Clinical Presentation, Management and Outcome of Japanese Patients With Acute Myocardial Infarction in the Troponin Era　– Japanese Registry of Acute Myocardial Infarction Diagnosed by Universal Definition (J-MINUET) –

Abstract

Background: New criteria for diagnosis of acute myocardial infarction (AMI) were proposed in 2000 as a universal definition, in which cardiac troponin (cTn) was the preferred biomarker. A large number of patients formerly classified by creatine kinase (CK) as unstable angina are now ruled-in by cTn as non-ST-elevation myocardial infarction (NSTEMI).

Methods and Results: The Japanese registry of acute Myocardial INfarction diagnosed by Universal dEfiniTion (J-MINUET) is a prospective and multicenter registry conducted in 28 institutions. We enrolled 3,283 consecutive patients with AMI diagnosed by cTn-based criteria who were admitted to participating institutions within 48 h of symptom onset. There were 2,262 patients (68.9%) with STEMI and 1,021 (31.1%) with NSTEMI. CK was not elevated more than twice the upper limit of normal in 458 patients (44.9%) with NSTEMI (NSTEMI-CK). Although there was no significant difference in the in-hospital mortality of STEMI and NSTEMI with CK elevation (NSTEMI+CK) patients (7.1% vs. 7.8%, P=0.57), it was significantly lower in patients with NSTEMI-CK than in those with STEMI or NSTEMI+CK (1.7%, P<0.001 for each).

Conclusions: J-MINUET revealed the clinical presentation, management and outcomes of Japanese patients with AMI in the current cTn era. We should be aware of the difference between AMI diagnosed by CK-based criteria and AMI diagnosed by cTn-based criteria when using universal definitions for the diagnosis of AMI.

Acute myocardial infarction (AMI) is a leading cause of death in Japan as well as in other Western countries. Over the past decades, the incidence of ST-elevation MI (STEMI) has declined in USA, but non-ST-elevation MI (NSTEMI) showed a transient increase from 2000.^1–3 This substantial change in the epidemiology of AMI was at least in part mediated by the change in the criteria of AMI. In 2000, the European Society of Cardiology (ESC) and the American College of Cardiology (ACC) recommended a new definition of AMI, a universal definition, in which cardiac troponin (cTn) was the preferred biomarker of myocardial injury.⁴ A large number of patients formerly classified by creatine kinase (CK) as unstable angina (UA) are now ruled-in by cTn as NSTEMI.⁵ However, in Japan, the CK-based criteria are used even in the recent AMI registries, in which STEMI still constitutes the majority of AMI cases.^6,7

The Japanese registry of acute Myocardial INfarction diagnosed by Universal dEfiniTion (J-MINUET) is a large-scale, prospective, multicenter registry of Japanese patients hospitalized for AMI diagnosed by the new universal definition. The purpose of this study was to describe clinical presentation, treatment and outcomes of Japanese patients with AMI in the contemporary cTn era.

Methods

Study Design and Subjects

The J-MINUET is a prospective observational multicenter study (UMIN000010037). Consecutive patients hospitalized within 48 h of onset of AMI at 28 Japanese medical institutions were enrolled between July 2013 and May 2014. Diagnosis of AMI was based on the ESC/ACC Foundation (ACCF)/American Heart Association (AHA)/World Heart Federation Task Force for the Universal Definition of Myocardial Infarction.⁸ Only type 1 AMI (spontaneous MI related to ischemia from primary coronary event) and type 2 (MI secondary to ischemia because of either increased oxygen demand or decreased supply) were included in this registry. In brief, AMI was diagnosed by the rise and/or fall of cardiac biomarkers (preferred: troponin) with at least 1 value above the 99^th percentile of the upper reference limit observed together with evidence of myocardial ischemia with at least one of the following: symptoms of ischemia, ECG changes indicative of new ischemia, development of pathological Q waves in the ECG and imaging evidence of new loss of viable myocardium or new regional wall motion abnormalities. The type of cTn (cTnT or cTnI) measured depended on the attending physician, and the cut-off value used at each institution was applied. In patients in whom CK was elevated more than twice the upper limit of normal (ULN), cTn measurement may not be required.

Patients were evaluated at baseline for demographic and clinical characteristics. STEMI was diagnosed in the presence of new ST elevation at the J point in at least 2 contiguous leads ≥2 mm (0.2 mV) in men or ≥1.5 mm (0.15 mV) in women in leads V2–3 and/or ≥1 mm (0.1 mV) in other contiguous chest leads or the limb leads.^4,9 New or presumably new left bundle branch block was considered a STEMI equivalent. Data on the treatment, including coronary interventions and medications, were recorded. Urgent coronary angiography (CAG) was defined as angiography performed within 48 h of hospital admission. Clinical events were collected at the time of discharge.

The primary endpoint was in-hospital mortality. The secondary endpoint was major adverse cardiac events (MACE), defined as a composite of all death, cardiac failure, ventricular tachycardia (VT) and/or ventricular fibrillation (VF) and bleeding during hospitalization. Cardiac failure was defined as congestive heart failure and/or cardiogenic shock that required treatment.

This study was conducted in accordance with the Declaration of Helsinki. The protocol was approved by the ethics committees of every participating institution.

Statistical Analysis

All continuous variables are presented as medians (25–75^th percentile) and unpaired t tests were used to compare groups. If the variables were not distributed normally, signed-rank tests were used. Non-continuous and categorical variables are presented as percentages and compared using the chi-square test. We applied ANOVA to the STEMI, NSTEMI+CK and NSTEMI-CK groups, then post hoc pairwise comparisons between each group were conducted with Bonferroni corrections. Univariate and multivariate logistic regression models are used to calculate odds ratios (ORs) for all cardiac events and 95% confidence intervals (CIs). Multivariable analyses are performed using covariates that established prognostic risk factors for cardiac events. Missing values were imputed by using the multivariate normal model, using the chained equations approach.¹⁰ Multiple imputation is used to replace each missing value with 2 or more acceptable values, representing a distribution of possible covariates. Multiple imputation method is a more sophisticated imputation method than the case-wise deletion method, which analyzing cases with complete information, or the single imputation method.¹¹ All statistical tests were 2-sided and P<0.05 was regarded as significant. P-values <0.0125 were used for post hoc pairwise comparisons conducted with Bonferroni corrections. Statistical analysis was performed with JMP, version 11.0.0 (SAS Institute Inc, Cary, NC, USA) and STATA, version 12 (StataCorp LP, College Station, TX, USA).

Results

A total of 3,283 patients were enrolled in the study and included in the analysis. cTn was measured in 3,099 patients (93.6%); cTnT in 64.0% and cTnI in 36.0% of the patients. In the remaining 212 patients (6.4%), AMI was diagnosed by CK elevation beyond twice the ULN without cTn measurement.

Baseline Characteristics of the Patients

Baseline clinical characteristics of the study patients are shown in Table 1. There were 2,262 patients (68.9%) with STEMI and 1,021 (31.1%) with NSTEMI (Figure 1). STEMI was associated with younger age, more males and current smokers, less history of hypertension, diabetes, dyslipidemia, atrial fibrillation, prior MI, stroke and peripheral artery disease, and shorter time from onset to admission. The incidence of type 2 MI was 5.2%, which was more frequent in the NSTEMI than in the STEMI patients. Prescription of antiplatelet drugs, antihypertensive drugs and statins before the onset of AMI was more frequent in patients with NSTEMI.

Table 1. Baseline Characteristics of the Study Patients Enrolled in J-MINUET

	Total (n=3,283)	STEMI (n=2,262)	NSTEMI			P value of ANOVA*	P value for post hoc pairwise comparison
			NSTEMI (n=1,021)	NSTEMI+CK (n=563)	NSTEMI-CK (n=458)		(STEMI vs. NSTEMI)	(STEMI vs. NSTEMI+CK)	(STEMI vs. NSTEMI-CK)	(NSTEMI+CK vs. NSTEMI-CK)
Age (years)	69 (61–78)	68 (60–77)	72 (63–80)	71 (62–80)	73 (63–80)	<0.001	<0.001	<0.001	<0.001	0.26
Male	75.2%	76.8%	71.8%	72.3%	71.2%	0.008	0.002	0.026	0.011	0.69
Concomitant diseases
Hypertension	66.5%	63.4%	73.2%	70.3%	76.8%	<0.001	<0.001	0.002	<0.001	0.020
Diabetes	36.4%	35.0%	39.5%	39.8%	39.1%	0.046	0.014	0.033	0.098	0.81
Dyslipidemia	51.9%	49.9%	56.4%	53.9%	59.4%	<0.001	<0.001	0.094	<0.001	0.077
CKD	44.8%	41.9%	51.1%	50.1%	52.4%	<0.001	<0.001	<0.001	<0.001	0.46
Current smoking	34.0%	37.3%	26.9%	26.9%	26.9%	<0.001	<0.001	<0.001	<0.001	0.98
Previous history
Previous MI	12.1%	9.3%	18.4%	16.0%	21.2%	<0.001	<0.001	<0.001	<0.001	0.034
Previous PCI	15.3%	11.2%	24.4%	21.1%	28.3%	<0.001	<0.001	<0.001	<0.001	0.010
Previous CABG	2.9%	1.8%	5.3%	4.2%	6.6%	<0.001	<0.001	0.001	<0.001	0.087
Atrial fibrillation	6.0%	5.5%	7.2%	6.4%	8.2%	0.079	0.059	0.43	0.026	0.26
Stroke	11.3%	10.4%	13.4%	13.5%	13.3%	0.053	0.016	0.044	0.080	0.93
PAD	4.6%	3.2%	7.8%	7.5%	8.2%	<0.001	<0.001	<0.001	<0.001	0.69
Systolic blood pressure (mmHg)	138 (118–160)	135 (114–157)	144 (124–164)	140 (120–160)	150 (130–170)	<0.001	<0.001	0.001	<0.001	<0.001
Heart rate (beats/min)	77 (65–90)	77 (64–90)	78 (67–92)	80 (67–96)	77 (66–90)	<0.001	<0.001	<0.001	0.14	0.028
Killip classification						<0.001	<0.001	0.006	<0.001	<0.001
Class 1	75.6%	74.4%	78.3%	71.0%	87.1%
Class 2	9.3%	9.5%	8.8%	9.7%	7.7%
Class 3	5.4%	5.4%	6.3%	8.8%	3.3%
Class 4	9.7%	11.1%	6.6%	10.4%	2.0%
Time from onset to admission (min)	154 (70–390)	140 (66–334)	195 (79–546)	215 (84–513)	180 (75–557)	<0.001	<0.001	<0.001	<0.001	0.81
Type 2 MI	5.2%	3.0%	10.0%	7.0%	13.6%	<0.001	<0.001	<0.001	<0.001	<0.001
Urgent coronary angiography	93.1%	96.9%	84.7%	88.6%	79.9%	<0.001	<0.001	<0.001	<0.001	<0.001
Radial approach	32.1%	27.7%	43.0%	32.9%	56.7%	<0.001	<0.001	0.021	<0.001	<0.001
LAD as the infarct artery	44.5%	45.4%	42.4%	38.8%	47.6%	0.021	0.16	0.011	0.46	0.016
Initial TIMI 0/1 flow	60.4%	70.5%	34.7%	48.9%	14.9%	<0.001	<0.001	<0.001	<0.001	<0.001
Multivessel disease	43.7%	41.5%	49.1%	53.1%	43.7%	<0.001	<0.001	<0.001	0.43	0.006
Primary PCI	85.1%	93.1%	67.4%	72.6%	60.8%	<0.001	<0.001	<0.001	<0.001	<0.001
Door-to-balloon time (min)	75 (52–121)	66 (49–92)	137 (88–286)	125 (80–236)	171 (100–399)	<0.001	<0.001	<0.001	<0.001	<0.001
Stent use†	90.6%	90.7%	90.5%	89.3%	92.1%	0.45	0.87	0.40	0.42	0.21
DES use‡	63.2%	59.6%	74.3%	71.2%	78.9%	<0.001	<0.001	<0.001	<0.001	0.032
Final TIMI 3 flow	91.8%	91.0%	94.3%	92.1%	97.4%	<0.001	0.007	0.45	<0.001	0.004
Urgent CABG	2.0%	1.1%	4.2%	6.0%	2.0%	<0.001	<0.001	<0.001	0.11	0.001
Max CK (IU/L)	1,447 (518–3,178)	2,017 (927–3,848)	505 (181–1,237)	1,151 (702–2,076)	161 (101–254)	<0.001	<0.001	<0.001	<0.001	<0.001

Data given as % or median (25–75^th percentile). *ANOVA for STEMI, NSTEMI+CK and NSTEIM-CK; ^†among patients treated with primary PCI; ^‡among patients treated with stent. CABG, coronary artery bypass graft; CK, creatine kinase; CKD, chronic kidney disease; J-MINUET, Japanese Registry of Acute Myocardial Infarction Diagnosed by Universal Definition; LAD, left anterior descending artery; MI, myocardial infarction; NSTEMI, non-STEMI; PAD, peripheral arterial disease; PCI, percutaneous coronary intervention; STEMI, ST-segment elevation myocardial infarction; TIMI, Thrombolysis in Myocardial Infarction.

Figure 1.

Prevalence of ST-elevation myocardial infarction (STEMI), non- STEMI plus creatine kinase (NSTEMI+CK) and NSTEMI-CK.

Among patients with NSTEMI, CK was elevated more than twice the ULN in 563 patients (55.1%) (NSTEMI+CK). Patients without CK elevation (NSTEMI-CK), who had been formerly classified as having UA by the CK-based criteria, had more incidence of prior MI and took more cardiovascular medications before the index episode of MI. Patients with NSTEMI+CK had advanced Killip class, lower systolic pressure and higher heart rate on admission. Among 2,262 patients with STEMI, 241 (10.7%) did not have CK elevation.

Acute Coronary Intervention

Urgent CAG was performed in 93.0% of the patients: 96.9% for STEMI and 84.5% for NSTEMI. Patents with NSTEMI had less initial TIMI 0/1 flow and more cases of multivessel disease.

Primary percutaneous coronary intervention (PCI) was performed in 85.1% of the study patients: 93.1% for STEMI and 67.4% for NSTEMI (P<0.001). Door-to-balloon time was ≤90 min in 74.3% of patients with STEMI undergoing primary PCI. Coronary stenting was performed in the majority of patients. A drug-eluting stent (DES), mostly a new-generation DES, was more frequently used for NSTEMI than for STEMI patients, but more than half of the STEMI patients received a DES (Figure 2). Final TIMI 3 flow was obtained in more than 90% of the patients undergoing PCI.

Figure 2.

Type of stent used for ST-elevation myocardial infarction (STEMI) and NSTEMI cases. BES, biolimus-eluting stent; BMS, bare-metal stent; EES, everolimus-eluting stent; PES, paclitaxel-eluting stent; ZES, zotarolimus-eluting stent.

In-Hospital Outcomes

Table 2 shows the in-hospital clinical outcomes. Overall in-hospital mortality was 6.5%: 7.1% for STEMI and 5.1% for NSTEMI (P=0.027). Although in-hospital mortality was comparable between STEMI and NSTEMI+CK (7.1% vs. 7.8%, P=0.57), it was significantly lower in patients with NSTEMI-CK than STEMI or NSTEMI+CK (1.7%, P<0.001 for each) (Figure 3). The incidence of MACE during hospitalization was also comparable between the STEMI and NSETMI+CK patients, and was significantly lower in patients with NSTEMI-CK. In the patients with STEMI, CK elevation was associated with higher rates of mortality (7.7% vs. 2.5%, P=0.003) and MACE (21.5% vs. 10.4%, P<0.001).

Table 2. In-Hospital Clinical Outcomes of the Study Patients Enrolled in J-MINUET

	Total (n=3,283)	STEMI (n=2,262)	NSTEMI			P value of ANOVA*	P value for post hoc pairwise comparison
			NSTEMI (n=1,021)	NSTEMI+CK (n=563)	NSTEMI-CK (n=458)		(STEMI vs. NSTEMI)	(STEMI vs. NSTEMI+CK)	(STEMI vs. NSTEMI-CK)	(NSTEMI+CK vs. NSTEMI-CK)
All-cause mortality	6.5%	7.1%	5.1%	7.8%	1.7%	<0.001	0.029	0.57	<0.001	<0.001
MACE	18.9%	20.3%	15.7%	22.7%	7.0%	<0.001	0.002	0.20	<0.001	<0.001
Composite of MACE
Cardiac failure	15.2%	16.3%	12.9%	19.3%	5.0%	<0.001	0.013	0.084	<0.001	<0.001
VT/VF	3.9%	4.5%	2.4%	4.2%	0.2%	<0.001	0.004	0.72	<0.001	<0.001
Bleeding	2.4%	2.5%	2.3%	2.7%	1.8%	0.57	0.70	0.77	0.34	0.31

Data given as %. *ANOVA for STEMI, NSTEMI+CK and NSTEMI-CK. MACE, major adverse cardiac events; VF, ventricular fibrillation; VT, ventricular tachycardia. Other abbreviations as in Table 1.

Figure 3.

In-hospital mortality of patients with ST-elevation myocardial infarction (STEMI), non- STEMI plus creatine kinase (NSTEMI+CK) and NSTEMI-CK. There was no significant difference in in-hospital mortality between STEMI and NSTEMI+CK. NSTEMI-CK was associated with significantly lower in-hospital mortality than STEMI or NSTEMI+CK.

In the multivariate analysis, in-hospital mortality and MACE were comparable between the STEMI and NSTEMI+CK groups. NSTEMI-CK was associated with less mortality and MACE (Table 3).

Table 3. Odds Ratios of In-Hospital Clinical Outcomes of the Study Patients Enrolled in J-MINUET

	STEMI vs. NSTEMI	STEMI vs. NSTEMI+CK	STEMI vs. NSTEMI-CK	NSTEMI+CK vs. NSTEMI-CK
Univariate model
All-cause mortality	1.43 (1.30–1.57) P<0.001	0.90 (0.81–1.61) P=0.058	4.31 (3.47–5.35) P<0.001	4.77 (3.79–6.00) P<0.001
MACE	1.37 (1.29–1.45) P<0.001	0.87 (0.81–0.93) P<0.001	3.38 (3.03–5.35) P<0.001	3.92 (3.46–4.43) P<0.001
Age, sex adjusted model
All-cause mortality	1.66 (1.51–1.83) P<0.001	1.03 (0.92–1.14) P=0.65	5.26 (4.23–6.54) P<0.001	4.96 (3.94–6.25) P<0.001
MACE	1.51 (1.43–1.61) P<0.001	0.94 (0.87–1.00) P=0.057	3.88 (2.57–5.36) P<0.001	4.11(3.63–4.66) P<0.001
Multivariate model
All-cause mortality	1.37 (1.21–1.54) P<0.001	1.10 (0.97–1.25) P=0.15	3.63 (2.81–4.69) P<0.001	2.70 (2.06–3.53) P<0.001
MACE	1.64 (1.51–1.78) P<0.001	1.18 (1.08–1.30) P<0.001	3.53 (3.06–4.07) P<0.001	2.88 (2.47–3.36) P<0.001

Data given as odds ratio (95% confidence interval). Multivariate model; adjusted for age, sex, hypertension, diabetes, dyslipidemia, CKD, current smoking, previous MI, atrial fibrillation, stroke, systolic blood pressure, heart rate, Killip class, logarithm of time from onset to admission, primary PCI and urgent CABG. Abbreviations as in Tables 1,2.

Discussion

This study presents the clinical presentation, management and in-hospital outcomes of Japanese patients with AMI diagnosed by cTn-based criteria. The prevalence of STEMI was twice as high as that of NSTEMI, even with the new cTn-based criteria. There were marked disparities in the baseline characteristics and management, but in-hospital mortality was comparable between the STEMI and NSTEMI groups. CK was not elevated in approximately half of the NSTEMI patients who were formerly classified as UA by CK-based criteria. Of note, in-hospital outcomes of patients with NSTEMI-CK were far more favorable than those of the STEMI and NSTEMI+CK patients.

AMI is defined as acute myocardial cell death caused by prolonged ischemia. In the past, the World Health Organization (WHO) proposed clinical criteria that diagnosed AMI by a combination of 2 of 3 characteristics: symptoms, ECG abnormalities and cardiac enzymes. Although CK (CK-MB) has been the most reliable biomarker of myocardial necrosis, its sensitivity and specificity are not high enough to diagnose patients with a small amount of myocardial necrosis. cTn is a component of the thin filament of the sarcomere of striated muscle. cTnT and cTnI are cardiac myocyte-specific isoforms that detect very small amounts of myocardial necrosis. The universal definition was first announced in 2000 and revised as the 3rd universal definition in 2012. It recommended using cTn as the preferred biomarker for the diagnosis of AMI. A large number of patients formerly classified by CK-based criteria as having UA are now ruled-in by cTn as NSTEMI. The improvement of diagnostic sensitivity significantly affects the number of AMI diagnoses. In the USA, the incidence of STEMI progressively decreased from 1999 to 2008, while that of NSTEMI showed a transient increase from 2000 to 2004, mostly related to the introduction of the universal definition.² Therefore, in the current study, we focused on comparing NSTEMI+CK and NSTEMI-CK.

Recent studies from the USA consistently report that the prevalence of NSTEMI is higher than that of STEMI, ranging from 55% to 76%.^2,3,12–15 However, previous large registries from Japan used CK-based criteria and showed a steady trend of an increasing incidence for AMI and higher prevalence of STEMI than NSTEMI.^6,7,16,17 In the Japanese Acute Coronary Syndrome Study (JACSS) that registered 5,325 consecutive patients with AMI between 2001 and 2003, the proportion of STEMI was 88%.⁶ The Prevention of AtherothrombotiC Incidents Following Ischemic Coronary attack (PACIFIC) study enrolled 3,597 patients between 2008 and 2009, and the proportions of STEMI, NSTEMI and UA were 59.4%, 10.4% and 30.2%, respectively;⁷ after exclusion of UA, the prevalence of STEMI was 85%. In the current study, the prevalence of STEMI was 68.9% and, after exclusion of NSTEMI-CK, it was 80%. The proportion of STEMI cases seemed to decrease progressively over the past 10 years in Japan. However, the prevalence of STEMI was still more than twice as high as that of NSTEMI in Japan.

Consistent with earlier studies, there were substantial disparities in the backgrounds of the STEMI patients and NSTEMI patients: STEMI was associated with younger age, more males and current smokers, and less history of hypertension, diabetes and dyslipidemia. Studies using intracoronary imaging have reported that plaque erosion at sites of negative remodeling and calcified plaque are more common in elderly patients, especially those with NSTEMI, whereas the culprit lesions in younger patients with STEMI are characterized by rupture of plaque containing more thrombus.^18,19 The higher prevalence of chronic treatment with aspirin and/or statins may also contribute to the higher frequency of NSTEMI.

Primary PCI was performed in 93.1% of STEMI and 67.4% of NSTEMI patients. Of note, DES were used in more than half of the STEMI patients. DES were first introduced to Japan in 2004, but not formally permitted for STEMI. DES was unavailable at the time of JACSS and used only in 21% of cases in PACIFIC where first-generation DES were mostly used. After that, new-generation DES were introduced and numerous studies have accumulated evidence about the safety and efficacy of DES for STEMI.²⁰ Both the ACC and AHA updated their guidelines in 2009 and stated that it is reasonable to use DES as an alternative to bare-metal stents for primary PCI in STEMI patients.²¹ The Japanese Circulation Society updated its guidelines in 2013. Although there is no recommendation on the use of DES for STEMI, it notes that DES may be considered for STEMI patients or for lesions with a high risk of restenosis.²² DES use for STEMI has rapidly increased over the past 5 years in Japan.

Reflecting more comorbid factors, previous studies consistently reported that NSTEMI is associated with worse long-term prognosis. However, there are inconsistent results about short-term outcomes.^12,13 One possible explanation for these inconsistent findings is disparities in the inclusion criteria for NSTEMI. Previous studies have shown that elevation of cTn is associated with worse outcomes in patients with acute coronary syndrome (ACS) who derive large clinical benefits from aggressive treatment.^23,24 However, it remains unclear whether we could deal with NSTEMI-CK as equivalent to NSTEMI+CK. In a single-center study at Nippon Medical College, 973 ACS patients were evaluated with both CK and cTn measurements.²⁵ Among patients with cTn elevation, lack of CK elevation was associated with a favorable outcome. In the current study, we also showed that patients with NSTEMI-CK had far more favorable outcomes than those with STEMI or NSTEMI+CK.

J-MINUET is the first large-scale multicenter registry of AMI diagnosed by cTn-based criteria in Japan. One of the unique features of this registry is that it permitted us to compare the clinical presentation, management and outcomes of NSTEMI+CK and NSTEMI-CK patients. Nearly half of the patients who were diagnosed as having NSTEMI by cTn-based criteria did not have elevation of CK. By the former CK-based criteria, they were classified as UA and excluded from the NSTEMI classification. There were appreciable disparities in clinical presentation between NSTEMI+CK and NSTEMI-CK patients. Although the use of primary PCI was less frequent, in-hospital outcomes were far more favorable for patients with NSTEMI-CK than NSTEMI+CK. Previous studies have shown that cTn-positive ACS patients derive more benefit from early invasive treatment than cTn-negative ACS patients. It is reasonable to use cTn for risk stratification of ACS at the emergency care level. However, we should be aware of the difference between AMI diagnosed by CK-based criteria and AMI diagnosed by cTn-based criteria when using the universal definition for the final diagnosis of AMI.

Study Limitations

This study has several limitations. We only included patients who were admitted to the participating institutions within 48 h of symptom onset. Other patients with NSTEMI who came to hospital after 48 h might have been excluded from this study. This is not a population-based study. Participating institutions are regional core centers capable of advanced medical management. There might have been selection bias for enrolled patients. In addition, data were obtained only during the index episode of hospitalization. A follow-up study should be contemplated.

Acknowledgments

This study was supported by the Intramural Research Fund, grant number 23-4-5, for Cardiovascular Diseases of the National Cerebral and Cardiovascular Center.

The authors thank all the enrolled patients, participating cardiologists, medical and other staffs who have contributed to this study. The J-MINUET investigators are listed in Appendix.

Appendix

J-MINUET Investigators

Masaharu Ishihara, Hyogo College of Medicine; Hisao Ogawa, National Cerebral and Cardiovascular Center, Kumamoto University Graduate School of Medical Sciences; Nobuaki Kokubu, Sapporo Medical University; Tadaya Sato, Akita Medical Center; Teruo Inoue, Dokkyo Medical University; Shigeru Oshima, Gunma Prefectural Cardiovascular Center; Hiroshi Funayama, Saitama Medical Center Jichi Medical University; Ken Kozuma, Hiroyuki Kyono, Teikyo University; Wataru Shimizu, Nippon Medical School; Satoru Suwa, Juntendo University Shizuoka Hospital; Kengo Tanabe, Mitsui Memorial Hospital; Tetsuya Tobaru, Sakakibara Heart Institute; Kazuo Kimura, Yokohama City University Medical Center; Junya Ako, Kitasato University; Mafumi Owa, Suwa Red Cross Hospital; Takahito Sone, Ogaki Municipal Hospital; Yukio Ozaki, Fujita Health University; Satoshi Yasuda, Teruo Noguchi, Masashi Fujino, Yoshihiro Miyamoto, Kunihiko Nishimura, National Cerebral and Cardiovascular Center; Junichi Kotani, Osaka University Graduate School of Medicine; Takashi Morita, Osaka General Medical Center; Atsunori Okamura, Sakurabashi Watanabe Hospital; Yoshihiko Saito, Nara Medical University; Masaaki Uematsu, Kansai Rosai Hospital; Hiroyuki Okura, Kawasaki Medical School; Atsushi Hirohata, The Sakakibara Heart Institute of Okayama; Yasuharu Nakama, Hiroshima City Hospital; Keijiro Saku, Fukuoka University School of Medicine; Seiji Hokimoto, Kumamoto University Graduate School of Medical Sciences; Koichi Nakao, Saiseikai Kumamoto Hospital; Kazuteru Fujimoto, National Hospital Organization Kumamoto Medical Center; Yoshisato Shibata, Miyazaki Medical Association Hospital; Kazuhito Hirata, Okinawa Prefectural Chubu Hospital.

References

• 1.    Rosamond  WD,  Chambless  LE,  Heiss  G,  Mosley  TH,  Coresh  J,  Whitsel  E, et al. Twenty-two-year trends in incidence of myocardial infarction, coronary heart disease mortality, and case fatality in 4 US communities, 1987–2008. Circulation 2012; 125: 1848–1857.
• 2.    Yeh  RW,  Sidney  S,  Chandra  M,  Sorel  M,  Selby  JV,  Go  AS. Population trends in the incidence and outcomes of acute myocardial infarction. N Engl J Med 2010; 362: 2155–2165.
• 3.    Roger  VL,  Weston  SA,  Gerber  Y,  Killian  JM,  Dunlay  SM,  Jaffe  AS, et al. Trends in incidence, severity, and outcome of hospitalized myocardial infarction. Circulation 2010; 121: 863–869.
• 4.   The Joint European Society of Cardiology/American College of Cardiology Committee. Myocardial infarction redefined-A consensus document of the Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. J Am Coll Cardiol 2000; 36: 959–969.
• 5.    Mueller  M,  Vafaie  M,  Biener  M,  Giannitsis  E,  Katus  HA. Cardiac troponin T: From diagnosis of myocardial infarction to cardiovascular risk prediction. Circ J 2013; 77: 1653–1661.
• 6.    Ogawa  H,  Kojima  S. Modern state of acute myocardial infarction in the interventional era: Observational case-control study-Japanese acute coronary syndrome study (JACSS). J Cardiol 2009; 54: 1–9.
• 7.    Daida  H,  Miyauchi  K,  Ogawa  H,  Yokoi  H,  Matsumoto  M,  Kitakaze  M, et al. Management and 2-year long-term clinical outcome of acute coronary syndrome in Japan: Prevention of atherothrombotic incidents following ischemic coronary attack (PACIFIC) registry. Circ J 2013; 77: 934–943.
• 8.    Thygesen  K,  Alpert  JS,  Jaffe  AS,  Simoons  ML,  Chaitman  BR,  White  HD, et al. Third universal definition of myocardial infarction. J Am Coll Cardiol 2012; 60: 1581–1598.
• 9.    O’Gara  PT,  Kushner  FG,  Ascheim  DD,  Casey  DE Jr,  Chung  MK,  de Lemos  JA, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013; 61: e78–e140, doi:10.1016/j.jacc.2012.11.019.
• 10.    Little  RJA,  Rubin  DB. Likelihood-based approaches to the analysis of missing data: Applications to some common models. In: Statistical analysis with missing data, 2nd edn. New Jersey: Wiley-InterScience 2002; 65–83.
• 11.    Rubin  DB. Inference and missing data. Biometrika 1972; 63: 581–592.
• 12.    Rogers  WJ,  Frederick  PD,  Stoehr  E,  Canto  JG,  Ornato  JP,  Gibson  CM, et al. Trends in presenting characteristics and hospital mortality among patients with ST elevation and non-ST elevation myocardial infarction in the National Registry of Myocardial Infarction from 1990 to 2006. Am Heart J 2008; 156: 1026–1034.
• 13.    McManus  DD,  Gore  J,  Yarzebski  J,  Spencer  F,  Lessard  D,  Goldberg  RJ. Recent trends in the incidence, treatment, and outcomes of patients with STEMI and NSTEMI. Am J Med 2011; 124: 40–47.
• 14.    Song  YB,  Hahn  JY,  Kim  JH,  Lee  SY,  Choi  SH,  Choi  JH, et al. Comparison of angiographic and other findings and mortality in non-ST-segment elevation versus ST-segment elevation myocardial infarction in patients undergoing early invasive intervention. J Cardiol 2010; 106: 1397–1403.
• 15.    Abbott  JD,  Ahmed  HN,  Vlachos  HA,  Selzer  F,  Williams  DO. Comparison of outcome in patients with ST-elevation versus non-ST-elevation acute myocardial infarction treated with percutaneous coronary intervention (from the National Heart, Lung, and Blood Institute Dynamic Registry). Am J Cardiol 2007; 100: 190–195.
• 16.    Takii  T,  Yasuda  S,  Takahashi  J,  Ito  K,  Shiba  N,  Shirato  K, et al. Trends in acute myocardial infarction incidence and mortality over 30 years in Japan: Report from the MIYAGI-AMI Registry Study. Circ J 2010; 74: 93–100.
• 17.    Hata  J,  Ninomiya  T,  Hirakawa  Y,  Nagata  M,  Mukai  N,  Gotoh  S, et al. Secular trends in cardiovascular disease and its risk factors in Japanese: Half-century data from the Hisayama Study (1961–2009). Circulation 2013; 128: 1198–1205.
• 18.    Hassani  SE,  Mintz  GS,  Fong  HS,  Kim  SW,  Xue  Z,  Pichard  AD, et al. Negative remodeling and calcified plaque in octogenarians with acute myocardial infarction: An intravascular ultrasound analysis. J Am Coll Cardiol 2006; 47: 2413–2419.
• 19.    Jia  H,  Abtahian  F,  Aguirre  AD,  Lee  S,  Chia  S,  Lowe  H, et al. In vivo diagnosis of plaque erosion and calcified nodule in patients with acute coronary syndrome by intravascular optical coherence tomography. J Am Coll Cardiol 2013; 62: 1748–1758.
• 20.    Palmerini  T,  Biondi-Zoccai  G,  Della Riva  D,  Stettler  C,  Sangiorgi  D,  D’Ascenzo  F, et al. Stent thrombosis with drug-eluting and bare-metal stents: Evidence from a comprehensive network meta-analysis. Lancet 2012; 379: 1393–1402.
• 21.    Kushner  FG,  Hand  M,  Smith  SC Jr,  King  SB 3rd,  Anderson  JL,  Antman  EM, et al. 2009 focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update): A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2009; 54: 2205–2241.
• 22.   Japanese Circulation Society. Guidelines for Diagnosis and Treatment of Cardiovascular Diseases (2012 Joint Working Groups Report). Guidelines for the management of patients with ST-elevation acute myocardial infarction (JCS 2013). http://www.j-circ.or.jp/guideline/pdf/JCS2013_kimura_h.pdf (in Japanese) (accessed February 20, 2015).
• 23.    Morrow  DA,  Cannon  CP,  Rifai  N,  Frey  MJ,  Vicari  R,  Lakkis  N, et al. Ability of minor elevations of troponins I and T to predict benefit from an early invasive strategy in patients with UA and non-ST elevation myocardial infarction: Results from a randomized trial. JAMA 2001; 286: 2405–2412.
• 24.    Kastrati  A,  Mehilli  J,  Neumann  FJ,  Dotzer  F,  ten Berg  J,  Bollwein  H, et al. Abciximab in patients with acute coronary syndromes undergoing percutaneous coronary intervention after clopidogrel pretreatment: The ISAR-REACT 2 randomized trial. JAMA 2006; 295: 1531–1538.
• 25.    Yamamoto  T,  Yasutake  M,  Takagi  H,  Akutsu  K,  Fujita  N,  Kasagami  Y, et al. Impact of the revised criteria for acute myocardial infarction using cardiac troponins in a Japanese population with acute coronary syndromes. Circ J 2005; 69: 774–779.