Trends Over Time in the Incidences of ST-Segment Elevation Myocardial Infarction and Non-ST-Segment Elevation Myocardial Infarction During the Past Decade in a Rural Japanese High-Aged Population

Abstract

Background: In developed countries, the incidence of non-ST-segment elevation myocardial infarction (NSTEMI) has outpaced that of ST-segment elevation myocardial infarction (STEMI). However, whether this trend is observed in Japan, in which the aging of society is rapidly progressing, remains to be elucidated.

Methods and Results: This study retrospectively investigated the trends over time in the incidence of acute coronary syndrome (ACS) between August 2009 and July 2019 at 2 institutions in Izumo City (in rural Japan), which has an elderly population. Crude and age-sex-adjusted incidences of total ACS, STEMI, and non-ST-segment elevation-ACS (NSTE-ACS; including NSTEMI and unstable angina pectoris) were calculated for each year. In the total population, factors associated with the development of NSTEMI were evaluated by multivariate analysis. In total, 1,087 patients were enrolled. The age-adjusted incidence of NSTE-ACS in male patients aged ≥75 years showed a significantly increasing trend. The proportion of NSTEMI per total ACS cases showed a significantly increasing trend over the entire study period. In the multivariate analysis, pre-development use of ≥3 medications for comorbidities was associated with the development of NSTEMI, independent of high-sensitivity cardiac troponin assay use.

Conclusions: This study demonstrated an increasing trend in the incidence of NSTEMI in a rural high-aged Japanese population. In addition to the widespread use of high-sensitivity cardiac troponin assays, early medication use for comorbidities might have contributed to this trend.

Acute myocardial infarction (AMI) remains the leading cause of death worldwide.^1,2 In developed countries, the incidence of non-ST-segment elevation myocardial infarction (NSTEMI) has outpaced that of ST-segment elevation myocardial infarction (STEMI) since the prevailing lipid-lowering agents and changes in diagnostic criteria were enacted based on cardiac troponin (cTn).^3–8 In Japan, no data on the trends, over time, in the incidence of NSTEMI are available from previous studies evaluating the incidence of AMI.^9–12 Thus, it remains unclear whether the incidence of NSTEMI has increased in Japan as in other developed countries, as previous studies surveying the incidence of NSTEMI in a single year showed that the prevalence of STEMI has remained much higher than that of NSTEMI, even in clinical settings in which the cTn assay was available.^13,14 Furthermore, the number of elderly adults, which are reportedly at a risk for the development of NSTEMI,⁵ has rapidly increased in the Japanese population since the 2010s.¹⁵ In addition, the number of patients who are prescribed medications for comorbidities, which reportedly reduce the risk of STEMI,¹⁶ prior to the development of AMI might have increased along with widespread use of guideline-recommended therapies. To elucidate whether this is the case, we analyzed patients who had developed acute coronary syndrome (ACS), which is composed of STEMI, and non-ST-elevation-ACS (NSTE-ACS; including NSTEMI and unstable angina pectoris [UAP]),¹⁷ during the past 10 years in Izumo City, a city in a rural area of Japan, through a retrospective analysis of 2 tertiary institutions in the city. Our aims in this study were as follows: (1) to investigate the trends over time in the incidence of NSTEMI; and (2) to identify factors associated with the development of NSTEMI.

Methods

Study Design and Data Collection

This retrospective 2-institution observational study was conducted at tertiary hospitals (Shimane Prefectural Central Hospital [Institution A] and Shimane University Hospital [Institution B]) in Izumo City. In the city, no other institution has a cardiac care unit or the equipment necessary for performing primary/elective percutaneous coronary interventions (PCI). Izumo City is a medium-sized city in the Shimane prefecture, a rural area of southwest Japan (Figure 1A). The population of the city generally remained stable during the study period (175,252 in 2009 and 175,593 in 2018). The proportion of the population aged >65 years increased from 25% (2009) to 29% (2018) and was consistently higher than that in the general Japanese population (23% in 2009 and 28% in 2018). The present study used an opt-out system, with the study information disclosed on the website of each institution. The requirement for informed consent was waived owing to the retrospective and opt-out design of the study.

Figure 1.

Location of study institutions and flow diagram of the study. (A) Map showing the area of Izumo City (gray) and the locations of Institutions A (blue diamond) and B (orange diamond). Black diamonds indicate other institutions that have cardiac care units or are equipped to perform percutaneous coronary interventions. (B) Flow diagram of the study. ACS, acute coronary syndrome; NSTE-ACS, non-ST-segment elevation-acute coronary syndrome; NSTEMI, non-ST-segment elevation myocardial infarction; STEMI, ST-segment elevation myocardial infarction; UAP, unstable angina pectoris.

Data collection and patient enrollment were performed by reviewing electronic medical records in each institution. Consecutive patients who developed ACS between August 2009 and July 2019 were enrolled. As the number of cardiologists in general hospitals in Izumo city, other than in institutions A and B, was limited, the time from symptom onset to diagnosis was longer for some patients with ACS. To catch such patients, we defined the study period of ACS as developing within 7 days.

Patients with a symptom onset of more than 7 days and inhabitants of areas other than Izumo City were excluded. Among patients who experienced cardiopulmonary arrest in out-of-hospital settings, those with a return of spontaneous circulation who subsequently met the diagnostic criteria were enrolled.

Data on comorbidities, medical history, and laboratory findings were collected from the time of ACS diagnosis. Pre-development use of therapeutic agents was defined as medications that were taken more than 1 month before the diagnosis of ACS. The therapeutic agents analyzed in the present study were acetylsalicylic acid (ASA)/P2Y12 inhibitors, angiotensin-converting enzyme inhibitors (ACEI)/angiotensin II receptor blockers (ARBs), β-blockers, calcium channel blockers (CCBs), anti-dyslipidemia agents (including statins), and oral hypoglycemic agents (OHAs)/insulin.

Each 1-year study period was defined from August of the corresponding year to July of the following year (i.e., 2009: August 2009–July 2010, 2010: August 2010–July 2011, etc.). The trends in the incidence (crude and age-sex-adjusted), proportion of NSTE-ACS, NSTEMI, comorbidities, and therapeutic options during the entire study period were evaluated. Trends over time in the distribution of NSTE-ACS subcategories (NSTEMI with/without creatinine kinase [CK] elevation, and UAP) were also evaluated. Clinical demographics were compared between patients with STEMI and NSTE-ACS. To identify risk factors for the development of NSTEMI, we performed a multivariate analysis for the total population.

Diagnosis of Myocardial Infarction

Based on the universal definition,¹⁸ STEMI/NSTEMI was defined as elevated cardiac enzymes with at least one of the following findings: (1) ischemic symptoms; (2) electrocardiographic changes in ST-T waves, new left bundle branch block, or pathological Q waves; and (3) new abnormal motion of the myocardium documented by echocardiography. The echocardiography equipment in each institution was maintained in accordance with a previously published guideline.¹⁹ cTn above the 99th percentile was considered as an elevation of cardiac enzymes. A high-sensitivity cTn assay has been available since November 2014 in Institution A and April 2012 in Institution B. With respect to the presentation of ACS, STEMI was diagnosed when an elevation of ST-T segments in at least 2 contiguous leads or development of left bundle branch block occurred; patients without these findings were diagnosed with NSTEMI.²⁰ Patients with unavailable troponin data were regarded as having elevated cardiac enzymes when the peak CK level was more than twice the upper normal limit. Patients with an absence of an elevation in cardiac enzymes were diagnosed with UAP.¹⁷ Patients who could not undergo coronary angiography or died before admission were enrolled when they fulfilled the MONItoring of Trends and Determinants in CArdiovascular Disease (MONICA) criteria.²¹

Statistical Analysis

Normally distributed variables are expressed as mean±standard deviation, whereas non-normally distributed variables are presented as median and interquartile (first and third) range. The age-sex-adjusted incidences of total ACS, STEMI, and NSTE-ACS per 100,000 person-years were calculated using the direct method. The 2015 Japanese population census data were applied for the standard population.²² The annual age-sex distribution in Izumo City was also used for the observed population. The crude/age-adjusted incidence during the study period was fitted to a linear regression model. A positive/negative slope with statistical significance reached by linear regression analysis was considered as indicating an increasing/decreasing trend during the study period. The trend in categorical variables was evaluated using the Cochran-Armitage test. The trend in continuous variables was analyzed using the Jonckheere-Terpstra test. Differences in continuous variables between the patients with STEMI and NSTE-ACS were compared using the Mann-Whitney U-test. Categorical variables are presented as frequency and proportion (%) and were compared using the chi-squared (χ²) test. We also performed sensitivity analysis by calculating the annual crude/age-adjusted incidence of ACS and the trends over time of the proportion of NSTEMI in patients developing ACS within 48 h prior to admission.

Logistic regression analysis was performed to identify risk factors for the development of NSTEMI in the total population. Clinical variables of fundamental characteristics (age, male sex, and body mass index), comorbidities (diabetes mellitus, hypertension, dyslipidemia, current smoker, past smoker, estimated glomerular filtration rate [eGFR] of <30 mL/min/1.73 m², history of stroke, PCI, OMI [old myocardial infarction], and coronary artery bypass graft [CABG]), pre-development use of ≥3 therapeutic agents (≥3 out of ASA/P2Y12 inhibitors, ACEI/ARBs, CCBs, β-blockers, anti-dyslipidemia agents, and OHAs/insulin), and use of a high-sensitivity cTn assay were evaluated using univariate analysis. Variables with a P value <0.05 on univariate analysis were entered into a subsequent multivariate analysis to identify independent risk factors, including a calculation of the odds ratio (OR) and 95% confidence interval (CI). All analyses were performed using JMP version 13.2 (SAS Institute Inc., Cary, NC, USA), with a P value <0.05 considered statistically significant.

Results

Study Population and Trends Over Time in the Incidence of Total ACS

The study flow diagram is shown in Figure 1B. A total of 1,087 patients with STEMI/NSTE-ACS were enrolled. Among them, 697 and 390 patients had STEMI and NSTE-ACS, respectively. In patients with NSTE-ACS, 271 (69%) and 119 (31%) patients were diagnosed with NSTEMI and UAP, respectively. In the total population, 92% of patients (1,002/1,087 patients) developed ACS within 48 h prior to admission. The trends over time in the crude and age-adjusted incidences of patients with STEMI/NSTE-ACS are shown in Figure 2 (A, male; B, female) and Table 1. For female patients, the age-adjusted incidence of total ACS showed a significantly decreasing trend during the study period (−1.2 for slope, P=0.02). The incidence of patients developing ACS within 48 h prior to admission is shown in Supplementary Table 1. The decreasing trend of age-adjusted incidence of total ACS in female patients persisted (−1.8 for slope, P=0.053).

Figure 2.

Incidences of total ACS, STEMI, and NSTE-ACS. (A) Crude and age-adjusted incidences in male patients for total ACS (gray), STEMI (blue), and NSTE-ACS (orange) from 2009 (August 2009–July 2010) to 2018 (August 2018–July 2019). The bars and lines show crude and age-adjusted incidences, respectively. (B) Crude and age-adjusted incidences in female patients for total ACS (gray), STEMI (blue), and NSTE-ACS (orange) from 2009 to 2018. The bars and lines show crude and age-adjusted incidences, respectively. *Statistical significance (P<0.05). ACS, acute coronary syndrome; NSTE-ACS, non-ST-segment elevation–acute coronary syndrome; P/Y, person-years; STEMI, ST-segment elevation myocardial infarction.

Table 1. Incidence of STEMI/NSTE-ACS

		Aug 2009– July 2010	Aug 2010– July 2011	Aug 2011– July 2012	Aug 2012– July 2013	Aug 2013– July 2014	Aug 2014– July 2015	Aug 2015– July 2016	Aug 2016– July 2017	Aug 2017– July 2018	Aug 2018– July 2019	Slope	P value
Male
Total	Crude	86	71	67	60	87	86	73	88	88	70	0.71	0.56
	AAI	119	98	94	85	118	116	98	118	115	89	0.07	0.96
STEMI	Crude	52	48	41	37	65	54	46	60	53	37	0.06	0.95
	AAI	71	67	57	53	89	73	62	81	69	47	−0.35	0.82
NSTE-ACS	Crude	34	23	26	23	22	32	27	28	35	33	0.64	0.25
	AAI	48	31	37	32	29	43	36	37	46	42	0.42	0.57
Female
Total	Crude	33	31	32	31	35	29	31	33	26	30	−0.38	0.17
	AAI*	41	38	39	35	41	34	36	37	23	32	−1.20	0.02
STEMI	Crude	23	21	21	23	23	12	20	20	18	22	−0.33	0.39
	AAI	29	26	25	26	27	15	23	22	16	25	−0.86	0.09
NSTE-ACS	Crude	10	10	11	8	12	17	11	13	8	8	−0.04	0.88
	AAI	12	12	14	9	14	19	13	15	7	7	−0.39	0.37

Crude incidence is expressed as a number (n). AAI is expressed as per 100,000 person-years. *Statistical significance (P<0.05). AAI, age-adjusted incidence; NSTE-ACS, non-ST-segment elevation-acute coronary syndrome; STEMI, ST-segment elevation myocardial infarction.

Comparison of Age-Adjusted Incidence in Patients With ACS in 2 Age Groups

The trends over time in the age-adjusted incidence of STEMI/NSTE-ACS during the study period in 2 age groups (≥75 years, and <75 years) are shown in Supplementary Table 2. The incidence of total ACS (−1.5 for slope, P=0.03) and STEMI (−1.1 for slope, P=0.03) in female patients aged <75 years showed a significantly decreasing trend. In contrast, the incidence of NSTE-ACS in male patients aged ≥75 years showed a significantly increasing trend during the study period (9.3 for slope, P=0.03).

Secular Trend in Patient Clinical Demographics

Trends over time of patient clinical demographics are shown in Table 2 and Supplementary Table 3. Over the entire study period, the proportion of high-sensitivity cTn assay use significantly increased (0% in 2009 and 100% in 2018, P<0.0001). The proportion of NSTEMI significantly increased over the entire study period (25% in 2009 and 32% in 2018, P=0.004), even though the proportion of NSTE-ACS did not show a significant increasing trend. In the sensitivity analysis, we calculated the trends over time of the proportion of NSTEMI in patients developing ACS within 48 h prior to admission (N=1,002). The increasing trend persisted in the study population (P=0.0002).

Table 2. Trends Over Time of Clinical Demographics of the Studied Population

	Total (N=1,087)	Aug 2009– July 2010 (N=119)	Aug 2010– July 2011 (N=102)	Aug 2011– July 2012 (N=99)	Aug 2012– July 2013 (N=91)	Aug 2013– July 2014 (N=122)	Aug 2014– July 2015 (N=115)	Aug 2015– July 2016 (N=104)	Aug 2016– July 2017 (N=121)	Aug 2017– July 2018 (N=114)	Aug 2018– July 2019 (N=100)	P value for trend
Use of a hs-cTn assay, n (%)*	594 (55)	0	0	4 (4)	18 (20)	40 (33)	93 (81)	104 (100)	121 (100)	114 (100)	100 (100)	<0.0001
NSTE-ACS, n (%)	390 (36)	44 (37)	33 (32)	37 (37)	31 (34)	34 (28)	49 (43)	38 (37)	41 (34)	43 (38)	40 (40)	0.44
NSTEMI, n (%)*	271 (25)	30 (25)	20 (20)	21 (21)	16 (18)	19 (16)	36 (31)	30 (29)	28 (23)	39 (34)	32 (32)	0.004
Age (years), mean±SD*	71±13	71±13	69±12	70±12	73±13	70±13	72±12	71±13	70±12	72±12	74±14	0.01
Male, n (%)	776 (71)	86 (72)	71 (70)	67 (68)	60 (66)	87 (71)	86 (75)	73 (70)	88 (73)	88 (77)	70 (70)	0.36
BMI (kg/m2), mean±SD	23±3.8	23±3.4	23±3.5	23±3.2	23±3.6	24±3.6	23±3.5	23±4	24±4.2	24±4.3	23±3.7	0.89
ASA/P2Y12 inhibitors, n (%)	238 (22)	23 (19)	15 (15)	20 (20)	27 (30)	31 (25)	26 (23)	19 (18)	22 (18)	29 (25)	26 (26)	0.23
ACEI/ARBs, n (%)*	369 (34)	29 (24)	25 (25)	33 (34)	43 (47)	36 (30)	46 (40)	40 (38)	43 (35)	40 (35)	34 (34)	0.04
β-blockers, n (%)	114 (10)	5 (4)	8 (8)	11 (11)	11 (12)	13 (11)	14 (12)	14 (13)	16 (13)	13 (11)	9 (9)	0.08
CCBs, n (%)*	412 (38)	35 (29)	25 (25)	34 (35)	46 (51)	39 (32)	52 (45)	43 (41)	52 (43)	43 (38)	43 (43)	0.003
Anti-dyslipidemia agents, n (%)	278 (26)	21 (18)	23 (23)	21 (21)	33 (36)	32 (26)	29 (25)	27 (26)	33 (27)	29 (25)	30 (30)	0.07
Statins, n (%)	245 (23)	19 (16)	21 (21)	19 (19)	28 (31)	30 (25)	24 (21)	23 (22)	28 (23)	26 (23)	27 (27)	0.14
OHAs/insulin, n (%)	250 (23)	19 (16)	16 (16)	26 (26)	27 (30)	28 (23)	32 (28)	26 (25)	24 (20)	27 (24)	25 (25)	0.17
Hospital stay (days), mean±SD*	13 (7, 19)	14 (9, 20)	14 (9, 19)	13 (6, 18)	11 (5, 17)	12 (7, 19)	14 (7, 20)	13 (8, 19)	12 (8, 19)	13 (6, 19)	13 (5, 19)	0.001
In-hospital mortality, n (%)	97 (9)	12 (10)	10 (10)	14 (14)	10 (11)	5 (4)	11 (10)	7 (7)	7 (6)	16 (14)	5 (5)	0.23

Numerical data are expressed as the mean±SD or as the median (IQR; first quartile, third quartile). Categorical data are expressed as the percentage (%) and number (n). *Statistical significance (P<0.05). ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin II receptor blockers; ASA, acetylsalicylic acid; BMI, body mass index; CCB, calcium channel blockers; hs-cTn, high-sensitivity cardiac troponin; IQR, interquartile range; NSTE-ACS, non-ST-segment elevation-acute coronary syndrome; NSTEMI, non-ST-segment elevation myocardial infarction; OHA, oral hypoglycemic agents; SD, standard deviation.

In the total population, the proportion of NSTEMI without CK elevation significantly increased over the entire study period (5% in 2009 and 13% in 2018, P=0.003). The mean age also showed a significantly increasing trend (71±13 years in 2009 and 74±14 years in 2018, P=0.01). The prevalence of patients prescribed ACEI/ARBs (P=0.04) and CCBs (P=0.003) significantly increased over the entire study period.

Trends Over Time in the Distribution of NSTE-ACS Subcategories

The trends over time in the distribution of NSTE-ACS subcategories are shown in Figure 3. The proportion of UAP showed a significantly decreasing trend (32% in 2009 and 20% in 2018, P<0.0001). In contrast, the proportion of NSTEMI without CK elevation showed a significantly increasing trend (14% in 2009 and 32% in 2018, P=0.004), whereas the proportion of NSTEMI with CK elevation remained unchanged (mean of 41%, P=0.51).

Figure 3.

Trends over time in the distribution of NSTE-ACS subcategories. Colored bars and numbers indicate the proportion (%) of each subcategory (UAP: pink, NSTEMI without CK elevation: purple, NSTEMI with CK elevation: green) for all NSTE-ACS cases in the corresponding year. Significantly decreasing (P=0.0001) and increasing trends (P=0.004) in the proportion of UAP and NSTEMI without CK elevation, respectively, were observed. *Statistical significance (P<0.01). CK, creatinine kinase; NSTE-ACS, non-ST-segment elevation acute coronary syndrome; NSTEMI, non-ST-segment elevation myocardial infarction; UAP, unstable angina pectoris.

Comparison of Characteristics Between Patients With STEMI and NSTE-ACS

The characteristics of patients with STEMI and NSTE-ACS were compared (Table 3). Higher proportions of patients had a history of OMI, PCI, and CABG in the NSTE-ACS group than in the STEMI group. Additionally, significantly higher proportions of patients were prescribed ASA/P2Y12 inhibitors (P<0.0001), ACEI/ARBs (P=0.02), β-blockers (P=0.003), CCBs (P=0.005), anti-dyslipidemia agents (P<0.0001), and OHAs/insulin (P=0.01) in the NSTE-ACS group than in the STEMI group. The trends over time in the pre-development use of therapeutic agents are shown in Figure 4, with detailed numbers presented in Supplementary Table 4. In the STEMI group, the proportion of prescribed CCBs showed a significantly increasing trend; however, the rate of other therapeutic agents remained unchanged. In the NSTE-ACS group, the proportions of prescribed ACEI/ARBs (P=0.01), β-blockers (P=0.03), and CCBs (P=0.03) showed significantly increasing trends. The proportion of prescribed OHAs/insulin also showed an increasing trend (P=0.07), although it did not reach statistical significance.

Table 3. Comparison of Characteristics Between Patients With STEMI and NSTE-ACS

	Total (n=1,087)	With STEMI (n=697)	With NSTE-ACS (n=390)	P value
Fundamental characteristics
Age (years), mean±SD	71±13	71±13	72±12	0.11
Male, n (%)	776 (71)	493 (70)	283 (73)	0.52
CPA at presentation, n (%)*	79 (7)	71 (10)	9 (2)	<0.0001
Killip class, mean±SD*	1.5±1	1.6±1.1	1.4±0.8	0.04
Time from symptom onset to arrival (h), median (IQR)*	3 (1–11)	2.5 (1–7.5)	3 (1.5–16.5)	<0.0001
BMI (kg/m2), mean±SD	23±3.8	23±3.6	23±4	0.68
PCI, n (%)*	921 (85)	619 (89)	302 (77)	<0.0001
CABG, n (%)*	53 (5)	13 (2)	40 (10)	<0.0001
Hospital stay (days), mean±SD*	13 (7, 19)	14 (10, 19)	10 (4, 18)	<0.0001
In-hospital mortality, n (%)*	97 (9)	78 (11)	19 (5)	0.0005
Comorbidities
DM, n (%)	406 (37)	252 (36)	154 (39)	0.27
HT, n (%)	742 (68)	462 (66)	280 (72)	0.06
DL, n (%)	621 (57)	403 (58)	218 (56)	0.54
Current smoker, n (%)*	306 (28)	216 (31)	90 (23)	0.005
Past smoker, n (%)*	311 (29)	185 (27)	126 (32)	0.04
Hx of stroke, n (%)	124 (11)	72 (10)	52 (13)	0.13
Hx of OMI, n (%)*	86 (8)	44 (6)	42 (11)	0.009
Hx of PCI, n (%)*	129 (12)	56 (8)	73 (19)	<0.0001
Hx of CABG, n (%)*	12 (1)	4 (0.5)	8 (2)	0.02
Therapeutic agents
ASA/P2Y12 inhibitors, n (%)*	238 (22)	110 (16)	128 (33)	<0.0001
ACEI/ARBs, n (%)*	369 (34)	219 (31)	150 (38)	0.02
β-blockers, n (%)*	114 (10)	59 (8)	55 (14)	0.003
CCBs, n (%)*	412 (38)	243 (35)	169 (43)	0.005
Anti-dyslipidemia agents, n (%)*	278 (26)	143 (21)	135 (35)	<0.0001
Statins, n (%)*	245 (23)	125 (18)	120 (31)	<0.0001
OHAs/Insulin, n (%)*	250 (23)	144 (21)	106 (27)	0.01
Laboratory findings
eGFR (mL/min/1.73 m2), mean±SD	64±27	65±26	61±28	0.06
Peak CK (IU/L), median (IQR)*	1,025 (242–2,497)	1,742 (731–3,249)	420 (184–1,188)	<0.0001

Numerical data are expressed as the mean±SD or as the median (IQR; first quartile, third quartile). Categorical data are expressed as the percentage (%) and number (n). *Statistical significance (P<0.05). CABG, coronary artery bypass graft; CK, creatine kinase; CPA, cardiopulmonary arrest; DL, dyslipidemia; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; HT, hypertension; Hx, history; OMI, old myocardial infarction; PCI, percutaneous coronary intervention. Other abbreviations as in Tables 1,2.

Figure 4.

Trends over time in the pre-development use of therapeutic agents (ASA/P2Y12 inhibitors: black, ACEI/ARBs: red, β-blockers: green, CCBs: orange, anti-dyslipidemia agents: blue, and OHAs/insulin, gray) in patients with STEMI (A) and with NSTE-ACS (B) during the entire study period (2009–2018). In patients with STEMI, a significantly increasing trend in the pre-development use of CCBs (P=0.04) was observed. In patients with NSTE-ACS, significantly increasing trends in the pre-development use of ACEI/ARBs (P=0.01), β-blockers (P=0.03), and CCBs (P=0.03) were observed. *Statistical significance (P<0.05). ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin II receptor blocker; ASA, acetylsalicylic acid; CCB, calcium channel blocker; NSTE-ACS, non-ST-segment elevation-acute coronary syndrome; OHA, oral hypoglycemic agent; STEMI, ST-segment elevation myocardial infarction.

Univariate and Multivariate Analyses

Univariate and multivariate analyses were performed for the total population (N=1,087). The results of the multivariate analysis are summarized in Table 4. In the univariate analysis, ≥75 years old, use of a high-sensitivity cTn assay, dyslipidemia, eGFR of <30 mL/min/1.73 m², current smoker, and use of ≥3 therapeutic agents were revealed as potential risk factors for the development of NSTEMI. After multivariate adjustment, the use of ≥3 therapeutic agents was associated with the development of NSTEMI, independent of the use of a high-sensitivity cTn assay. In contrast, dyslipidemia was an independent factor that was not associated with the development of NSTEMI.

Table 4. Univariate and Multivariate Analyses to Identify Factors Associated With the Development of NSTEMI

	Univariate		Multivariate
	OR (95% CI)	P value	OR (95% CI)	P value
Aged ≥75 years	1.5 (1.1–1.9)	0.004	1.3 (0.96–1.7)	0.09
Use of hs-cTn assay*	1.4 (1.06–1.9)	0.01	1.4 (1.04–1.8)	0.02
Dyslipidemia*	0.7 (0.54–0.94)	0.01	0.67 (0.5–0.91)	0.01
eGFR <30 mL/min/1.73 m2	1.5 (1.009–2.3)	0.045	1.2 (0.8–1.9)	0.31
Current smoker	0.69 (0.5–0.95)	0.02	0.83 (0.59–1.2)	0.27
Use of ≥3 therapeutic agents*	1.5 (1.1–2.0)	0.009	1.5 (1.1–2.1)	0.01

*Statistical significance after adjustment by multivariate analysis (P<0.05). CI, confidence interval; OR, odds ratio. Other abbreviations as in Tables 2,3.

Discussion

General Overview

The important findings of our study are as follows. The age-adjusted incidence of NSTE-ACS in older male patients (≥75 years) showed a significantly increasing trend. In particular, the proportion of NSTEMI showed a significantly increasing trend during the entire study period. This trend was attributed to an increase in NSTEMI without CK elevation. Additionally, the pre-development prescription of ≥3 therapeutic agents was revealed to be associated with the development of NSTEMI, independent of the use of a high-sensitivity cTn assay, on multivariate analysis.

Secular Trend in the Incidence of Total AMI

A few studies on the trends over time in the incidence of AMI since the 2000 s in the Japanese population have been published.^9–12 Although there were variances in the studied period, studied area, age distribution, and socioeconomic status among the studies, they commonly showed that the total age-adjusted incidence of total ACS in females had generally decreased. In accordance with these previous results, our data also showed a significant reduction in the age-adjusted incidence in females. The general decreasing trend was explained by the use of prevailing anti-cholesterol drugs and the contribution of early interventions for coronary risk factors, as observed in other developed countries.^9,11 In contrast, the trend in age-adjusted incidence in males in previous studies has varied, with controversy (decreasing,^9,10 increasing^11,12). Although our data showed no statistical increasing or decreasing trend in the incidence of total ACS in males, our data firstly revealed a significant increase in the incidence of NSTE-ACS in older males. This increase might reflect the result of the progression of an elderly society, because our data were collected from a population that included a higher proportion of older people than even is in all of Japan, which has the largest aged population worldwide.

We also showed the incidence of NSTEMI in females aged ≥75 years was unchanged; however, the proportion of females aged ≥75 years was larger than that for males. Older females with myocardial infarction tend to present atypical symptoms and delay visiting medical institutions.²³ NSTEMI symptoms are less obvious than those of STEMI; therefore, the gap in incidence might reflect under-detection of older females who developed NSTEMI.

Regarding our finding that the incidence of male NSTEMI was increasing, similar trends over time have been observed in other Asian populations. In Taiwan, the incidence rate of AMI has been dramatically increasing, driven by the increase of NSTEMI.²⁴ In accordance with our results, the incidence in males was apparently increased; however, that in females was unchanged. In South Korea, the incidence of NSTEMI outpaced that of STEMI, although the total incidence of AMI was decreased.²⁵ Also, in the South Korean population, the proportion of male NSTEMI steadily increased. Both studies demonstrated that the mean developing age also increased. In a Western population, a German study investigating nationwide inpatient records showed the proportion of male NSTEMI was significantly increased during the study period, correlating with the increased age.⁵ These results suggest the increase of NSTEMI in older males might be a global issue, irrespective of race.

Incidence and Factors Associated With NSTEMI

To the best of our knowledge, the present study is the first to show an increasing trend in NSTEMI in Japan. A previous study evaluating the prevalence of STEMI and NSTEMI in a single year revealed that the prevalence of STEMI was twice as high as that of NSTEMI, even according to cTn-based criteria.¹³ By implementing cTn-based criteria, patients with ACS, who classically are diagnosed as having UAP, tend to be diagnosed as having NSTEMI.³ In the United States, a community-based study showed the incidence of NSTEMI increased up to 49% after prevailing cTn-based criteria, although the incidence was unchanged if diagnosed by using CK-based criteria.⁶ Furthermore, another study revealed that ~24% of patients diagnosed with UAP by using CK-based criteria were re-classified as having myocardial infarction if cTn-based criteria were used.²³ Since the introduction of the high-sensitivity cTn assay in the late 2000s, detection of very small myocardial injuries has been possible.²⁶ After implementation of the high-sensitivity cTn assay, a study revealed that 20% of patients previously diagnosed with UAP by cTn criteria shifted to a NSTEMI diagnosis; however, the proportion of STEMI was unchanged.²⁷ In France, a study comparing 5 nationwide registries over a 20-year study period showed the proportion of NSTEMI outpaced STEMI in 2015, in which the high-sensitivity cTn assay prevailed over the previous cTn criteria.⁵

Although we also observed that the incidence of STEMI was still higher than that of NSTE-ACS in entire studied period, the proportion of NSTEMI without CK elevation increased along with the widespread use of a high-sensitivity cTn assay. Furthermore, multivariate analysis showed that, independent of the use of a high-sensitivity cTn assay, older age (≥75 years) was not associated with development of total NSTEMI. This finding might reflect that the increase of total NSTEMI originated from the widespread use of high-sensitivity cTn-based diagnostic criteria, as found in other countries,^5,27 and not due to the progression of an aging society. We also showed an association between pre-development use of multiple (≥3) therapeutic agents and the development of NSTEMI, independent of the use of a high-sensitivity cTn assay. Several studies have shown that patients who were prescribed therapeutic agents for cardiovascular risk factors, such as ACEIs, β-blockers, ASA, and statins, prior to admission, tend to develop NSTEMI rather than STEMI.^22,28,29 There might be underlying mechanisms inhibiting transmural coronary ischemia, such as the pleiotropic effects of statins.³⁰ We also showed an increasing trend in the pre-development use of therapeutic agents (ACEI/ARBs, β-blockers, CCBs, and OHAs/insulin) in patients with NSTE-ACS over the entire study period. Our results might also suggest that early treatment for comorbidities contributes to a shift in the presentation of AMI.

Strengths and Limitations

The present study is the first to show the trends over time in ACS during the 2010s in a high-aged population. In the future, the progression of aging societies will be faster in Asian countries, including Japan, than in other countries,³¹ and studies have shown that STEMI remains the predominant presentation of AMI in some Asian countries.^32,33 Our data, which indicated an increasing trend in older male patients with NSTEMI, and the association of multiple therapeutic agents with the development of NSTEMI might be useful in predicting future trends in the incidence of AMI in areas in Japan and other Asian countries in which aging societies are progressing.

Our study has some limitations that should be noted. First, this was a 2-institution study with a retrospective observational design. Unmeasured factors may be associated with the development of NSTEMI. Furthermore, patients who completed treatment for ACS at other institutions might have been missed. Nevertheless, this population would be very limited because an inter-institutional cooperation in Izumo City was established. Patients diagnosed with ACS at other institutions were consulted as quickly as possible and referred to Institution A or B, even if they were bedridden or very elderly. Second, in our study design, patients with AMI with cardiopulmonary arrest were enrolled only if they achieved a return of spontaneous circulation. Patients who died before arrival or who could not achieve a return of spontaneous circulation could have been missed even if they developed AMI. Third, our data were collected from an area with a relatively high proportion of elderly people compared to other areas in Japan. It remains unclear whether our data can be extrapolated to other areas in Japan. In particular, the speed of progression of the aging society would vary within the studied area. Thus, studies conducted in other areas are warranted to validate our findings. Finally, our result that the pre-development use of multiple therapeutic agents was associated with the development of NSTEMI might not imply that the use of multiple therapeutic agents increased the risk of NSTEMI, but rather might represent comorbidities associated with the development of NSTEMI. Further studies with comparable numbers of matched patients with both treated and untreated comorbidities that compare the incidence of NSTEMI would elucidate the association between therapeutic agents and NSTEMI.

Conclusions

The present study findings suggest that the incidence of NSTEMI showed a significantly increasing trend in a Japanese high-aged population. Pre-development prescription of ≥3 therapeutic agents was associated with the development of NSTEMI, independent of the use of a high-sensitivity cTn assay. Our data might contribute to the prediction of future trends over time in the incidence of AMI in other areas in Japan in which aging societies are progressing.

Acknowledgments

We would like to thank Editage (www.editage.jp) for English-language editing, as well as Hiromi Tokuda, a chief medical assistant at the Shimane Prefectural Central Hospital, for data collection.

Disclosures

K. Tanabe and M. Yano are members of Circulation Journal’s Editorial Team. The other authors declare that they have no conflicts of interest. This research received no grants from any funding agency in the public, commercial, or not-for-profit sectors.

Ethical Considerations

This study was conducted in accordance with the tenets of the Declaration of Helsinki and the ethical standards of the responsible committee on human experimentation. The Institutional Review Boards of Shimane Prefectural Central Hospital (Churin R20-12) and Shimane University Hospital (20200515-2-4691) approved this study.

Data Availability

The deidentified participant data will not be shared.

Supplementary Files

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-20-0955

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