Impact of Sex Differences on Clinical Outcomes in Patients Following Primary Revascularization for Acute Myocardial Infarction　― Insights From the Japanese Nationwide Registry ―

Abstract

Background: Women with acute myocardial infarction (AMI) often present a worse risk profile and experience a higher rate of in-hospital mortality than men. However, sex differences in post-discharge prognoses remain inadequately investigated. We examined the impact of sex on 1-year post-discharge outcomes in patients with AMI undergoing percutaneous coronary intervention.

Methods and Results: We extracted patient-level data for the period January 2017–December 2018 from the J-PCI OUTCOME Registry, endorsed by the Japanese Association of Cardiovascular Intervention and Therapeutics. One-year all-cause and cardiovascular mortality and major adverse cardiovascular events were compared between men and women. In all, 29,856 AMI patients were studied, with 6,996 (23.4%) being women. Women were significantly older and had a higher prevalence of comorbidities than men. Crude all-cause mortality was significantly higher among women than men (7.5% vs. 5.4% [P<0.001] for ST-elevation myocardial infarction [STEMI]; 7.0% vs. 5.2% [P=0.006] for non-STEMI). These sex-related differences in post-discharge outcomes were attenuated after stratification by age. Multivariate analysis demonstrated an increase in all-cause mortality in both sexes with increasing age and advanced-stage chronic kidney disease (CKD).

Conclusions: Within this nationwide cohort, women had worse clinical outcomes following AMI than men. However, these sex-related differences in outcomes diminished after adjusting for age. In addition, CKD was significantly associated with all-cause mortality in both sexes.

Various aspects of coronary artery disease exhibit sex differences, including the development of coronary artery disease, symptoms at presentation, and the extent of coronary atherosclerosis.^1–3 Women tend to develop acute myocardial infarction (AMI) at an older age and are more likely to have comorbidities, such as hypertension and diabetes, than men.^4–10 Men and women, especially young adults (aged ≤50–55 years), are equally likely to have chest pain as the predominant symptom of AMI.^11,12 However, women are more likely to present with other associated symptoms, such as shortness of breath, fatigue, palpitations, nausea, and back or jaw pain, which can lead to delayed diagnosis and treatment.^4,13,14 These sex-related differences could potentially affect the clinical prognosis of patients with AMI.

Although several studies have shown that women exhibit higher rates of in-hospital mortality and worse risk profiles,^4–8 the existence of long-term prognostic differences between women and men remains a subject of debate, particularly in Asian patients.¹⁵ Previous reports on the prognosis of Japanese women following AMI have mainly relied on relatively small cohorts.^8,9 Moreover, only a limited number of studies have investigated sex differences in the post-discharge outcomes of patients following AMI, specifically in Japan, a nation renowned as the world’s foremost superaging society.⁹ Therefore, the aim of this study was to examine the impact of sex differences on post-discharge clinical outcomes in patients with AMI who underwent percutaneous coronary intervention (PCI), stratified by AMI presentation type.

Methods

Data Source

The J-PCI Registry is a prospective, multicenter, and nationwide registry endorsed by the Japanese Association of Cardiovascular Intervention and Therapeutics that was designed to record the clinical background and presentation, angiographic and procedural details, and in-hospital outcomes of patients who undergo PCI.¹⁶ Since 2013, the J-PCI Registry has been incorporated into the National Clinical Data System, a web-based registry for medical and surgical board certification. Because registration in the J-PCI Registry is mandatory for certification, data completeness is high. Of the >900 hospitals in the J-PCI Registry, 179 volunteered to participate in the J-PCI OUTCOME Registry, which collected data on the incidence of fatal and non-fatal events during the first year following the initial PCI.¹⁶

The protocol of the present study was approved by the independent central ethics committee of the Clinical Research Promotion Network Japan and the local institutional review boards at each participating site. Informed consent was obtained from patients through an opt-out format notification on websites and/or posters, and the procedures were conducted in accordance with the principles of the Declaration of Helsinki.

Study Population

In all, 105,592 patients who underwent PCI, survived, and were discharged from hospital between January 2017 and December 2018 were enrolled in the J-PCI OUTCOME Registry. All patients diagnosed with AMI were included in the present analysis. Based on the clinical presentation, the study subjects were divided into ST-elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI) groups.

Definitions of Key Variables

Full definitions of the variables in the J-PCI Registry have been provided elsewhere.¹⁶ Briefly, AMI was defined as persistent myocardial ischemia accompanied by elevated levels of cardiac markers. “Elevated cardiac biomarkers” refers to an increase in specific markers, such as creatine kinase (CK) or CK-MB (2-fold higher than normal values) and elevated troponin (≥99th percentile). AMI was classified as STEMI or NSTEMI. STEMI was defined as: ST-segment elevation on ≥2 contiguous leads (≥0.2 mV in a precordial lead at the J point or ≥0.1 mV in a limb lead); new left bundle branch block; or posterior myocardial infarction (MI) on a 12-lead electrocardiogram (ECG). NSTEMI was defined as ECG changes that either do not qualify as ST-segment elevation or are not present at all. Estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease (MDRD) study equation modified to fit the Japanese population,¹⁷ and an eGFR of <60 mL/min/1.73 m² was defined as chronic kidney disease (CKD). Kidney disease was classified into 5 stages according to severity based on eGFR.¹⁸

Definitions of Clinical Outcomes

The clinical endpoints were defined according to the 2017 Cardiovascular and Stroke Endpoint Definition for Clinical Trials.¹⁹ Definite stent thrombosis was registered for cardiac death and non-fatal acute coronary syndrome (ACS) events according to the Academic Research Consortium-2 Consensus Documents.²⁰ A maximum of 3 events for non-fatal ACS, stroke, bleeding, and acute heart failure and up to a maximum of 5 events for planned revascularization were registered in the database. Mode of death was divided into non-cardiac death, death due to an unknown cause, and cardiac death with subcategories of sudden cardiac death, death due to ACS, heart failure, stroke, procedural complications, and bleeding events. Major adverse cardiovascular events (MACE) were defined as composite events of cardiovascular death, non-fatal MI, or non-fatal ischemic stroke.

Statistical Analysis

For descriptive statistics, continuous variables are expressed as the mean±SD or median with interquartile range, as appropriate. Categorical variables are expressed as numbers and percentages. Baseline characteristics, angiographic and procedural data, and clinical outcomes were compared between women and men using the unpaired Student’s t-test, whereas the significance of differences between categorical variables was examined using the Chi-squared test or Fisher’s exact test, as appropriate. To calculate 1-year all-cause mortality and the incidence of MACE, stratified by the presentation of STEMI and NSTEMI, Kaplan-Meier curves were plotted for men and women separated into 3 age categories: young adults (age ≤59 years), middle-aged adults (age 60–79 years), and older adults (age ≥80 years). Unadjusted and adjusted multilevel mixed-effect Cox proportional hazard ratios (HRs) were used to calculate effect estimates with 95% confidence intervals (CI). To account for the multisite design, all models included the registration hospital site as a random intercept. Univariate and multivariate HRs were calculated, with the latter adjusting for age categories, diabetes, CKD stage, peripheral artery disease, prior heart failure, acute heart failure within 24 h, cardiogenic shock, cardiac arrest, number of diseased vessels, and presentation of AMI. Analyses were performed separately for women and men.

All data were managed by the National Clinical Database and by data analysts belonging to the J-PCI Registry statistical analysis team. All analyses were performed using Stata/IC Version 15.1 for Macintosh (StataCorp, College Station, TX, USA). P values are 2-sided and statistical significance was set at P<0.05.

Results

Baseline Patient Characteristics

This study included 30,213 patients from the J-PCI OUTCOME Registry who were registered between January 2017 and December 2018. After excluding patients with missing data, 29,856 patients (76.2% [n=22,739] with STEMI and 23.8% [n=7,117] with NSTEMI) were analyzed in the present study. Of these patients, 6,996 (23.4%) were women and 22,860 (76.6%) were men. The baseline clinical characteristics of the patients are summarized in Table 1. Women were significantly older than men in both the STEMI (76 vs. 66 years; P<0.001) and NSTEMI (76 vs. 69 years; P<0.001) groups. Women were more likely to have hypertension and a history of heart failure than men. However, men were more likely to smoke and had a higher prevalence of chronic obstructive pulmonary disease, a history of MI, and PCI than women. The CKD stage was more advanced in women than in men. The prevalence of diabetes did not significantly differ between the sexes.

Table 1.

Baseline Characteristics

	STEMI				NSTEMI
	Total (n=22,739)	Women (n=5,344)	Men (n=17,395)	P value	Total (n=7,117)	Women (n=1,652)	Men (n=5,465)	P value
Age (years)	69±13	76±11	66±13	<0.001	70±13	76±11	69±12	<0.001
Prior history
Prior MI	1,932 (8.5)	294 (5.5)	1,638 (9.4)	<0.001	1,154 (16.2)	224 (13.6)	930 (17.0)	0.003
Prior PCI	2,437 (10.7)	412 (7.7)	2,025 (11.6)	<0.001	1,404 (19.7)	267 (16.2)	1,137 (20.8)	<0.001
Prior CABG	237 (1.0)	50 (0.9)	187 (1.1)	0.57	238 (3.3)	68 (4.1)	170 (3.1)	0.093
Prior HF	1,072 (4.7)	339 (6.3)	733 (4.2)	<0.001	868 (12.2)	261 (15.8)	607 (11.1)	<0.001
Comorbidities
Diabetes	7,753 (34.1)	1,722 (32.2)	6,031 (34.7)	0.060	2,728 (38.3)	652 (39.5)	2,076 (38.0)	0.073
Hypertension	15,097 (66.4)	3,800 (71.1)	11,297 (64.9)	<0.001	5,200 (73.1)	1,266 (76.6)	3,934 (72.0)	<0.001
Dyslipidemia	12,695 (55.8)	2,933 (54.9)	9,762 (56.1)	0.45	4,285 (60.2)	988 (59.8)	3,297 (60.3)	0.49
Smoking	9,179 (40.4)	802 (15.0)	8,377 (48.2)	<0.001	2,544 (35.7)	209 (12.7)	2,335 (42.7)	<0.001
Peripheral artery disease	698 (3.1)	169 (3.2)	529 (3.0)	0.41	372 (5.2)	95 (5.8)	296 (5.4)	0.46
COPD	528 (2.3)	71 (1.3)	457 (2.6)	<0.001	190 (2.7)	25 (1.5)	165 (3.0)	0.001
CKD staging				<0.001				<0.001
Stage 1	7,788 (34.2)	1,712 (32.0)	6,076 (34.9)		2,388 (33.6)	485 (29.4)	1,903 (34.8)
Stage 2	6,422 (28.2)	1,362 (25.5)	5,060 (29.1)		1,917 (26.9)	438 (26.5)	1,479 (27.1)
Stage 3	2,758 (12.1)	790 (14.8)	1,968 (11.3)		939 (13.2)	269 (16.3)	670 (12.3)
Stage 4	411 (1.8)	153 (2.9)	258 (1.5)		158 (2.2)	63 (3.8)	95 (1.7)
Stage 5	495 (2.2)	152 (2.8)	343 (2.0)		332 (4.7)	82 (5.0)	250 (4.6)
Missing data	4,865 (21.4)	1,175 (22.0)	3,690 (21.2)		1,383 (19.4)	315 (19.1)	1,068 (19.5)
Hemodialysis	517 (2.3)	142 (2.7)	375 (2.2)	0.013	359 (5.0)	93 (5.6)	266 (4.9)	0.15
Cardiogenic shock	2,812 (12.4)	280 (5.2)	1,288 (7.4)	<0.001	377 (5.3)	61 (3.7)	316 (5.8)	0.003
Cardiopulmonary arrest	1,568 (6.9)	700 (13.1)	2,112 (12.1)	0.100	575 (8.1)	149 (9.0)	426 (7.8)	0.24
Laboratory tests
Hemoglobin (g/dL)	14±2	12±2	14±2	<0.001	13±2	12±2	14±2	<0.001
Creatinine (mg/dL)	1.1±1.2	1.0±1.1	1.1±1.2	<0.001	1.3±1.7	1.1±1.4	1.4±1.8	<0.001
No. diseased vessels				0.94				0.22
1	14,064 (61.8)	3,306 (61.9)	10,758 (61.8)		3,732 (52.4)	835 (50.5)	2,896 (53.0)
2	5,587 (24.6)	1,304 (24.4)	4,283 (24.6)		2,025 (28.4)	492 (29.8)	1,533 (28.1)
3	3,035 (13.3)	718 (13.4)	2,317 (13.3)		1,311 (18.4)	317 (19.2)	1,014 (18.6)
Left main trunk	840 (3.7)	195 (3.6)	645 (3.7)	0.84	416 (5.8)	102 (6.2)	314 (5.7)	0.52
Target lesion
RCA	9,441 (41.5)	2,290 (42.9)	7,151 (41.1)	0.015	2,105 (29.6)	493 (29.8)	1,612 (29.5)	0.79
LMT/LAD	12,105 (53.2)	2,817 (52.7)	9,288 (53.4)	0.38	3,542 (49.8)	853 (51.6)	2,689 (49.2)	0.083
LCX	3,221 (14.2)	718 (13.4)	2,503 (14.4)	0.080	2,490 (35.0)	561 (34.0)	1,929 (35.3)	0.32
Bypass graft	45 (0.2)	13 (0.2)	32 (0.2)	0.39	46 (0.6)	11 (0.7)	35 (0.6)	0.91
Access site				<0.001				<0.001
Transfemoral	7,732 (34.0)	1,976 (37.0)	5,756 (33.1)		1,805 (25.3)	494 (29.9)	1,311 (24.0)
Transradial	14,368 (63.2)	3,187 (59.6)	11,181 (64.3)		5,083 (71.4)	1,083 (65.6)	4,000 (73.2)
Others	639 (2.8)	181 (3.4)	458 (2.6)		229 (3.2)	75 (4.5)	153 (2.8)
Procedure
Balloon	18,871 (83.0)	4,501 (84.2)	14,370 (82.6)	0.006	6,115 (85.9)	1,450 (87.8)	4,665 (85.4)	0.014
DCB	1,265 (5.6)	271 (5.1)	994 (5.7)	0.073	755 (10.6)	167 (10.1)	588 (10.8)	0.45
BMS	237 (1.0)	46 (0.9)	191 (1.1)	0.14	55 (0.8)	10 (0.6)	45 (0.8)	0.38
DES	19,715 (86.7)	4,562 (85.4)	15,153 (87.1)	0.001	5,943 (83.5)	1,349 (81.7)	4,594 (84.1)	0.021
BVS	22 (0.1)	5 (0.1)	17 (0.1)	0.93	8 (0.1)	2 (0.1)	6 (0.1)	0.90
Rotational atherectomy	131 (0.6)	44 (0.8)	87 (0.5)	0.006	185 (2.6)	81 (4.9)	104 (1.9)	<0.001
Aspiration	12,620 (55.5)	2,747 (51.4)	9,873 (56.8)	<0.001	1,696 (23.8)	335 (20.3)	1,361 (24.9)	<0.001
Distal protection	2,201 (19.7)	377 (7.1)	1,824 (10.4)	<0.001	306 (4.3)	43 (2.6)	263 (4.8)	<0.001
Guidewire unsuccessful	280 (1.2)	72 (1.3)	208 (1.2)	0.38	192 (2.7)	51 (3.1)	141 (2.6)	0.26

Unless indicated otherwise, data are given as the mean±SD or n (%). BMS, bare metal stent; BVS, bioresorbable vascular scaffold; CABG, coronary artery bypass graft; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; DCB, drug-coating balloon; DES, drug-eluting stent; HF, heart failure; LAD, left anterior descending artery; LCX, left circumflex artery; LMT, left main trunk; MI, myocardial infarction; NSTEMI, non-ST-elevation myocardial infarction; PCI, percutaneous coronary intervention; RCA, right coronary artery; STEMI, ST-elevation myocardial infarction.

Angiographic and procedural characteristics are also summarized in Table 1. The number of diseased vessels was not significantly different between women and men. The distribution of the culprit lesions was similar, with the left anterior descending artery being the most involved. Regarding the procedure, thrombus aspiration and distal protection were performed more frequently in men than in women. Detailed baseline patient characteristics stratified by age are presented in the Supplementary Tables 1,2.

Clinical Outcomes During the First Year After AMI

Tables 2,3 present the clinical outcomes during the first year after PCI in the STEMI and NSTEMI groups, respectively. All-cause mortality was significantly higher in women than in men in both the STEMI (7.5% vs. 5.4%; P<0.001) and NSTEMI groups (7.0% vs. 5.2%; P=0.006). The incidence of MACE was also higher in women than in men in both the STEMI (6.0% vs. 4.6%; P<0.001) and NSTEMI groups (5.9% vs. 4.3%; P=0.006), driven by a numerically higher rate of cardiac death. The incidence of hospitalization for heart failure was higher among women than men. The worse outcomes for women in terms of all-cause mortality and the incidence of MACE were attenuated when stratified by age (Tables 2,3; Figures 1–4). Although not statistically significant, the Kaplan-Meier curves suggest some possibilities regarding sex differences. First, among patients with STEMI aged ≥80 years, women had a higher rate of MACE than men, and this disparity appeared to emerge within the first 1–2 months (Figure 2B). Second, among patients with NSTEMI, the differences in all-cause mortality and MACE between men and women tended to widen over time (Figures 3A,4A). Furthermore, among those aged ≥80 years, men were at a higher risk of all-cause mortality than women, whereas among those aged 60–79 years, women had a higher mortality risk than men (Figure 3B).

Table 2.

Clinical Outcomes During the 1-Year Period After PCI in Patients With STEMI

	Entire cohort				Age ≥80 years			Age 60–79 years			Age ≤59 years
	Total (n=22,739)	Women (n=5,344)	Men (n=17,395)	P value	Women (n=2,260)	Men (n=2,821)	P value	Women (n=2,649)	Men (n=9,508)	P value	Women (n=435)	Men (n=5,066)	P value
All-cause mortality	1,343 (5.9)	399 (7.5)	944 (5.4)	<0.001	239 (10.6)	316 (11.2)	0.477	147 (5.5)	508 (5.3)	0.677	13 (3.0)	120 (2.4)	0.419
MACE	1,115 (4.9)	322 (6.0)	793 (4.6)	<0.001	180 (8.0)	200 (7.1)	0.239	132 (5.0)	463 (4.9)	0.811	10 (2.3)	130 (2.6)	0.239
Cause of death
Cardiac death	851 (3.7)	255 (4.8)	596 (3.4)	<0.001	153 (6.8)	171 (6.1)	0.305	94 (3.5)	339 (3.6)	0.967	8 (1.8)	86 (1.7)	0.827
Non-cardiac death	407 (1.8)	115 (2.2)	292 (1.7)	0.022	67 (3.0)	118 (4.2)	0.021	44 (1.7)	147 (1.5)	0.674	4 (0.9)	27 (0.5)	0.304
Unknown reason	85 (0.4)	29 (0.5)	56 (0.3)	0.021	19 (0.8)	27 (1.0)	0.663	9 (0.3)	22 (0.2)	0.328	1 (0.2)	7 (0.1)	0.483
Causes of cardiac death
ACS	508 (2.2)	146 (2.7)	362 (2.1)	0.005	89 (3.9)	93 (3.3)	0.222	50 (1.9)	204 (2.1)	0.412	7 (1.6)	65 (1.3)	0.510
Bleeding	13 (0.1)	2 (0.04)	11 (0.1)	0.745	0 (0.0)	4 (0.1)	0.134	2 (0.1)	5 (0.1)	0.651	0 (0.0)	2 (0.04)	1.000
HF	261 (1.1)	80 (1.5)	181 (1.0)	0.006	47 (2.1)	62 (2.2)	0.773	32 (1.2)	102 (1.1)	0.556	1 (0.2)	17 (0.3)	1.000
Sudden death	4 (0.02)	2 (0.04)	2 (0.01)	0.238	1 (0.04)	0 (0.0)	0.445	1 (0.04)	2 (0.02)	1.000	0 (0.0)	0 (0.0)	1.000
Procedural complications	68 (0.3)	25 (0.5)	43 (0.2)	0.010	16 (0.7)	14 (0.5)	0.328	9 (0.3)	25 (0.3)	0.508	0 (0.0)	4 (0.1)	1.000
Stroke	6 (0.03)	1 (0.02)	5 (0.03)	1.000	0 (0.0)	2 (0.1)	0.506	1 (0.04)	3 (0.03)	1.000	0 (0.0)	0 (0.0)	1.000
Stent thrombosis	17 (0.1)	3 (0.1)	14 (0.1)	0.777	2 (0.1)	2 (0.1)	1.000	1 (0.0)	9 (0.1)	0.701	0 (0.0)	3 (0.1)	1.000
Non-fatal ACS	259 (1.1)	55 (1.0)	204 (1.2)	0.387	20 (0.9)	26 (0.9)	0.891	32 (1.2)	123 (1.3)	0.728	3 (0.7)	55 (1.1)	0.624
Non-fatal stroke	103 (0.5)	36 (0.7)	67 (0.4)	0.006	16 (0.7)	12 (0.4)	0.176	19 (0.7)	47 (0.5)	0.167	1 (0.2)	8 (0.2)	0.524
Non-fatal HF	476 (2.1)	152 (2.8)	324 (1.9)	<0.001	94 (4.2)	96 (3.4)	0.158	55 (2.1)	192 (2.0)	0.854	3 (0.7)	36 (0.7)	1.000
Non-fatal bleeding	365 (1.6)	110 (2.1)	255 (1.5)	0.003	60 (2.7)	61 (2.2)	0.253	49 (1.8)	150 (1.6)	0.329	1 (0.2)	44 (0.9)	0.260
Any revascularization	3,355 (14.8)	693 (13.0)	2,662 (15.3)	<0.001	230 (10.2)	374 (13.3)	0.001	414 (15.6)	1,557 (16.4)	0.356	49 (11.3)	731 (14.4)	0.069

Unless indicated otherwise, data are given as n (%). ACS, acute coronary syndrome; MACE, major adverse cardiovascular events. Other abbreviations as in Table 1.

Table 3.

Clinical Outcomes During the 1-Year Period After PCI in Patients With NSTEMI

	Entire cohort				Age ≥80 years			Age 60–79 years			Age ≤59 years
	Total (n=7,117)	Women (n=1,652)	Men (n=5,465)	P value	Women (n=736)	Men (n=1,158)	P value	Women (n=771)	Men (n=3,017)	P value	Women (n=145)	Men (n=1,290)	P value
All-cause mortality	402 (5.6)	116 (7.0)	286 (5.2)	0.006	59 (8.0)	118 (10.2)	0.113	51 (6.6)	132 (4.4)	0.010	6 (4.1)	36 (2.8)	0.361
MACE	333 (4.7)	98 (5.9)	235 (4.3)	0.006	51 (6.9)	75 (6.5)	0.700	40 (5.2)	108 (3.6)	0.040	7 (4.8)	52 (4.0)	0.647
Cause of death
Cardiac death	217 (3.0)	72 (4.4)	145 (2.7)	<0.001	42 (5.7)	53 (4.6)	0.272	26 (3.4)	64 (2.1)	0.042	4 (2.8)	28 (2.2)	0.557
Non-cardiac death	138 (1.9)	31 (1.9)	107 (2.0)	0.833	11 (1.5)	50 (4.3)	0.001	19 (2.5)	51 (1.7)	0.154	1 (0.7)	6 (0.5)	0.526
Unknown reason	47 (0.7)	13 (0.8)	34 (0.6)	0.469	6 (0.8)	15 (1.3)	0.729	6 (0.8)	17 (0.6)	0.493	1 (0.7)	2 (0.2)	0.274
Causes of cardiac death
ACS	111 (1.6)	26 (1.6)	85 (1.6)	0.958	17 (2.3)	26 (2.2)	0.927	8 (1.0)	34 (1.1)	0.833	1 (0.7)	25 (1.9)	0.507
Bleeding	4 (0.1)	3 (0.2)	1 (0.0)	0.041	3 (0.4)	0 (0.0)	0.059	0 (0.0)	1 (0.03)	1.000	0 (0.0)	0 (0.0)	1.000
HF	80 (1.1)	32 (1.9)	48 (0.9)	<0.001	18 (2.4)	26 (2.2)	0.778	12 (1.6)	20 (0.7)	0.016	2 (1.4)	2 (0.2)	0.053
Sudden death	0 (0.0)	0 (0.0)	0 (0.0)	1.000	0 (0.0)	0 (0.0)	1.000	0 (0.0)	0 (0.0)	1.000	0 (0.0)	0 (0.0)	1.000
Procedural complication	25 (0.4)	11 (0.7)	14 (0.3)	<0.001	4 (0.5)	2 (0.2)	0.887	6 (0.8)	11 (0.4)	0.125	1 (0.7)	1 (0.1)	0.192
Stroke	4 (0.1)	1 (0.1)	3 (0.1)	1.000	0 (0.0)	1 (0.1)	1.000	1 (0.1)	2 (0.1)	0.495	0 (0.0)	0 (0.0)	1.000
Stent thrombosis	4 (0.1)	0 (0.0)	4 (0.1)	0.579	0 (0.0)	1 (0.1)	1.000	0 (0.0)	2 (0.1)	1.000	0 (0.0)	1 (0.1)	1.000
Non-fatal ACS	116 (1.6)	27 (1.6)	89 (1.6)	0.987	8 (1.1)	17 (1.5)	0.479	17 (2.2)	47 (1.6)	0.213	2 (1.4)	25 (1.9)	0.639
Non-fatal stroke	24 (0.3)	5 (0.3)	19 (0.3)	0.782	2 (0.3)	7 (0.6)	0.496	2 (0.3)	9 (0.3)	1.000	1 (0.7)	3 (0.2)	0.347
Non-fatal HF	154 (2.2)	51 (3.1)	103 (1.9)	0.003	37 (5.0)	46 (4.0)	0.274	11 (1.4)	52 (1.7)	0.565	3 (2.1)	5 (0.4)	0.039
Non-fatal bleeding	88 (1.2)	23 (1.4)	65 (1.2)	0.513	10 (1.4)	27 (2.3)	0.136	12 (1.6)	27 (0.9)	0.104	1 (0.7)	11 (0.9)	0.838
Any revascularization	1,161 (16.3)	252 (15.3)	909 (16.6)	0.184	90 (12.2)	134 (11.6)	0.666	142 (18.4)	565 (18.7)	0.844	20 (13.8)	210 (16.3)	0.439

Unless indicated otherwise, data are given as n (%). Abbreviations as in Tables 1,2.

Figure 1.

Kaplan-Meier curves for the cumulative incidence of all-cause mortality in patients with ST-elevation myocardial infarction according to sex. (A) Crude analysis; (B) curves after stratification by age.

Figure 2.

Kaplan-Meier curves for the cumulative incidence of major adverse cardiovascular events (MACE; cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke) in patients with ST-elevation myocardial infarction according to sex. (A) Crude analysis; (B) curves after stratification by age.

Figure 3.

Kaplan-Meier curves for the cumulative incidence of all-cause mortality in patients with non-ST-elevation myocardial infarction according to sex. (A) Crude analysis; (B) curves after stratification by age.

Figure 4.

Kaplan-Meier curves for the cumulative incidence of major adverse cardiovascular events (MACE; cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke) in patients with non-ST-elevation myocardial infarction according to sex. (A) Crude analysis; (B) curves after stratification by age.

Predictors of All-Cause Mortality

Multivariate logistic analysis (Table 4) revealed that the risk of all-cause mortality in women increased with increasing age and CKD stage. A similar trend was observed among men. Further, the presence of peripheral artery disease contributed to all-cause mortality for both men and women. Finally, diabetes and 3-vessel and/or left main lesions were prognostic factors for all-cause mortality in men, but not in women.

Table 4.

Multivariate Logistic Analysis for All-Cause Mortality According to Sex

	Women						Men
	Univariate			Multivariate			Univariate			Multivariate
	OR	95% CI	P value	OR	95% CI	P value	OR	95% CI	P value	OR	95% CI	P value
Age
≤59 years (Reference)
60–79 years	1.82	1.15–2.88	0.011	1.93	1.06–3.48	0.03	1.82	1.15–2.88	0.011	1.81	1.46–2.23	<0.001
≥80 years	3.30	2.10–5.19	<0.001	2.63	1.45–4.77	0.001	3.30	2.10–5.19	<0.001	3.39	2.69–4.26	<0.001
Diabetes	1.17	0.98–1.39	0.09				1.46	1.30–1.63	<0.001	1.20	1.05–1.38	0.007
Renal function
CKD Stage 1–2 (Reference)
CKD Stage 3	3.22	2.55–4.08	<0.001	2.20	1.71–2.82	<0.001	4.06	3.50–4.70	<0.001	2.12	1.81–2.49	<0.001
CKD Stage 4	6.96	5.21–9.30	<0.001	4.41	3.24–6.00	<0.001	6.51	5.18–8.17	<0.001	2.93	2.30–3.73	<0.001
Hemodialysis	4.83	3.33–6.99	<0.001	3.46	2.32–5.16	<0.001	5.53	4.34–7.05	<0.001	3.48	2.70–4.49	<0.001
Peripheral artery disease	3.09	2.33–4.09	<0.001	2.11	1.50–2.97	<0.001	2.65	2.18–3.22	<0.001	1.41	1.12–1.79	0.004
Prior history of HF	2.34	1.87–2.93	<0.001	1.07	0.80–1.42	0.651	2.85	2.43–3.34	<0.001	1.05	0.86–1.29	0.613
Acute HF within 24 h	3.61	3.02–4.31	<0.001	1.29	0.99–1.69	0.058	6.26	5.57–7.03	<0.001	1.73	1.44–2.08	<0.001
Cardiogenic shock	4.90	4.11–5.85	<0.001	2.52	1.90–3.34	<0.001	7.88	7.03–8.83	<0.001	2.71	2.22–3.32	<0.001
Cardiac arrest	5.09	4.08–6.33	<0.001	1.93	1.38–2.68	<0.001	7.46	6.62–8.42	<0.001	2.78	2.30–3.36	<0.001
No. diseased vessels
1 (Reference)
2	1.02	0.82–1.62	0.849	0.86	0.67–1.12	0.274	1.39	1.21–1.59	<0.001	1.12	0.94–1.32	0.206
3	1.64	1.31–2.05	<0.001	1.14	0.87–1.50	0.332	1.95	1.67–2.28	<0.001	1.27	1.06–1.53	0.012
Left main trunk lesion	2.27	1.65–3.12	<0.001	0.93	0.62–1.39	0.71	4.95	4.17–5.88	<0.001	1.52	1.22–1.89	<0.001
Presentation
STEMI (Reference)
NSTEMI	0.89	0.73–1.09	0.258				0.93	0.81–1.06	0.254

CI, confidence interval; OR, odds ratio. Other abbreviations as in Tables 1,2.

Discussion

This study describes the effect of sex on the post-discharge clinical outcomes of patients undergoing PCI for AMI. The main findings of this study are that: (1) women with AMI were significantly older than men and had a higher prevalence of a prior history of heart failure, hypertension, and advanced-stage CKD; (2) unadjusted all-cause mortality and the incidence of MACE were significantly higher in women than in men, whereas these sex differences were attenuated after adjusting for age; and (3) the presence of CKD was an independent predictor of all-cause mortality in both sexes.

The J-PCI OUTCOME Registry, a real-world dataset from Japan, provides valuable insights into sex differences in AMI. Consistent with previous reports,^4–10 the present study revealed that women with AMI tended to be older than men with AMI. Notably, the age distribution of patients enrolled in this registry was higher than that of patients enrolled in Western registries. In the US, the mean age at AMI presentation is 65.0 years for men and 71.8 years for women.²¹ The advanced age of women in the present study likely contributed to the higher prevalence of comorbidities such as hypertension, diabetes, and CKD, which can potentially impact prognosis after AMI. The disparity in age at AMI onset between men and women can be attributed to the protective role of estrogen. A decline in estrogen levels during menopause leads to endothelial dysfunction and lipid deposition in the vasculature, increasing the risk of AMI.^22,23 This hormonal factor may contribute to the older age at which women develop AMI compared with men.

Interestingly, in the present study, Kaplan-Meier curves showed that among patients with NSTEMI, men had a higher risk of all-cause mortality in the group aged ≥80 years, whereas the risk was reversed in the group aged 60–79 years, with women being at higher mortality risk. This finding was attributed to the higher incidence of cardiac deaths, particularly those due to heart failure, in women aged 60–79 years with NSEMI. The high prevalence of diabetes and advanced-stage CKD and the frequent use of rotational atherectomy in women in this group suggest that women aged 60–79 years with NSEMI have more complex coronary artery lesions, which may be a possible reason for the high rate of cardiac deaths. In contrast, men aged ≥80 years in the NSTEMI group tended to have higher all-cause mortality, particularly with a significantly higher incidence of non-cardiac death. This may be because men generally have a shorter life expectancy than women. Moreover, we speculated that the widening disparities in all-cause mortality and MACE between men and women in the NSTEMI group could be attributed to the slightly higher incidence of heart failure among women. Patients presenting with NSTEMI comprise a heterogeneous population in terms of clinical presentation.

Many previous studies have consistently shown that the short-term prognosis after AMI is worse for women than men, mainly because women are older and have more comorbidities, such as hypertension or diabetes.^5,6,8,24 In addition to older age and more complex comorbidities, other possible reasons for the poorer prognosis following AMI in women may include later presentation due to atypical symptoms and a longer time to treatment with coronary revascularization.^4,13,14 However, the existence of sex-related differences in long-term mortality remains controversial.¹⁵ The effect of sex would not be the same for short- and long-term prognoses following AMI. In our study, the first-year mortality rates were 7.3% for women and 5.4% for men with STEMI, and 7.0% for women and 5.2% for men with NSTEMI. In contrast, Roumeliotis et al reported that the first-year mortality rates were 13.9% for women and 7.1% for men with STEMI, and 6.1% for women and 4.5% for men with NSTEMI,¹⁰ with these mortality rates being similar to those in the present study for the NSTEMI group, but higher for both sexes than in the present study for the STEMI group. In the present study, with respect to post-discharge outcomes, all-cause mortality and the incidence of MACE were significantly higher among women than men in both the STEMI and NSTEMI groups, but the differences in clinical outcomes between the sexes were attenuated after stratification by age. Similar to our study, previous studies have demonstrated crudely higher long-term mortality for women after AMI; however, the differences in mortality between men and women were attenuated after adjusting for confounders.^7,10,25–27 Pancholy et al conducted a meta-analysis for the association of sex differences and mortality among patients with STEMI and showed a higher risk for crude first-year mortality (risk ratio [RR] 1.58; 95% CI 1.36–1.84; P<0.001) in women than in men; however, after age adjustment the risk for first-year mortality in women was no longer significant (RR 0.90; 95% CI 0.69–1.17; P=0.42).²⁸ In addition, in the present study, the incidence of heart failure was significantly higher among women than men. Women were more likely to have comorbidities including hypertension, CKD, and a history of heart failure than men, which would contribute to the higher incidence of heart failure among women. Older age and a higher prevalence of comorbidities in women could explain the sex differences in post-discharge clinical outcomes following presenting with for AMI.

CKD is an independent risk factor for the development of coronary artery disease²⁹ and is associated with poor AMI prognosis.^30,31 However, sex differences in the prognostic effect of CKD on AMI have been poorly evaluated in the literature. In the present study, CKD was an independent predictor of long-term mortality in both sexes. After multivariate adjustment, there was an approximate 2- to 4-fold increased risk of long-term mortality based on CKD staging. Similar to our study, Lawesson et al reported that CKD was associated with a 2- to 2.5-fold higher risk of in-hospital mortality and an approximate 1.5-fold higher risk of long-term mortality in both men and women.²⁶ From the J-PCI OUTCOME registry, Tobe et al previously reported that ischemic events, defined as a composite of post-discharge cardiovascular death, non-fatal MI, and non-fatal ischemic stroke, increased with advanced CKD stage when adjusted for age.³² The poor prognosis for female patients with concomitant AMI and CKD may be affected by the complexity of their comorbidities, underuse of cardioprotective medicines, risk of developing acute kidney injury, and higher risk of bleeding events.^26,33

Our study has several strengths. First, this study used a large national registry with the enrolment of almost all patients who underwent PCI in Japan, the world’s foremost superaging society, thus providing a real-world dataset for a large cohort. Second, patients who died in the hospital were excluded from the J-PCI OUTCOME Registry; therefore, this study reflected post-discharge outcomes after AMI. Third, our study examined STEMI and NSETMI separately and the results were consistent in both groups.

Study Limitations

Several limitations of the J-PCI OUTCOME Registry design should be noted. First, this study used a non-randomized observational design, which may have introduced potential bias related to unmeasured or hidden covariates, although multivariate analyses were used to reduce bias. Second, details regarding medications at discharge and uptitration of optimal medical treatment, which could likely affect long-term prognosis, are unknown. The duration of dual antiplatelet therapy in our database was also unknown. Third, among the 29,856 participants analyzed in this study, less than one-quarter were women. Although this unequal representation of women could introduce bias, it reflects the real-world scenario of underrepresentation of women in these studies. Fourth, spontaneous coronary artery dissection has also been reported as a mechanism of MI in women; however, it was not possible to study this in our dataset. In addition, there were no data on the coexistence of valvular heart disease or cardiomyopathy. Fifth, it was not possible to stratify CKD based on proteinuria or albuminuria due to the lack of data, and eGFR may be overestimated in women with low muscle mass and small body size. Finally, this study assessed the clinical outcomes within the 1-year period after AMI; long-term follow-up beyond the first year was not performed.

Conclusions

In this nationwide cohort study, we observed that women undergoing PCI for AMI had worse clinical outcomes, including higher 1-year mortality rates and incidence of MACE, than men. However, after stratifying the data according to age, sex differences in clinical outcomes diminished. Furthermore, CKD was significantly associated with an increased all-cause mortality in both sexes. These findings highlight the importance of understanding sex differences to provide appropriate management and achieve comparable outcomes between men and women. Tailored approaches that consider both sex- and age-specific factors are essential to optimize patient outcomes. Identifying high-risk groups after AMI, such as women with CKD, and providing them with interventions, including lifestyle modification and appropriate medical treatment, would help improve post-discharge clinical outcomes.

Acknowledgments

The authors acknowledge all the participating hospitals for their assistance and cooperation and the J-PCI OUTCOME Registry for its data contribution. The authors thank Editage (www.editage.jp) for English language editing a draft of this manuscript.

Sources of Funding

This study was supported by a grant from the Japan Agency for Medical Research and Development (17ek0210097 h0001) and Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research (18K17332 and 21K08064).

Disclosures

H.I. has received lecture fees from AstraZeneca Inc., Bayer Pharmaceutical Co. Ltd., Boehringer Ingelheim, Japan, Bristol-Myers Squibb Inc., Daiichi-Sankyo Pharma Inc., MSD K.K., Mitsubishi Tanabe Pharma Co. Ltd., Mochida Pharmaceutical Co. Ltd., Novartis Japan, and Pfizer Japan Inc. S.K. has received lecture fees from the Bristol-Myers Squibb Pfizer Alliance and a research grant from Novartis, Japan. T.A and K.K. are Associate Editors of the Circulation Journal. H.I. is on the Editorial Board of Circulation Journal.

IRB Information

The study protocol was approved by the independent Central Ethics Committee of the Clinical Research Promotion Network Japan and local institutional review boards at each participating site.

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circj.CJ-23-0966

References

• 1.   Mehta L, Beckie T, DeVon H, Grines C, Krumholz H, Johnson M, et al. Acute myocardial infarction in women: A scientific statement from the american heart association. Circulation 2016; 133: 916–947.
• 2.   Chiha J, Mitchell P, Gopinath B, Plant AJH, Kovoor P, Thiagalingam A. Gender differences in the severity and extent of coronary artery disease. Int J Cardiol Heart Vasc 2015; 8: 161–166.
• 3.   Reynolds HR, Shaw LJ, Min JK, Spertus JA, Chaitman BR, Berman DS, et al. Association of sex with severity of coronary artery disease, ischemia, and symptom burden in patients with moderate or severe ischemia: Secondary analysis of the ISCHEMIA randomized clinical trial. JAMA Cardiol 2020; 5: 773–786.
• 4.   Canto JG, Rogers WJ, Goldberg RJ, Peterson ED, Wenger NK, Vaccarino V, et al. Association of age and sex with myocardial infarction symptom presentation and in-hospital mortality. JAMA 2012; 307: 813–822.
• 5.   Kuehnemund L, Koeppe J, Feld J, Wiederhold A, Illner J, Makowski L, et al. Gender differences in acute myocardial infarction: A nationwide German real-life analysis from 2014 to 2017. Clin Cardiol 2021; 44: 890–898.
• 6.   Cenko E, Yoon J, Kedev S, Stankovic G, Vasiljevic Z, Krljanac G, et al. Sex differences in outcomes after STEMI: Effect modification by treatment strategy and age. JAMA Intern Med 2018; 178: 632–639.
• 7.   Bonarjee VVS, Rosengren A, Snappin SM, James MK, Dickstein K. Sex-based short- and long-term survival in patients following complicated myocardial infarction. Eur Heart J 2006; 27: 2177–2183.
• 8.   Takeji Y, Morimoto T, Shiomi H, Kato ET, Imada K, Yoshikawa Y, et al. Sex differences in clinical outcomes after percutaneous coronary intervention. Circ J 2023; 87: 277–286.
• 9.   Toyota T, Furukawa Y, Ehara N, Funakoshi S, Morimoto T, Kaji S, et al. Sex-based differences in clinical practice and outcomes for Japanese patients with acute myocardial infarction undergoing primary percutaneous coronary intervention. Circ J 2013; 77: 1508–1517.
• 10.   Roumeliotis A, Claessen BE, Sartori S, Cao D, Qiu H, Camaj A, et al. Impact of sex on long-term cardiovascular outcomes of patients undergoing percutaneous coronary intervention for acute coronary syndromes. Catheter Cardiovasc Interv 2021; 98: E494–E500.
• 11.   Lichtman J, Leifheit E, Safdar B, Bao H, Krumholz H, Lorenze N, et al. Sex differences in the presentation and perception of symptoms among young patients with myocardial infarction: Evidence from the VIRGO study (Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients). Circulation 2018; 137: 781–790.
• 12.   DeFilippis EM, Collins BL, Singh A, Biery DW, Fatima A, Qamar A, et al. Women who experience a myocardial infarction at a young age have worse outcomes compared with men: The Mass General Brigham YOUNG-MI Registry. Eur Heart J 2020; 41: 4127–4137.
• 13.   Khan NA, Daskalopoulou SS, Karp I, Eisenberg MJ, Pelletier R, Tsadok MA, et al. Sex differences in acute coronary syndrome symptom presentation in young patients. JAMA Intern Med 2013; 173: 1863–1871.
• 14.   Canto JG, Goldberg RJ, Hand MM, Bonow RO, Sopko G, Pepine CJ, et al. Symptom presentation of women with acute coronary syndromes: Myth vs reality. Arch Intern Med 2007; 167: 2405–2413.
• 15.   Bucholz E, Butala N, Rathore S, Dreyer R, Lansky A, Krumholz H. Sex differences in long-term mortality after myocardial infarction: A systematic review. Circulation 2014; 130: 757–767.
• 16.   Sawano M, Yamaji K, Kohsaka S, Inohara T, Numasawa Y, Ando H, et al. Contemporary use and trends in percutaneous coronary intervention in Japan: An outline of the J-PCI Registry. Cardiovasc Interv Ther 2020; 35: 218–226.
• 17.   Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, et al. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis 2009; 53: 982–992.
• 18.   Inker LA, Astor BC, Fox CH, Isakova T, Lash JP, Peralta CA, et al. KDOQI US commentary on the 2012 KDIGO clinical practice guideline for the evaluation and management of CKD. Am J Kidney Dis 2014; 63: 713–735.
• 19.   Hicks K, Mahaffey K, Mehran R, Nissen S, Wiviott S, Dunn B, et al. 2017 cardiovascular and stroke endpoint definitions for clinical trials. Circulation 2018; 137: 961–972.
• 20.   Garcia-Garcia HM, McFadden EP, Farb A, Mehran R, Stone GW, Spertus J, et al. Standardized end point definitions for coronary intervention trials: The Academic Research Consortium-2 consensus document. Circulation 2018; 137: 2635–2650.
• 21.   Mozaffarian D, Benjamin E, Go A, Arnett D, Blaha M, Cushman M, et al. Heart disease and stroke statistics – 2015 update: A report from the American Heart Association. Circulation 2015; 131: e29–e322.
• 22.   Chakrabarti S, Morton JS, Davidge ST. Mechanisms of estrogen effects on the endothelium: An overview. Can J Cardiol 2014; 30: 705–712.
• 23.   Rosano GMC, Vitale C, Marazzi G, Volterrani M. Menopause and cardiovascular disease: The evidence. Climacteric 2007; 10: 19–24.
• 24.   Numasawa Y, Inohara T, Ishii H, Kuno T, Kodaira M, Kohsaka S, et al. Comparison of outcomes of women versus men with non-ST-elevation acute coronary syndromes undergoing percutaneous coronary intervention (from the Japanese Nationwide Registry [J-PCI Registry]). Am J Cardiol 2017; 119: 826–831.
• 25.   Kanic V, Vollrath M, Tapajner A, Sinkovic A. Sex-related 30-day and long-term mortality in acute myocardial infarction patients treated with percutaneous coronary intervention. J Womens Health (Larchmt) 2017; 26: 374–379.
• 26.   Sederholm Lawesson S, Alfredsson J, Szummer K, Fredrikson M, Swahn E. Prevalence and prognostic impact of chronic kidney disease in STEMI from a gender perspective: Data from the SWEDEHEART register, a large Swedish prospective cohort. BMJ Open 2015; 5: e008188.
• 27.   Park HW, Han S, Park G, Ann SH, Suh J, Kim Y, et al. Sex-related impacts on clinical outcomes after percutaneous coronary intervention. Sci Rep 2020; 10: 15262.
• 28.   Pancholy SB, Shantha GPS, Patel T, Cheskin LJ. Sex differences in short-term and long-term all-cause mortality among patients with ST-segment elevation myocardial infarction treated by primary percutaneous intervention: A meta-analysis. JAMA Intern Med 2014; 174: 1822–1830.
• 29.   Sarnak MJ, Levey AS, Schoolwerth AC, Coresh J, Culleton B, Hamm LL, et al. Kidney disease as a risk factor for development of cardiovascular disease: A statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Circulation 2003; 108: 2154–2169.
• 30.   Hashimoto Y, Ozaki Y, Kan S, Nakao K, Kimura K, Ako J, et al. Impact of chronic kidney disease on in-hospital and 3-year clinical outcomes in patients with acute myocardial infarction treated by contemporary percutaneous coronary intervention and optimal medical therapy: Insights from the J-MINUET study. Circ J 2021; 85: 1710–1718.
• 31.   Anavekar NS, McMurray JJV, Velazquez EJ, Solomon SD, Kober L, Rouleau J, et al. Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. New Eng J Med 2004; 351: 1285–1295.
• 32.   Tobe A, Sawano M, Kohsaka S, Ishii H, Tanaka A, Numasawa Y, et al. Ischemic and bleeding outcomes in patients who underwent percutaneous coronary intervention with chronic kidney disease or dialysis (from a Japanese Nationwide Registry). Am J Cardiol 2023; 195: 37–44.
• 33.   Redfors B, Angerås O, Råmunddal T, Petursson P, Haraldsson I, Dworeck C, et al. Trends in gender differences in cardiac care and outcome after acute myocardial infarction in western Sweden: A report from the Swedish Web System for Enhancement of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART). J Am Heart Assoc 2015; 4: e001995.