docling/tests/data/groundtruth/docling_v2/1349-7235-63-2595.nxml.md

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An In-depth Single-center Retrospective Assessment of In-hospital Outcomes in Acute Myocardial Infarction Patients with and without Diabetes

Sho Hitomi; Division of Cardiology, Department of Internal Medicine, Iwate Medical University, Japan; Yorihiko Koeda; Division of Cardiology, Department of Internal Medicine, Iwate Medical University, Japan; Kengo Tosaka; Division of Cardiology, Department of Internal Medicine, Iwate Medical University, Japan; Nozomu Kanehama; Division of Cardiology, Department of Internal Medicine, Iwate Medical University, Japan; Masanobu Niiyama; Department of Cardiology, Japanese Red Cross Hachinohe Hospital, Japan; Masaru Ishida; Division of Cardiology, Department of Internal Medicine, Iwate Medical University, Japan; Tomonori Itoh; Division of Cardiology, Department of Internal Medicine, Iwate Medical University, Japan; Yoshihiro Morino; Division of Cardiology, Department of Internal Medicine, Iwate Medical University, Japan

Objective This study examined variations in in-hospital mortality causes and identified independent mortality predictors among patients with acute myocardial infarction (AMI) with and without diabetes mellitus (DM). Methods We examined factors influencing in-hospital mortality in a single-center retrospective observational study. Separate multivariate analyses were conducted for both groups to identify independent predictors of in-hospital mortality. Patients This study included consecutive patients admitted to Iwate Medical University Hospital between January 2012 and December 2017 with a diagnosis of AMI. Results Of 1,140 patients meeting the AMI criteria (average age: 68.2±12.8 years old, 75% men), 408 (35.8%) had diabetes. The DM group had a 1.87-times higher 30-day mortality rate, a lower prevalence of ST-elevated MI (56.6% vs. 65.3% in non-DM, p=0.004), and more frequent non-cardiac causes of death (32% vs. 14% in non-DM, p=0.046) than the non-DM group. Independent predictors of in-hospital mortality in both groups were cardiogenic shock (CS) [DM: hazard ratio (HR) 6.59, 95% confidence interval (CI) 2.90-14.95; non-DM: HR 4.42, 95% CI 1.99-9.77] and renal dysfunction (DM: HR 5.64, 95% CI 1.59-20.04; non-DM: HR 5.92, 95% CI 1.79-19.53). Among patients with DM, a history of stroke was an additional independent predictor of in-hospital mortality (HR 2.59, 95% CI 1.07-6.31). Conclusion Notable disparities were identified in the causes of death and predictive factors of mortality between these two groups of patients with AMI. To further improve AMI outcomes, individualized management and prioritizing non-cardiac comorbidities during hospitalization may be crucial, particularly in patients with DM.

Introduction

Diabetes mellitus (DM) is widely recognized as being associated with poor clinical scenarios across various facets of ischemic heart disease. Indeed, it is a significant risk factor for coronary disease. Furthermore, atherosclerotic changes in coronary arteries tend to exhibit a more extensive distribution in individuals with DM than in those without DM. Following revascularization, a higher occurrence of restenosis or major adverse clinical events is expected in patients with DM than in those without DM during the follow-up period. Drug-eluting stents have also been employed in such cases (1).

Acute myocardial infarction (AMI) has remained a significant contributor to mortality worldwide. Based on an observational multicenter registry in Japan, 36.4% of AMI patients were found to have DM as a comorbidity (2).

With the widespread adoption of primary coronary intervention (PCI), AMI mortality has substantially declined. The current nationwide registry database in Japan has indicated that the mortality rate could be reduced to less than 3% if AMI patients were to receive primary PCI (3). However, a German study that compared outcomes between 2005 and 2021 highlighted that the rates of in-hospital death remained significantly higher in myocardial infarction (MI) patients with DM than in those without DM, despite an overall reduction in in-hospital mortality (4). Even with the contemporary utilization of primary PCI, patients with DM still experience higher in-hospital mortality than those without DM (5), and the long-term prognosis has also been observed to be worse within this population (6).

Study population

The study population comprised patients admitted to Iwate Medical University Hospital between January 2012 and December 2017 due to AMI, specifically those who met the criteria outlined in the 3rd universal definition of MI (7).

AMI was diagnosed based on the evidence of myocardial necrosis in patients with acute myocardial ischemia in a clinical setting. The criteria for detection included the presence of a rise and/or fall in cardiac biomarker values, with at least one value exceeding the 99th percentile upper reference limit. In addition, at least one of the following conditions had to be met: 1) symptoms of ischemia; 2) new or presumed new significant ST-segment-T wave changes or new left bundle branch block; 3) development of a pathological Q wave on an electrocardiogram (ECG); 4) imaging evidence of new loss of viable myocardium or new regional wall motion abnormality; and 5) identification of an intracoronary thrombus by angiography or autopsy. Furthermore, in accordance with the classification of MI (types 1 to 5) as defined by the 3rd universal definition (7), the patients were classified as either type 1, spontaneous MI; type 2, MI secondary to an ischemia imbalance; or MI resulting in death when biomarker values were unavailable.

Definition

The definition of each parameter used in this study was established by referring to previous studies that are widely regarded as representative in the field. Hypertension was defined (in accordance with the ACC/AHA Stage 2 hypertension guidelines) as a systolic blood pressure of ≥140 mmHg, a diastolic blood pressure of ≥90 mmHg upon admission, or the use of antihypertensive medication (8). Diabetes was defined as a blood sugar level ≥200 mg/dL upon admission, an HbA1c level of ≥6.5%, or the administration of diabetes medication (9). For cases that did not meet this definition, fasting blood sugar, daily blood sugar fluctuation, and glucose tolerance tests were not conducted. Dyslipidemia was defined in line with the guidelines in Japan as low-density lipoprotein (LDL)-cholesterol ≥140 mg/dL or high-density lipoprotein (HDL)-cholesterol <40 mg/dL (10) and included a total cholesterol level of ≥240 mg/dL or the administration of lipid-lowering drugs. A history of ischemic heart disease was defined as a history of AMI or revascularization (PCI or CABG). A current smoking habit was defined as smoking within the year prior to admission. A history of stroke was defined as any past stroke that required hospitalization, including cerebral infarction and intracranial hemorrhaging. Consequently, incidental asymptomatic lacunar infarctions identified on imaging were excluded. Atrial fibrillation was defined as any history of treatment, regardless of whether it was chronic or paroxysmal, or any evidence of atrial fibrillation found on previous Holter monitoring or a 12-lead ECG. Cases of transient paroxysmal atrial fibrillation observed during hospitalization without a previous record were not included. However, those with consistent atrial fibrillation waveforms upon admission, even without prior records, were included. Obesity was defined as a body mass index (BMI) ≥25.0 kg/m2 or higher upon admission (11). Renal dysfunction was defined as an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m2 upon admission (12) or dialysis.

Patient and clinical characteristics

The participants were stratified into two groups based on the presence of DM. Table 1 shows a comparison of the baseline clinical characteristics between the DM and non-DM groups. The DM group had a significantly higher BMI and a higher prevalence of hyperlipidemia than the non-DM group. In contrast, a current smoking habit and hypertension were significantly more prevalent in the non-DM group than in the DM group. Regarding the history of major vascular diseases, a history of coronary artery disease or stroke was significantly more frequent in the DM group than in the non-DM group. Importantly, the frequency of cardiac arrest on admission was significantly higher in the DM group than in the non-DM group, despite no apparent differences in systolic and diastolic blood pressure values on admission between the two groups.

Patient management and overall in-hospital outcomes

A detailed comparison of the patient management strategies is presented in Table 2. In the DM group, emergent coronary angiography and PCI were performed significantly less frequently than in the non-DM group. In addition, the prevalence of lesions involving the left main coronary artery was significantly higher in the DM group than in the non-DM group. Furthermore, patients in the DM group underwent CABG significantly more frequently than in the non-DM group.

Regarding mechanical support, patients in the DM group received significantly more frequent treatments with mechanical ventilation, intra-aortic balloon pump, and veno-atrial extracorporeal membrane oxygenation than in the non-DM group. As a result, in-hospital mortality was significantly higher and the length of hospital stay significantly longer in the DM group than in the non-DM group. The Kaplan-Meier survival curve of in-hospital mortality (within 30 days after admission), illustrated in Fig. 1, shows a significant difference between the two groups. The HR for in-hospital mortality in the DM group was 1.87 (95% confidence interval: 1.19-2.93, p=0.007).

An in-depth analysis of the causes of in-hospital deaths and predictive factors

The in-hospital mortality rate of the 1,140 patients included in this study was 6.6%. A comparison of the causes of in-hospital death between the two groups is shown in Fig. 2. Nearly half of the causes were attributed to cardiogenic shock (CS) in both groups. However, the remaining causes of death appeared to differ between the two groups, particularly in terms of mechanical complications, infection, and malignant disease. When comparing the causes of death, a higher proportion of non-cardiac deaths (including infections, malignancies, strokes, and multiple organ failures) were observed in the DM group than in the non-DM group (32% vs. 14%, p=0.046, respectively). Deaths due to mechanical complications were more frequent in the non-DM group than in the DM group; however, the difference was not statistically significant (DM: 16% vs. non-DM: 32%, p=0.119). When examining the relationship between the timing of death and its causes, it was found that, for both groups, the majority of deaths until the third clinical day were predominantly due to CS or mechanical complications. However, regarding the causes of death after the tenth clinical day, in the DM group, the proportion of deaths attributed to CS or mechanical complications was <30%, with a greater number of patients dying from other causes, such as lethal arrhythmias, cerebral infarction, infections, and malignancies. In contrast, in the non-DM group, the proportion of patients dying from CS or mechanical complications remained high (65%).

Factors potentially associated with in-hospital mortality were individually compared between those who survived and those who died in both the DM and non-DM groups (Table 3). In the DM group, statistically significant differences were observed in the age, hypertension, current smoking habit, history of stroke, Killip status, ejection fraction on admission, renal dysfunction (eGFR <60 mL/min/1.73 m2), and serum BNP levels between the survival and in-hospital death subgroups. However, these factors showed slight variation in the non-DM group. Interestingly, the sex, history of atrial fibrillation, and ST elevation were also found to be significantly different factors in the non-DM group. Notably, in the non-DM group, a history of stroke no longer had a significant impact on in-hospital death when comparing the surviving and deceased patients.

The predictors of in-hospital mortality for both the DM and non-DM groups were analyzed separately using univariate analyses, and the results are shown in Table 4. Any factors found to be statistically significant in the univariate analyses in either group were included in the Cox's proportional hazards model to identify independent predictors of in-hospital death, as shown in Table 5. Consequently, CS, renal dysfunction, and a history of stroke independently predicted in-hospital mortality in the DM group. Conversely, CS and renal dysfunction were independent predictors of in-hospital mortality in the non-DM group. Furthermore, in the non-DM group, patients who underwent revascularization (emergency PCI or CABG) had a lower risk of in-hospital mortality than those who did not, but this difference was not statistically significant in the DM group. An interaction test for in-hospital death using a two-way analysis of variance showed that there was an interaction between “DM” and “a history of stroke” (p=0.006).

Discussion

In Japan, there is a limited amount of research regarding predictors of in-hospital mortality for AMI based on the presence or absence of DM or differences in the specific causes of death. Although we have conducted large-scale studies related to AMI in Japan, such as the JROAD registry (13) and the J-PCI Registry (3), these registry surveys are limited in terms of available parameters, and it is speculated that they may not be suitable for in-depth research analyses.

Although previous studies have documented an adverse prognosis in AMI patients with comorbid diabetes mellitus (5,14,15), our study adds clarity by demonstrating a substantial impact on mortality. Notably, we identified an HR of 1.87 for mortality, even in a cohort in which nearly 85% of the patients underwent invasive strategies. Cardiovascular deaths (including those due to CS, mechanical complications, and lethal arrhythmias) accounted for nearly 85% of in-hospital fatalities in the non-DM group. Conversely, they constituted only 68% of in-hospital deaths in the DM group, signifying a higher prevalence of noncardiovascular causes of mortality in this population. Infections, strokes, and malignancies have emerged as direct causes of death in this subgroup. Considering the systemic nature of disorders in patients with DM, these results are not surprising, but they underscore the importance of comprehensive care or systemic management for this population to further improve survival rates.

In the DM group, we observed a higher prevalence of an advanced Killip status upon admission and a greater frequency of mechanical cardiac support devices than in the non-DM group. Consequently, the patients' conditions tended to deteriorate further from the time of admission than in the non-DM group. Nevertheless, the DM group exhibited lower actual rates of both coronary angiography and revascularization than the non-DM group, similar to a previous report (16). The lower frequency of ST-elevation MI and an increased possibility of asymptomatic patients, concerns related to an impaired renal function, as well as the use of contrast agents may partially explain the lower rate of emergent angiography. The higher frequency of left main coronary artery involvement in the DM group than in the non-DM group led to the reduced use of PCI and increased use of CABG. These factors are hypothesized to not only influence the lower frequency of revascularization procedures but also explain the divergent prognostic outcomes of these procedures between the DM and non-DM groups.

CS continues to be a significant factor influencing mortality in patients with AMI, as supported by numerous previous studies (17-19). However, our findings revealed that there was no marked difference in the in-hospital mortality between DM and non-DM patients with CS, consistent with a previous study (20). Because the management of CS remains a paramount concern in both groups, alternative approaches, such as the utilization of left ventricle unloading devices (21,22) or intracoronary supersaturated oxygen therapy (23), should be explored to enhance the outcomes of patients experiencing CS.

Study limitations

Several limitations associated with the present study warrant mention. In this study, diabetes was defined according to criteria established from prior AMI research and existing literature. Intraday glucose variability and oral glucose tolerance tests were not performed, potentially leading to some cases of diabetes or impaired glucose tolerance being categorized as nondiabetic. This limitation was inherent to this study. Furthermore, despite the availability of the latest 4th version of the universal definition (24), we chose to apply the 3rd version of the universal definition (7) in this study. This decision was made because the 3rd definition was used during the recruitment period. However, it is important to acknowledge that the composition of the enrolled patient population may not have substantially differed; therefore, we employed the 3rd universal definition (25). Finally, the door-to-balloon time is a well-established mortality parameter in AMI patients (26). However, our study had a substantial proportion of NSTEMI patients (approximately 40%); therefore, we did not include this parameter in our analysis.

Tables

Table 1. A Comparison of Baseline Clinical Characteristics between the DM or Non-DM Groups.

Variables Total (n=1140) DM (n=408) Non-DM (n=732) p value
Age (years) 68.2±12.8 68.3±12.1 68.0±13.1 0.977
Sex (male) 76.0% 74.8% 76.6% 0.475
BMI (kg/m2) 24.4±4.0 25.0±4.2 24.0±3.8 <0.001
Obesity (BMI≥25) 38.1% 45.6% 34.6% <0.001
DM 35.8% 100% 0
Hypertension 69.9% 78.7% 64.9% <0.001
Dyslipidemia 51.3% 62.8% 44.8% <0.001
Current smoker 34.9% 34.4% 35.2% 0.784
History of CAD 13.5% 21.4% 9.0% <0.001
History of stroke 11.5% 15.3% 9.4% 0.005
History of atrial fibrillation 7.9% 9.1% 7.2% 0.266
CPA on admission 5.3% 7.2% 4.2% 0.029
Systolic BP on admission (mmHg) 145±34 144±34 145±34 0.517
Diastolic BP on admission (mmHg) 85±21 83±21 86±22 0.027
HR on admission (bpm) 81±19 82±20 81±19 0.105
STEMI 62.2% 56.6% 65.3% 0.004
Killip I-IV (%) 71.6/14.3/5.5/8.6 64.2/16.3/7.9/11.6 75.8/13.1/4.1/6.9 <0.001
LVEF (%) 51.4±19.7 49.6±28.9 52.3±11.6 <0.001
Serum creatinine (mg/dL) 1.24±1.65 1.57±2.12 1.06±1.29 0.008
eGFR (mL/min/1.73 m2) 68.0±28.5 64.3±33.0 70.1±25.5 0.003
Renal dysfuncti on (eGFR<60) 36.9% 44.4% 32.8% <0.001
Hemodialysis or CAPD 4.4% 8.1% 2.3% <0.001
Blood glucose (mg/dL) 163±78 207±97 140±50 <0.001
Hemoglobin A1c (%) 6.1±1.5 7.1±1.5 5.6±0.5 <0.001
Triglyceride (mg/dL) 127±111 138±146 120±84 0.002
Total cholesterol (mg/dL) 186±45 179±49 189±42 <0.001
LDL-cholesterol (mg/dL) 115±37 109±37 119±37 <0.001
HDL-cholesterol (mg/dL) 47±14 45±15 48±14 <0.001
L/H ratio 2.6±1.0 2.5±1.0 2.6±1.0 0.144
Brain natriuretic peptide (pg/mL) 381±800 511±975 308±673 0.001

Table 2. A Comparison of Patient Management between the Two Groups.

Variables Total (n=1,140) DM (n=408) Non-DM (n=732) p value
Emergency coronary angiography 87.8% 84.2% 89.7% 0.007
Lesion of left main trunk 9.7% 13.9% 7.3% 0.001
Multivessel coronary artery disease 59.6% 71.4% 53.0% <0.001
Emergency PCI 78.4% 73.8% 81.0% 0.004
Slow-flow or no-reflow post PCI 14.2% 16.1% 13.1% 0.203
Coronary artery bypass grafting 9.2% 12.3% 7.5% 0.008
Respirator 10.5% 14.2% 8.5% 0.004
Intra-aortic balloon pumping 11.4% 16.7% 8.4% <0.001
VA-ECMO 2.0% 3.3% 1.3% 0.023
Peak creatine kinase (IU/L) 2,198±2,758 2,073±2,850 2,269±2,705 0.003
Hospitalization days 19±48 20±22 18±57 0.002
In-hospital mortality 6.6% 9.3% 5.1% 0.005

Table 3. Comparisons of Clinical Characteristics between AMI Patients Who Survived and Those Who Died from Both the DM and Non-DM Groups.

Variables DM (n=408) DM (n=408) DM (n=408) DM (n=408) DM (n=408) Non-DM (n=732) Non-DM (n=732) Non-DM (n=732) Non-DM (n=732) Non-DM (n=732)
Variables Survivors (n=370) In-hospital death (n=38) p value Survivors (n=695) In-hospital death (n=37) p value
Age (years) 67.9±12.3 72.8±9.6 0.025 67.6±13.0 75.7±12.7 <0.001
Sex (male) 74.3% 78.9% 0.532 77.6% 59.5% 0.011
Obesity (BMI≥25) 46.1% 40.5% 0.520 35.1% 24.2% 0.199
Hypertension 80.3% 63.2% 0.014 64.0% 82.9% 0.022
Dyslipidemia 63.3% 57.9% 0.510 45.1% 40.0% 0.556
Current smoker 35.9% 14.3% 0.020 36.1% 14.3% 0.018
History of CAD 21.9% 16.2% 0.422 8.7% 14.3% 0.263
History of stroke 13.8% 28.6% 0.022 9.7% 3.2% 0.227
History of atrial fibrillation 8.4% 15.8% 0.130 6.1% 27.8% <0.001
Cardiogenic shock (Killip IV) 6.5% 62.2% <0.001 4.5% 52.8% <0.001
STEMI 55.4% 68.4% 0.123 64.2% 86.1% 0.007
LVEF (%) 49.5±12.0 50.8±89.3 <0.001 52.7±11.4 44.2±13.8 <0.001
Blood glucose (mg/dL) 200±88 282±149 0.001 128±27 133±47 0.252
Renal dysfunction (eGFR<60) 40.5% 81.6% <0.001 39.6% 84.8% <0.001
Brain natriuretic peptide (pg/mL) 463.6±935.3 972.4±1225.5 <0.001 279.8±625.9 834.9±1146.0 <0.001
Revascularization (emergency PCI or CABG) 82.7% 73.7% 0.169 86.3% 62.2% <0.001
- Emergency PCI 74.1% 71.1% 0.689 82.4% 54.1% <0.001
- CABG 13.2% 2.6% 0.057 7.3% 10.8% 0.435

Table 4. Univariate Analyses for In-hospital Death.

Variables DM (n=408) DM (n=408) DM (n=408) DM (n=408) DM (n=408) Non-DM (n=732) Non-DM (n=732) Non-DM (n=732) Non-DM (n=732) Non-DM (n=732)
Variables HR 95%CI p value HR 95%CI p value
Age (years) 1.03 (0.99-1.06) 0.061 1.05 (1.02-1.08) 0.002
Sex (female) 0.77 (0.35-1.69) 0.517 2.10 (1.09-4.06) 0.028
Hypertension 0.45 (0.23-0.87) 0.017 2.45 (1.02-5.91) 0.046
History of stroke 1.90 (0.91-3.97) 0.087 0.26 (0.36-1.93) 0.263
History of atrial fibrillation 1.90 (0.79-4.58) 0.15 4.07 (1.93-8.55) <0.001
Cardiogenic shock (Killip IV) 8.84 (4.49-17.41) <0.001 10.82 (5.48-21.38) <0.001
STEMI 1.79 (0.90-3.57) 0.098 2.96 (1.15-7.63) 0.025
LVEF (%) 1.00 (0.99-1.01) 0.19 0.96 (0.94-0.99) 0.002
Renal dysfunction (eGFR<60) 4.30 (1.89-9.86) <0.001 11.32 (4.39-29.20) <0.001
Revascularization (emergency PCI or CABG) 0.61 (0.30-1.25) 0.178 0.23 (0.12-0.45) <0.001

Table 5. Multivariate Analyses for In-hospital Death.

Variables DM (n=408) DM (n=408) DM (n=408) DM (n=408) DM (n=408) Non-DM (n=732) Non-DM (n=732) Non-DM (n=732) Non-DM (n=732) Non-DM (n=732)
Variables HR 95%CI p value HR 95%CI p value
Age (years) 0.99 (0.95-1.03) 0.497 1.01 (0.96-1.04) 0.980
Sex (female) 0.78 (0.26-2.38) 0.668 1.40 (0.63-3.01) 0.406
Hypertension 0.81 (0.34-1.93) 0.634 1.38 (0.53-3.58) 0.506
History of stroke 2.59 (1.07-6.31) 0.036 0.34 (0.045-2.61) 0.302
History of atrial fibrillation 1.60 (0.54-4.76) 0.396 2.07 (0.83-5.19) 0.119
Cardiogenic shock (Killip IV) 6.59 (2.90-14.95) <0.001 4.42 (1.99-9.77) <0.001
STEMI 1.85 (0.71-4.80) 0.206 2.46 (0.89-6.71) 0.080
LVEF (%) 0.98 (0.95-1.01) 0.160 0.99 (0.96-1.02) 0.354
Renal dysfunction (eGFR<60) 5.64 (1.59-20.04) 0.008 5.92 (1.79-19.53) 0.004
Revascularization (emergency PCI or CABG) 0.66 (0.28-1.58) 0.350 0.24 (0.10-0.56) <0.001

Figures

Figure 1. Thirty-day cumulative survival rates in patients with acute myocardial infarction, stratified by DM status. Patients with DM (shown in red) had a significantly lower survival rate than those without DM (shown in blue).

Figure 2. Pie charts illustrating the causes of death in each group reveal differences. In the DM group, a higher percentage of non-cardiac deaths, such as infections, malignancies, strokes, and multiple organ failures, was observed than in the non-DM group (32% vs. 14%, respectively), with a statistically significant difference (p=0.046). Among the six cases of mechanical complications in patients who died in the DM group, there were two cases of ventricular septal rupture (VSR) and four cases of free-wall rupture (FWR). In the non-DM group, out of the 12 cases of mechanical complications in deceased patients, there were 4 cases of VSR, 7 of FMR, and 1 of papillary muscle rupture (PMR).

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