Vol 29, No 6 (2022)
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Sex difference after acute myocardial infarction patients with a history of current smoking and long-term clinical outcomes: Results of KAMIR Registry

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: 33438183
Cardiol J 2022;29(6):954-965.

Abstract

Background: The contribution of sex as an independent risk factor for cardiovascular disease still remains controversial. The present study investigated the impact of sex on long-term clinical outcomes in Korean acute myocardial infarction (AMI) patients with a history of current smoking on admission after drug-eluting stents (DESs).
Methods: A total of 12,565 AMI patients (male: n = 11,767 vs. female: n = 798) were enrolled. Major adverse cardiac events (MACEs) comprising all-cause death, recurrent myocardial infarction (Re-MI), and any repeat revascularization were the primary outcomes that were compared between the two groups. Probable or definite stent thrombosis (ST) was the secondary outcome.
Results: After adjustment, the early (30 days) cumulative incidences of MACEs (adjusted hazard ratio [aHR]: 1.457; 95% confidence interval [CI]: 1.021–2.216; p = 0.035) and all-cause death (aHR: 1.699; 95% CI: 1.074–2.687; p = 0.023) were significantly higher in the female group than in the male group. At 2 years, the cumulative incidences of all-cause death (aHR: 1.561; 95% CI: 1.103–2.210; p = 0.012) and Re-MI (aHR: 1.800; 95% CI: 1.089–2.974; p = 0.022) were significantly higher in the female group than in the male group. However, the cumulative incidences of ST were similar between the two groups (aHR: 1.207; 95% CI: 0.583–2.497; p = 0.613).
Conclusions: The female group showed worse short-term and long-term clinical outcomes compared with the male group comprised of Korean AMI patients with a history of current smoking after successful DES implantation. However, further studies are required to confirm these results.

10_CJ_2022_6_Kim_Sex

clinicAL CARDIOLOGY

original article

Cardiology Journal

2022, Vol. 29, No. 6, 954–965

DOI: 10.5603/CJ.a2020.0185

Copyright © 2022 Via Medica

ISSN 1897–5593

eISSN 1898–018X

Sex difference after acute myocardial infarction patients with a history of current smoking and long-term clinical outcomes: Results of KAMIR Registry

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

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: 25.03.2020 Accepted: 6.12.2020 Early publication date: 31.12.2020

*The first two authors (Yong Hoon Kim and Ae-Young Her) are equally contributed 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 contribution of sex as an independent risk factor for cardiovascular disease still remains controversial. The present study investigated the impact of sex on long-term clinical outcomes in Korean acute myocardial infarction (AMI) patients with a history of current smoking on admission after drug-eluting stents (DESs).

Methods: A total of 12,565 AMI patients (male: n = 11,767 vs. female: n = 798) were enrolled. Major adverse cardiac events (MACEs) comprising all-cause death, recurrent myocardial infarction (Re-MI), and any repeat revascularization were the primary outcomes that were compared between the two groups. Probable or definite stent thrombosis (ST) was the secondary outcome.

Results: After adjustment, the early (30 days) cumulative incidences of MACEs (adjusted hazard ratio [aHR]: 1.457; 95% confidence interval [CI]: 1.021–2.216; p = 0.035) and all-cause death (aHR: 1.699; 95% CI: 1.074–2.687; p = 0.023) were significantly higher in the female group than in the male group. At 2 years, the cumulative incidences of all-cause death (aHR: 1.561; 95% CI: 1.103–2.210; p = 0.012) and Re-MI (aHR: 1.800; 95% CI: 1.089–2.974; p = 0.022) were significantly higher in the female group than in the male group. However, the cumulative incidences of ST were similar between the two groups (aHR: 1.207; 95% CI: 0.583–2.497; p = 0.613).

Conclusions: The female group showed worse short-term and long-term clinical outcomes compared with the male group comprised of Korean AMI patients with a history of current smoking after successful DES implantation. However, further studies are required to confirm these results. (Cardiol J 2022; 29, 6: 954–965)

Key words: myocardial infarction, sex, smoking

Introduction

As age increases, the incidence and mortality rates of cardiovascular disease (CVD) also increases. Moreover, other factors affecting the long-term prognosis of CVD are of utmost importance for public heath investigators and cardiologists. Previously, based on sex difference, a higher mortality rate of myocardial infarction (MI) was observed in women than in men [1, 2]. However, the contribution of sex as an independent risk factor for CVD still remains controversial. Proposed explanations for higher mortality rate among women are advanced age and increased incidence of diabetes mellitus (DM), chronic heart failure (HF), and hypertension prior to MI [3]. Cigarette smoking is an important correctable risk factor and a major causative factor of recurrent MI and death after percutaneous coronary intervention (PCI) [4]. According to a recent report, the estimated prevalence of cigarette smoking was not strongly associated with sex difference [5]. In 2012, the estimated prevalence rates of smokers were greater than 40% among men and lower than 5% in women [5]. Additionally, controversy exists whether sex difference is associated with smoking and adverse cardiovascular clinical outcomes [6]. To date, the cumulative incidences of acute myocardial infarction (AMI) are increasing in South Korea [7]. In real-world practice, the use of bare-metal stent (BMS) is limited. Therefore, we investigated the impact of sex difference on the 2-year clinical outcomes in Korean AMI patients with a history of current smoking on admission who underwent successful PCI with drug-eluting stents (DESs).

Methods

Study design and population

This study was a nonrandomized, multicenter, observational retrospective cohort study, and the study population was obtained from the Korea AMI Registry (KAMIR). Detailed information about the KAMIR has already been published [7, 8]. A total of 20,174 AMI patients who were active smokers on admission between November 2005 and June 2015 were evaluated. Patients with the following characteristics were excluded from the study: (1) patients who underwent fibrinolysis (n = 609, 3.0%), (2) patients who did not undergo PCI (n = 616, 3.1%), (3) patients with failed PCI (n = 415, 2.1%), (4) patients who underwent coronary artery bypass graft (n = 55, 0.3%), (5) patients with BMS (n = 942, 4.7%), (6) patients with incomplete laboratory results (n = 3562, 17.6%), and (7) patients who were lost to follow-up (n = 1410, 7.0%). Finally, a total of 12,565 AMI patients who were active smokers at the time of admission who underwent successful PCI with DESs were enrolled. They were grouped based on their sex; male (n = 11,767, 93.6%) and female groups (n = 798, 6.4%) (Fig. 1, Table 1). This study was conducted according to the ethical guidelines of the 1975 Declaration of Helsinki. This study protocol was approved by the ethics committee of each participating center, and informed consent was obtained from all individual participants prior to their enrollment. All 12,565 AMI patients completed a 2-year clinical follow-up, and were tracked the enrolled patients via direct interviews, telephone contact, and chart reviews [9]. All clinical events were evaluated by an independent event adjudication committee. The event adjudication processes were described in a previous publication established by the KAMIR investigators [8].

Figure 1. Flow chart; AMI — acute myocardial infarction; BMS — bare-metal stent; CABG — coronary artery bypass grafting; PCI — percutaneous coronary intervention.

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

Variables

Male (n = 11,767)

Female (n = 798)

P

SD

Age [years]

56.7 ± 11.2

68.3 ± 11.5

< 0.001

1.21

LVEF [%]

52.6 ± 11.0

52.5 ± 11.8

0.724

–0.09

LVEF < 40%

1256 (10.7%)

96 (12.6%)

0.232

0.70

BMI [kg/m2]

24.3 ± 3.1

23.3 ±3.6

<0.001

–2.98

SBP [mmHg]

130.0 ± 27.2

128.4 ± 28.9

0.103

–0.57

DBP [mmHg]

80.2 ± 16.6

77.5 ± 17.2

< 0.001

–1.60

STEMI

7480 (63.6%)

468 (58.6%)

0.005

–1.33

Primary PCI

6919 (92.5%)

429 (91.7%)

0.508

–0.33

NSTEMI

4287 (36.4%)

330 (41.4%)

0.005

1.34

PCI within 24 h

3342 (78.0%)

250 (75.8%)

0.354

–0.66

Hypertension

4237 (36.3%)

410 (51.4%)

< 0.001

3.99

Diabetes mellitus

2510 (21.3%)

216 (27.1%)

< 0.001

1.70

Dyslipidemia

1273 (10.8%)

80 (10.0%)

0.484

–0.31

Previous MI

338 (2.9%)

15 (1.9%)

0.101

–0.60

Previous PCI

476 (4.0%)

29 (3.6%)

0.567

–0.22

Previous CABG

27 (0.2%)

2 (0.3%)

0.904

0.07

Previous CVA

431 (3.7%)

51 (6.4%)

< 0.001

1.23

Previous HF

59 (0.5%)

11 (1.4%)

0.001

0.58

Cardiogenic shock

454 (3.9%)

48 (6.0%)

0.003

0.97

CPR on admission

364 (3.1%)

27 (3.4%)

0.648

0.16

CK-MB [mg/dL]

152.9 ± 149.4

140.4 ± 173.1

0.177

–0.77

Troponin-I [ng/mL]

52.1 ± 91.4

44.0 ± 41.5

0.473

–1.14

NT-ProBNP [pg/mL]

1042.6 ± 1119.8

3008.0 ± 3822.9

< 0.001

6.98

hs-CRP [mg/dL]

9.4 ± 51.0

8.6 ± 39.9

0.716

–0.17

Serum creatinine [mg/L]

1.1 ± 1.3

0.9 ± 0.6

0.001

–1.85

Total cholesterol [mg/dL]

187.4 ± 43.6

195.9 ± 48.2

< 0.001

1.98

Triglyceride [mg/L]

151.2 ± 129.5

137.2 ± 106.7

0.003

–1.18

HDL cholesterol [mg/L]

42.7 ± 18.5

45.0 ± 11.8

0.001

1.48

LDL cholesterol [mg/L]

119.5 ± 41.1

125.0 ± 42.7

< 0.001

1.31

Discharge medications:

Acetylsalicylic acid

11410 (97.0%)

757 (94.9%)

0.001

–1.02

Clopidogrel

10473 (89.0%)

744 (93.2%)

< 0.001

1.88

Ticagrelor

648 (5.5%)

24 (3.0%)

0.002

–1.38

Prasugrel

485 (4.1%)

16 (2.0%)

0.003

–1.25

Cilostazole

2798 (23.8%)

194 (24.3%)

0.733

0.15

BBs

9563 (81.3%)

594 (74.4%)

< 0.001

–2.05

ACEIs

7207 (61.2%)

464 (58.1%)

0.082

–0.82

ARBs

2465 (20.9%)

160 (20.1%)

0.546

-0.25

CCBs

674 (5.7%)

56 (7.0%)

0.132

0.58

Lipid lowering agents

9669 (82.2%)

624 (78.2%)

0.005

-1.24

Angiographic and procedural characteristics

Infarct-related artery

Left main

174 (1.5%)

10 (1.3%)

0.608

–0.13

Left anterior descending

5765 (48.9%)

324 (40.6%)

< 0.001

–2.23

Left circumflex

2033 (17.3%)

133 (16.6%)

0.659

–0.24

Right coronary artery

3795 (32.3%)

331 (41.5%)

< 0.001

2.46

Treated vessel:

Left main

249 (2.1%)

18 (2.3%)

0.791

0.12

Left anterior descending

6655 (56.6%)

403 (50.5%)

0.001

–1.61

Left circumflex

2956 (25.1%)

190 (23.8%)

0.408

–0.40

Right coronary artery

4530 (38.5%)

377 (47.2%)

< 0.001

2.30

ACC/AHA lesion type:

Type B1

1801 (15.3%)

126 (15.8%)

0.714

0.17

Type B2

3554 (30.2%)

215 (26.9%)

0.052

–0.96

Type C

5148 (43.7%)

379 (47.5%)

0.039

1.00

Extent of coronary artery disease:

1-vessel

5962 (50.7%)

369 (46.2%)

0.016

–1.19

2-vessel

3695 (31.4%)

233 (29.2%)

0.293

–0.63

≥ 3-vessel

2110 (17.9%)

196 (24.6%)

< 0.001

2.01

Drug-eluting stents:

SES

2155 (18.3%)

168 (21.1%)

0.054

0.88

PES

1866 (15.9%)

141 (17.6%)

0.177

0.56

ZES

2866 (24.4%)

204 (25.6%)

0.332

0.36

EES

3640 (30.9%)

217 (27.2%)

0.027

–1.08

BES

1085 (9.2%)

56 (7.0%)

0.036

–0.98

Others

155 (1.3%)

12 (1.5%)

0.656

0.12

Stent diameter [mm]

3.2 ± 0.4

3.1 ± 0.4

< 0.001

–2.50

Stent length [mm]

26.1 ± 9.5

25.7 ± 8.9

0.327

–0.43

Number of stents

1.4 ± 0.8

1.5 ± 0.8

0.011

1.25

Values are mean ± standard deviation or number (%). The p values for continuous data were obtained from the analysis of the unpaired t-test. The p values for categorical data were obtained from the chi-square test. SD — standardized difference; LVEF — left ventricular ejection fraction; BMI — body mass index; SBP — systolic blood pressure; DBP — diastolic blood pressure; STEMI — ST-segment elevation myocardial infarction; NSTEMI — non-STEMI; PCI — percutaneous coronary intervention; MI — myocardial infarction; CABG — coronary artery bypass grafting; CVA — cerebrovascular accidents; HF — heart failure; CPR — cardiopulmonary resuscitation; CK-MB — creatine kinase myocardial band; NT-proBNP — N-terminal pro-B-type natriuretic peptide; HDL — high-density lipoprotein; LDL — low-density lipoprotein; BBs — beta-blockers; ACEIs — angiotensin converting enzyme inhibitors; ARBs — angiotensin receptor blockers; CCBs — calcium channel blockers; ACC/AHA — American College of Cardiology/American Heart Association; SES — sirolimus-eluting stents; PES — paclitaxel-eluting stents; ZES — zotarolimus-eluting stents; EES — everolimus-eluting stents; BES — biolimus-eluting stents

Percutaneous coronary intervention procedure and medical treatment

Coronary angiography and PCI were performed as described before [10]. Before PCI, 200 to 300 mg of acetylsalicylic acid (ASA) and 300 to 600 mg of clopidogrel was administered. If possible, 180 mg of ticagrelor or 60 mg of prasugrel was administered. After discharge, 100 to 200 mg/ /day of ASA was continued indefinitely, and 75 mg/ /day of clopidogrel was maintained for at least 12 months. Triple antiplatelet therapy (TAPT) (100 mg of cilostazol [Pletaal®, Otsuka Pharmaceutical Co., Tokyo, Japan] twice a day added on a dual antiplatelet therapy) was left to the discretion of the individual operators [9].

Study definitions and clinical outcomes

Acute myocardial infarction was defined according to the current guidelines [11, 12]. Current smoking was defined as cigarette smoking within 1 year before the index PCI [9, 13]. Smoking history was assessed based on patient medical records. In this study, the occurrence of major adverse cardiac events (MACEs) was the primary endpoint. MACEs comprised all-cause death, recurrent myocardial infarction (Re-MI), and any repeat revascularization during a 2-year follow-up period. All-cause death was classified as a cardiac death (CD) or a non-CD. Re-MI was defined as the reoccurrence of AMI [14]. Any repeat revascularization comprised target lesion revascularization (TLR), target vessel revascularization (TVR), and non-TVR. Previously, the definitions of TLR, TVR, and non-TVR were published [14]. The secondary endpoint, the cumulative incidences of definite or probable stent thrombosis (ST), was defined according to the onset of this event as follows: acute (0–24 h), subacute (24 h–30 days), late (30 days–1 year), and very late (> 1 year) [14, 15].

Statistical analyses

The Statistical Package for the Social Sciences software version 20 (International Business Machines Corporation, Armonk, NY, USA) was used during the statistical analyses of this study. In case of continuous variables, differences between the groups were evaluated using the unpaired t-test, and the data are expressed as the mean ± standard deviations. In case of categorical variables, the differences between two groups were analyzed with the c2 test, or, if not applicable, the Fisher exact test, and data are expressed as counts and percentages. Various clinical outcomes of this study were evaluated using the Kaplan-Meier method, and differences between two groups were compared using the log-rank test. Among the total covariates, only significant confounding covariates (p < 0.001 or those having predictive values) were included when performing multivariate Cox regression analysis, as shown in Table 2. For all analyses, two-sided p values < 0.05 were considered statistically significant [13].

Results

Baseline clinical, laboratory, angiographic, and procedural characteristics

The baseline, laboratory, angiographic, and procedural characteristics of the present study population are summarized in Table 1. The mean age of the patients in the female group was higher than that of the male group (68.3 ± 11.5 years vs. 56.7 ± 11.2 years, p < 0.001). The average level of left ventricular ejection fraction (LVEF) was similar and well preserved between the two groups (52.6 ± ± 11.0% vs. 52.5 ± 11.8, p = 0.724). The proportion of patients who had decreased LVEF (< 40%) was also similar between the two groups. The following values were higher in the male group than in the female group: number of ST-segment elevation myocardial infarction (STEMI); mean value of body mass index, diastolic blood pressure; serum creatinine level; triglyceride level; prescription rates of ASA, ticagrelor, prasugrel, beta-blockers, and lipid-lowering agents; and numbers of left anterior descending (LAD) artery as the infarct-related artery (IRA) or treated vessel; single-vessel disease; and the deployment of everolimus-eluting stents and biolimus-eluting stents. By contrast, the female group showed higher values than the male group for the following: number of non-STEMI; proportion of hypertension, DM, previous cerebrovascular accident (CVA), and HF; mean values of serum N-terminal pro-B-type natriuretic peptide, total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol; prescription rates of clopidogrel; numbers of right coronary artery (RCA) as the IRA and treated vessel; ACC/ /AHA type C lesion; ≥ three-vessel disease; and number of deployed stent.

Clinical outcomes

Table 2 and Figure 2 show the clinical outcomes at 30 days, 1 year, and 2 years. During 1 month, the cumulative incidences of MACEs and all-cause death were significantly higher in the female group than in the male group. At 1 year after the index PCI, the cumulative incidences of MACEs, all-cause death, and Re-MI were also higher in the female group in the male group. Moreover, at 2 years, the cumulative incidences of all-cause death (adjusted hazard ratio [aHR]: 1.561; 95% confidence interval [CI]: 1.103–2.210; p = 0.012) and Re-MI (aHR: 1.800; 95% CI: 1.089–2.974; p = 0.022) were significantly higher in the female group than those in the male group. However, the cumulative incidences of ST, any repeat revascularization, TLR, TVR, and non-TVR were similar between the two groups.

Table 2. Clinical outcomes by the Kaplan-Meier analysis and the Cox-proportional hazard ratio analysis up to 2 years.

Outcomes

Cumulative events (%)

Unadjusted

Adjusted*

Male (n = 11,767)

Female (n = 798)

Log- -rank

HR (95% CI)

P

HR (95% CI)

P

30 days

MACE

221 (1.9)

32 (4.0)

< 0.001

2.155 (1.487–3.122)

< 0.001

1.457 (1.021–2.216)

0.035

All-cause death

155 (1.3)

22 (2.8)

0.001

2.105 (1.347–3.289)

0.001

1.699 (1.074–2.687)

0.023

Cardiac death

145 (1.2)

19 (2.4)

0.006

1.942 (1.204–3.134)

0.007

1.505 (0.921–2.457)

0.102

Re-MI

47 (0.4)

6 (0.8)

0.133

1.896 (0.810–4.434)

0.140

1.806 (0.757–4.310)

0.183

Any revascularization

31 (0.3)

5 (0.6)

0.060

2.409 (0.937–6.196)

0.068

2.045 (0.865–3.374)

0.345

TLR

9 (0.1)

2 (0.3)

0.104

3.314 (0.716–15.34)

0.125

2.702 (0.539–13.56)

0.227

TVR

16 (0.1)

4 (0.5)

0.011

3.737 (1.249–11.18)

0.018

2.433 (0.990–8.502)

0.076

Non-TVR

14 (0.1)

1 (0.1)

0.951

1.066 (0.140–8.103)

0.951

1.131 (0.144–8.910)

0.907

ST (definite or probable)

Acute

10 (0.1)

0 (0.0)

0.410

Subacute

29 (0.2)

3 (0.4)

0.483

1.342 (0.409–4.410)

0.627

1.031 (0.266–3.991)

0.965

Total

39 (0.3)

3 (0.4)

0.833

1.004 (0.310–3.249)

0.995

1.173 (0.322–4.264)

0.809

1 year

MACEs

660 (5.7)

70 (8.9)

< 0.001

1.585 (1.239–2.028)

< 0.001

1.402 (1.090–1.803)

0.009

All-cause death

245 (2.1)

35 (4.4)

< 0.001

2.121 (1.489–3.023)

< 0.001

1.660 (1.153–2.390)

0.006

Cardiac death

204 (1.7)

24 (3.0)

0.009

1.747 (1.144–2.666)

0.010

1.238 (0.831–1.980)

0.261

Re-MI

107 (0.9)

16 (2.1)

0.002

2.229 (1.318–3.770)

0.003

2.040 (1.189–3.501)

0.010

Any revascularization

340 (3.0)

23 (3.0)

0.980

1.005 (0.659–1.534)

0.980

0.974 (0.635–1.495)

0.905

TLR

97 (0.9)

7 (0.9)

0.857

1.073 (0.498–2.311)

0.857

1.011 (0.464–2.204)

0.978

TVR

166 (1.5)

12 (1.6)

0.812

1.072 (0.598–1.929)

0.812

1.048 (0.578–1.900)

0.877

Non-TVR

177 (1.6)

11 (1.5)

0.794

1.084 (0.590–1.994)

0.794

1.174 (0.636–2.176)

0.608

ST (definite or probable)

Late

35 (0.3)

4 (0.5)

0.316

1.885 (0.667–5.329)

0.232

1.343 (0.403–4.479)

0.631

Total (0–365 days)

74 (0.6)

7 (0.9)

0.397

1.372 (0.631–2.984)

0.424

1.116 (0.481–2.591)

0.799

2 years

MACEs

819 (7.2)

78 (10.0)

0.003

1.419 (1.125–1.790)

0.003

1.264 (1.001–1.598)

0.052

All-cause death

283 (2.5)

38 (4.8)

< 0.001

1.988 (1.417–2.789)

< 0.001

1.561 (1.103–2.210)

0.012

Cardiac death

224 (1.9)

25 (3.2)

0.016

1.654 (1.094–2.500)

0.017

1.216 (0.797–1.857)

0.364

Re-MI

142 (1.3)

18 (2.4)

0.010

1.885 (1.154–3.078)

0.011

1.800 (1.089–2.974)

0.022

Any revascularization

444 (4.0)

27 (3.6)

0.594

1.111 (0.754–1.639)

0.594

1.161 (0.785–1.717)

0.453

TLR

121 (1.1)

8 (1.1)

0.956

1.021 (0.499–2.087)

0.956

1.008 (0.471–1.982)

0.982

TVR

228 (2.1)

14 (1.9)

0.726

1.101 (0.642–1.889)

0.726

1.094 (0.626–1.864)

0.745

Non-TVR

223 (2.0)

13 (1.7)

0.602

1.160 (0.663–2.030)

0.602

1.273 (0.725–2.235)

0.400

ST (definite or probable)

Very late

15 (0.1)

1 (0.1)

0.988

1.021 (0.131–9.274)

0.684

1.042 (0.967–11.23)

0.280

Total (0–730 days)

89 (0.8)

8 (1.0)

0.445

1.104 (0.533–2.285)

0.790

1.207 (0.583–2.497)

0.613

*Adjusted by age, BMI, SBP, DBP, hypertension, diabetes, previous CVA, cardiogenic shock, NT-proBNP, total cholesterol, LDL cholesterol, clopidogrel, beta-blockers, lipid lowering agents, infarct-related artery (LAD and RCA), treated vessel (RCA), ≥ 3-vessel, stent diameter. HR — hazard ratio; CI — confidence interval; MACEs — major adverse cardiac events; Re-MI — re-myocardial infarction; TLR — target lesion revascularization; TVR — target vessel revascularization; ST — stent thrombosis

Figure 2. Kaplan-Meier Analysis for major adverse cardiac events (MACEs) (A), stent thrombosis (B), all-cause (C) and recurrent myocardial infarction (D); CI — confidence interval; aHR — adjusted hazard ratio.

Table 3 shows independent predictors for all-cause death and Re-MI at 2 years. Figure 3 shows the subgroup analyses for MACEs. In cases of over 40% of LVEF, non-hypertensive patients, ACC/ /AHA non-type C lesion, and patients who had non--RCA as IRA, who received lipid-lowering agents, and who currently smoke on admission showed worse outcomes for the female group compared with the male group in terms of MACEs.

Table 3. Multivariable Cox-proportional regression analysis for predictors of all-cause death and recurrent myocardial infarction (Re-MI) at 2 years.

Variables

All-cause death

Re-MI

Univariate

Multivariate

Univariate

Multivariate

HR (95% CI)

P

HR (95% CI)

P

HR (95% CI)

P

HR (95% CI)

P

Male vs. female

1.988 (1.417–2.789)

< 0.001

2.642 (1.984–3.327)

< 0.001

1.885 (1.154–3.078)

0.011

1.733 (1.035–2.902)

0.037

Age ≥ 65 years

3.656 (2.931–4.560)

< 0.001

2.507 (1.974–3.183)

< 0.001

1.335 (0.959–1.858)

0.087

1.128 (0.788–1.616)

0.510

LVEF < 40%

5.173 (4.127–6.483)

< 0.001

3.596 (2.831–4.568)

< 0.001

1.752 (1.159–2.650)

0.008

1.422 (0.927–2.180)

0.106

Diastolic blood pressure

0.989 (0.982–0.995)

0.001

1.005 (0.997–1.012)

0.242

1.001 (0.991–1.010)

0.863

1.002 (0.991–1.012)

0.756

STEMI

1.020 (0.813–1.279)

0.864

1.114 (0.945–1.281)

0.711

1.195 (0.859–1.664)

0.291

1.217 (0.862–1.720)

0.265

Hypertension

1.372 (1.101–1.710)

0.005

1.025 (0.813–1.291)

0.837

1.054 (0.766–1.450)

0.748

1.121 (0.801–1.568)

0.507

Diabetes mellitus

1.743 (1.380–2.202)

< 0.001

1.386 (1.085–1.771)

0.009

1.520 (1.082–2.136)

0.016

1.412 (0.991–2.010)

0.056

Previous CVA

2.896 (2.020–4.152)

< 0.001

1.772 (1.225–2.564)

0.002

2.441 (1.411–4.225)

0.001

2.178 (1.238–3.831)

0.007

Cardiogenic shock

3.103 (2.194–4.389)

< 0.001

2.829 (1.863–4.296)

< 0.001

1.132 (1.531–2.415)

0.748

1.226 (0.534–2.817)

0.631

Primary PCI

1.030 (0.825–1.286)

0.793

1.239 (0.706–2.174)

0.455

1.173 (0.852–1.615)

0.329

1.034 (0.480–2.226)

0.933

PCI within 24 h

1.069 (0.841–1.357)

0.586

1.423 (0.873–2.322)

0.157

1.288 (0.830–1.699)

0.346

1.190 (0.576–2.456)

0.639

Clopidogrel

1.344 (0.886–2.038)

0.165

1.075 (0.706–1.639)

0.735

1.199 (0.724–1.986)

0.480

1.322 (0.793–2.203)

0.284

Beta-blockers

3.796 (3.049–4.727)

< 0.001

3.153 (2.521–3.944)

< 0.001

1.007 (0.695–1.555)

0.849

1.061 (0.706–1.592)

0.777

LAD (IRA)

1.147 (0.921–1.428)

0.220

1.054 (0.779–1.406)

0.735

1.657 (1.207–2.275)

0.002

1.639 (1.203–2.626)

0.040

RCA (IRA)

1.221 (0.958–1.555)

0.106

1.657 (1.042–2.635)

0.033

1.478 (0.784–2.114)

0.032

1.237 (0.608–2.014)

0.284

RCA (treated)

1.108 (0.813–1.274)

0.879

1.248 (0.858–1.817)

0.247

1.260 (0.908–1.749)

0.166

1.141 (0.654–1.991)

0.642

ACC/AHA type B2/C lesion

1.266 (0.973–1.648)

0.079

1.256 (0.963–1.639)

0.093

1.059 (0.743–1.510)

0.751

1.019 (0.712–1.457)

0.919

≥ 3-vessel

2.013 (1.590–2.550)

< 0.001

1.329 (1.034–1.708)

0.027

1.429 (0.996–2.049)

0.053

1.291 (0.883–1.887)

0.188

HR — hazard ratio; CI — confidence interval; LVEF — left ventricular ejection fraction; STEMI — ST-segment elevation myocardial infarction; CVA — cerebrovascular accidents; PCI — percutaneous coronary intervention; LAD — left anterior descending coronary artery; IRA — infarct-related artery; RCA — right coronary artery; ACC/AHA — American College of Cardiology/American Heart Association

Figure 3. Subgroup analyses for major adverse cardiac events (MACEs). CI — confidence interval; LVEF — left ventricular ejection fraction; ACC/AHA — American College of Cardiology/American Heart Association; LAD — left anterior descending coronary artery; RCA — right coronary artery; IRA — infarct-related artery; STEMI — ST-segment elevation myocardial infarction.

Discussion

The main findings of the current study are as follows: 1) During 1 month, the cumulative incidences of MACEs and all-cause death were significantly higher in the female group than those in the male group; 2) At 1 year, the cumulative incidences of MACEs, all-cause death, and Re-MI were also higher in the female group than those in the male group; 3) At 2 years, the cumulative incidences of all-cause death and Re-MI were significantly higher in the female group than those in the male group; 4) However, the cumulative incidences of ST, any repeat revascularization, TLR, TVR, and non-TVR were similar between the two groups after adjustment.

To date, sex difference for MACEs and mortality showed debatable results [16, 17]. Other studies have reported that women have smaller arterial diameter and lower sensitivity to cardiac function tests and receive a more suboptimal medical treatment compared with men [18–20]. In the present cohort, before risk adjustment, the female group had less favorable baseline characteristics for CVD risk factor profiles such as old age, higher proportions of hypertension, DM, previous history of CVA, HF, cardiogenic shock, and smaller mean diameter of deployed stents and showed significantly higher cumulative incidences of MACEs compared with the male group. These study results are consistent with the results of Bell’s and Nappi’s study [3]. The unfavorable effects of smoking on CAD include increasing plasma fibrinogen level, reducing high-density lipoprotein cholesterol level, increasing carboxyhemoglobin level, and increasing platelet stickiness and aggregation under the milieu of AMI [21, 22]. Furthermore, endothelial dysfunctions, including reduced nitric oxide release [23] and inflammations [24], are involved in this process.

In this study, the cumulative incidence of all-cause death, both early (30 days) and late (1 year and 2 year), and the cumulative incidence of Re-MI after 1 month of the index PCI, were higher in the female group than that in the male group after adjustment (Fig. 2). The possible explanation for these worse clinical outcomes in the female smokers’ group is related with the decreased estrogen activity or production [25]. Additionally, a Danish report suggested that women may be more sensitive compared with men to the deleterious effects of smoking [6]. According to other studies [21, 26], women are more susceptible to the effects of nicotine consumption, which causes vasoconstriction, compared with men. Although previous studies [20, 27] have reported that less aggressive treatment of acute coronary syndrome may be a causative factor to poorer outcomes in women than in men, in this study, the proportions of primary PCI (92.5% vs. 91.7%, p = 0.508) and PCI within 24 h (78.0% vs. 75.8%, p = 0.354) were similar at baseline (Table 1). Moreover, both primary PCI and PCI within 24 h were not predictors of all-cause death and Re-MI in our study (Table 3).

In the GUSTO-1 trial, single-vessel disease was more frequently observed in smokers compared with nonsmokers (63% vs. 55%) [28]. In the current study, singe-vessel disease was also more frequently observed compared with multivessel disease in both sexes (Table 1). It is highly likely that the mortality rate for RCA as an IRA is lower than for LAD [29]. Despite the number of RCA as an IRA was higher in the female group than that in the male group (47.2% vs. 43.7%, p = 0.039), all- -cause death was significantly higher in the female group than that in the male group after adjustment. Hence, sex difference for the major clinical outcomes was strongly suggested in this cohort study.

Approximately 23% of patients who quit smoking at 30 days had relapsed at 12 months [30]. One Asian study showed that a total of 34.1% of smokers continued to smoke or relapsed after a period of time of quitting smoking [31]. Therefore, it can be assumed that greater than 30% of the enrolled patients continued to smoke after the index PCI during the follow-up period.

In the present cohort study, the proportion of women was relatively smaller compared to the total number of men (93.6% vs. 6.4%). This proportional difference of enrolled patients between the two groups is consistent with the previous studies [32, 33]. In the previous studies, the number of smokers is relatively lower in women than in men with some regional variations, specifically in Asian regions where the prevalence of women smoking is less than 10% [32, 33]. Moreover, the KAMIR is a nationwide, prospective, observational multicenter registry in South Korea, and more than 50 high-volume university or community hospitals participated in this study [7, 8]. Therefore, we believe that in this study, the study population is not small for providing reasonably accurate results.

Limitations of the study

This study has the following limitations. First, due to the characteristics of the nonrandomized retrospective nature of the study, there may be some incomplete variables. Second, the smoking status of the study population was assessed on admission, and the registry data did not include full detailed data concerning the status of smoking including before admission and during the follow-up period [9, 13]. Therefore, these factors may contribute bias. Third, this study assessed the discharge medications. Fourth, it was not possible to compare the initial laboratory results with the serial follow-up results because of the limited registry data, subsequently introducing bias. Fifth, although multivariate Cox proportional regression analysis was performed, the results of the present study are relatively different according to the variables included or excluded when performing this analysis. Sixth, the strategy of antiplatelet therapy (e.g., dual antiplatelet therapy or TAPT) was left to the physician’s discretion, which may have influenced the major clinical outcomes [9]. Finally, AMI was defined according to the current guidelines including the 3rd universal definition of MI [11, 12] in this study. However, the fourth universal definition of MI [34] contains more updated and accurate diagnostic criteria than those of the third universal definition of MI.

Conclusions

In conclusion, the female group showed worse short-term and long-term clinical outcomes compared with the male group comprising Korean AMI patients with history of current smoking who underwent successful DES implantation. However, additional studies are required to determine the clinical implications of these results.

Acknowledgments

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

Korea Acute Myocardial Infarction (KAMIR) Investigators

Myung Ho Jeong, MD, Young Keun 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, Byung Ok Kim, 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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