed time and effort to this study, as well as the Korea Acute Myocardial Infarction (KAMIR) Investigators.

The following investigators took part in the Korea Acute Myocardial infarction Registry (KAMIR): 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; Junghan 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; 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.

Conflict of interest: None declared

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