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Young-Keun Ahn - Top 30 Publications

Effects of Bisoprolol Are Comparable with Carvedilol in Secondary Prevention of Acute Myocardial Infarction in Patients Undergoing Percutaneous Coronary Intervention.

Although the benefits of carvedilol have been demonstrated in the era of percutaneous coronary intervention (PCI), very few studies have evaluated the efficacy of bisoprolol in the secondary prevention of acute myocardial infarction (MI) in patients treated with PCI. We hypothesized that the effect of bisoprolol would not be different from carvedilol in post-MI patients. A total of 13,813 patients who underwent PCI were treated either with carvedilol or bisoprolol at the time of discharge. They were enrolled from the Korean Acute MI Registry (KAMIR). After 1:2 propensity score matching, 1,806 patients were enrolled in the bisoprolol group and 3,612 patients in the carvedilol group. The primary end point was the composite of major adverse cardiac events (MACEs), which was defined as cardiac death, nonfatal MI, target vessel revascularization, and coronary artery bypass surgery. The secondary end point was defined as all-cause mortality, cardiac death, nonfatal MI, any revascularization, or target vessel revascularization. After adjustment for differences in baseline characteristics by propensity score matching, the MACE-free survival rate was not different between the groups (HR=0.815, 95% CI:0.614-1.081, p=0.156). In the subgroup analysis, the cumulative incidence of MACEs was lower in the bisoprolol group in patients having a Killip class of III or IV than in the carvedilol group (HR=0.512, 95% CI: 0.263-0.998, p=0.049). The incidence of secondary end points was similar between the two beta-blocker groups. In conclusion, the benefits of bisoprolol were comparable with those of carvedilol in the secondary prevention of acute MI.

Efficacy and Tolerability of Telmisartan/Amlodipine + Hydrochlorothiazide Versus Telmisartan/Amlodipine Combination Therapy for Essential Hypertension Uncontrolled With Telmisartan/Amlodipine: The Phase III, Multicenter, Randomized, Double-blind TAHYTI Study.

This 8-week study in Korea aimed to evaluate the efficacy and tolerability of a telmisartan/amlodipine + hydrochlorothiazide (TAH) combination versus telmisartan/amlodipine (TA) combination in patients with essential hypertension that did not respond appropriately to 4-week treatment with TA.

Bioresorbable Vascular Scaffold Korean Expert Panel Report.

Bioresorbable vascular scaffold (BRS) is an innovative device that provides structural support and drug release to prevent early recoil or restenosis, and then degrades into nontoxic compounds to avoid late complications related with metallic drug-eluting stents (DESs). BRS has several putative advantages. However, recent randomized trials and registry studies raised clinical concerns about the safety and efficacy of first generation BRS. In addition, the general guidance for the optimal practice with BRS has not been suggested due to limited long-term clinical data in Korea. To address the safety and efficacy of BRS, we reviewed the clinical evidence of BRS implantation, and suggested the appropriate criteria for patient and lesion selection, scaffold implantation technique, and management.

Multiple giant calcified aneurysms of three coronary arteries.

Evaluation of the impact of statin therapy on the obesity paradox in patients with acute myocardial infarction: A propensity score matching analysis from the Korea Acute Myocardial Infarction Registry.

The phenomenon of obesity paradox after acute myocardial infarction (AMI) has been reported under strong recommendation of statin therapy. However, the impact of statin therapy on this paradox has not been investigated. This study investigated the impact of statin therapy on 1-year mortality according to obesity after AMI. A total of 2745 AMI patients were included from the Korea Acute Myocardial Infarction Registry after 1:4 propensity score matching analysis (n = 549 for nonstatin group and n = 2196 for statin group). Primary and secondary outcomes were all-cause and cardiac death, respectively. During 1-year follow-up, the incidence of all-cause (8.4% vs 3.7%) and cardiac (6.2% vs 2.3%) death was higher in nonstatin group than in statin (P < .001, respectively). In nonstatin group, the incidence of all-cause (7.2% vs 9.0%) and cardiac (5.5% vs 6.5%) death did not differ significantly between obese and nonobese patients. However, in statin group, obese patients had lower 1-year rate of all-cause (1.7% vs 4.8%) and cardiac (1.2% vs 2.9%) death (P < .05, respectively), and lower cumulative rates by Kaplan-Meier analysis of all-cause and cardiac death compared with nonobese patients (log-rank P < .05, respectively). The overall risk of all-cause death was significantly lower in obese than in nonobese patients only in statin group (hazard ratio: 0.35; P = .001). After adjusting for confounding factors, obesity was independently associated with decreased risk of all-cause death in statin group. In conclusion, the greater benefit of statin therapy for survival in obese patients is further confirmation of the obesity paradox after AMI.

Interactions between pro-inflammatory cytokines and statins on depression in patients with acute coronary syndrome.

Pro-inflammatory cytokines are associated with the development of depression and statins exert anti-inflammatory and antidepressant effects. The present study aimed to investigate associations between interleukin (IL)-6 and IL-18 and depression in patients with acute coronary syndrome (ACS) and potential interactions between statin use and pro-inflammatory cytokines on depression in this population.

Prognostic impact of hyponatremia occurring at various time points during hospitalization on mortality in patients with acute myocardial infarction.

We investigated the incidence and prognostic impact of hyponatremia occurring at various time points during hospitalization on long-term mortality in acute myocardial infarction (AMI) survivors. We retrospectively studied 1863 patients diagnosed with AMI. Baseline, nadir, and discharge sodium levels during hospitalization were recorded and analyzed. Hyponatremia was defined as a serum sodium level <135 mEq/L. On the basis of baseline, nadir, and discharge sodium levels during hospitalization, hyponatremia was diagnosed in 309 (16.6%), 518 (27.8%), and 147 (7.9%) patients, respectively. In a multivariate Cox-proportional regression analysis, discharge sodium level had the strongest significant relationship with long-term mortality (hazard ratio [HR] as continuous variable = 1.06, 95% confidence interval [CI]: 1.01-1.11, P = .026; HR as categorical variable = 1.71; 95% CI: 1.06-2.75; P = .028), but baseline and nadir sodium had no prognostic impact on long-term mortality after adjustment. The serum sodium level and incidence of hyponatremia varied at different time points during hospitalization. In addition, the association between sodium level and long-term mortality differed at these various time points. The discharge sodium level, among the various time points, seems the best predictor of long-term mortality in AMI survivors.

ENOblock, a unique small molecule inhibitor of the non-glycolytic functions of enolase, alleviates the symptoms of type 2 diabetes.

Type 2 diabetes mellitus (T2DM) significantly impacts on human health and patient numbers are predicted to rise. Discovering novel drugs and targets for treating T2DM is a research priority. In this study, we investigated targeting of the glycolysis enzyme, enolase, using the small molecule ENOblock, which binds enolase and modulates its non-glycolytic 'moonlighting' functions. In insulin-responsive cells ENOblock induced enolase nuclear translocation, where this enzyme acts as a transcriptional repressor. In a mammalian model of T2DM, ENOblock treatment reduced hyperglycemia and hyperlipidemia. Liver and kidney tissue of ENOblock-treated mice showed down-regulation of known enolase target genes and reduced enolase enzyme activity. Indicators of secondary diabetic complications, such as tissue apoptosis, inflammatory markers and fibrosis were inhibited by ENOblock treatment. Compared to the well-characterized anti-diabetes drug, rosiglitazone, ENOblock produced greater beneficial effects on lipid homeostasis, fibrosis, inflammatory markers, nephrotoxicity and cardiac hypertrophy. ENOblock treatment was associated with the down-regulation of phosphoenolpyruvate carboxykinase and sterol regulatory element-binding protein-1, which are known to produce anti-diabetic effects. In summary, these findings indicate that ENOblock has potential for therapeutic development to treat T2DM. Previously considered as a 'boring' housekeeping gene, these results also implicate enolase as a novel drug target for T2DM.

Impact of low high-density lipoprotein-cholesterol level on 2-year clinical outcomes after acute myocardial infarction in patients with diabetes mellitus.

It is still unclear whether low high-density lipoprotein cholesterol (HDL-C) affects cardiovascular outcomes after acute myocardial infarction (AMI), especially in patients with diabetes mellitus.

Clinical outcome of statin plus ezetimibe versus high-intensity statin therapy in patients with acute myocardial infarction propensity-score matching analysis.

It is unclear whether simvastatin-ezetimibe could be an alternative therapy to high-intensity statin therapy in high-risk patients. The aim of this study was to compare the clinical outcomes of simvastatin-ezetimibe and high-intensity statin therapy in patients with acute myocardial infarction (AMI), and especially in those with high-risk factor.

Comparison of 2-year clinical outcomes between diabetic versus nondiabetic patients with acute myocardial infarction after 1-month stabilization: Analysis of the prospective registry of DIAMOND (DIabetic acute myocardial infarctiON Disease) in Korea: an observational registry study.

This study assessed the 2-year clinical outcomes of patients with diabetes mellitus (DM) after acute myocardial infarction (AMI) in a cohort of the DIAMOND (DIabetic Acute Myocardial infarctiON Disease) registry. Clinical outcomes were compared between 1088 diabetic AMI patients in the DIAMOND registry after stabilization of MI and 1088 nondiabetic AMI patients from the KORMI (Korean AMI) registry after 1 : 1 propensity score matching using traditional cardiovascular risk factors. Stabilized patients were defined as patients who did not have any clinical events within 1 month after AMI. Primary outcomes were the 2-year rate of major adverse cardiac events (MACEs), a composite of all-cause death, recurrent MI (re-MI), and target vessel revascularization (TVR). Matched comparisons revealed that diabetic patients exhibited significantly lower left ventricular ejection fraction (LVEF) and estimated glomerular filtration rate and smaller stent size. Diabetic patients exhibited significantly higher 2-year rates of MACE (8.0% vs 3.7%), all-cause death (3.9% vs 1.4%), re-MI (2.8% vs 1.2%), and TVR (3.5% vs 1.3%) than nondiabetic patients (all P < 0.01), and higher cumulative rates in Kaplan-Meier analyses of MACE, all-cause death, and TVR (all P < 0.05). A multivariate Cox regression analysis revealed that chronic kidney disease, LVEF < 35%, and long stent were independent predictors of MACE, and large stent diameter and the use of drug-eluting stents were protective factors against MACE. The 2-year MACE rate beyond 1 month after AMI was significantly higher in DM patients than non-DM patients, and this rate was associated with higher comorbidities, coronary lesions, and procedural characteristics in DM.

Roles of High-Density Lipoprotein Cholesterol in Patients With Acute Myocardial Infarction.

Many observational studies showed hogh-density lipoprotein cholesterol (HDL-C) is a strong inverse predictor of cardiovascular (CV) outcome. However, recent large clinical trials evaluating therapies to raise HDL-C level in those already on statin therapy have been discouraging. This complexity is not well-known.A total of 28,357 acute myocardial infarction (AMI) patients were enrolled in the Korea Acute Myocardial Infarction Registry (KAMIR), which was a prospective, multicenter, nationwide, web-based database of AMI in Korea. From this registry, we evaluated 3574 patients with AMI who have follow-up HDL-C level to investigate its association with clinical outcomes. The primary endpoint was the relationship between follow-up change in HDL-C and a 12-month composite of major adverse cardiac events (MACEs).Patients with initial HDL-C ≥ 40 mg/dL showed significantly lower rates of 12-month MACEs, especially cardiac and all-cause mortalities (P < 0.001). When patients were stratified into 4 groups according to the change of HDL-C, patients with decreasing HDL-C showed significantly higher rates of 12-month MACEs as comparable with patients with increasing HLD-C. A multivariate analysis indicated that HDL-C level was a significant predictor of CV events (hazard ratio, 1.38; 95% confidence interval, 1.12-1.71) after correcting for confounding variables.The follow-up change in HDL-C level was significantly related with CV outcomes in patients with AMI.

Comparison of dual antiplatelet therapy prescribed as one-pill versus two-pill regimen. A pooled analysis of individual patient data from the three MR-CAPCIS trials.

Fixed-dose combination (FDC) drugs can simplify the medication regimen and potentially improve adherence. However, evidence is lacking about the efficacy and safety of FDC drugs of clopidogrel plus aspirin. Individual data from the three independent MR-CAPCIS trials were pooled and analysed. In those trials, subjects who had been treated with either dual antiplatelet therapy (DAPT) or aspirin alone after drug-eluting stent (DES) implantation were randomly assigned to one-pill or to two-pill DAPT group. Platelet reactivity was measured with VerifyNow-P2Y12 and aspirin point-of-care assays at baseline and eight weeks after treatment. In the present study, primary efficacy endpoint was changes in platelet reactivity unit (PRU) between baseline and eight weeks. A total of 965 subjects were analysed. In prior clopidogrel and aspirin users, PRU was well maintained regardless of switching to either one-pill or two-pill DAPT (ΔPRU=0.4 vs 0.0, p=0.939). In prior aspirin users, PRU was decreased by 73.7 in one-pill DAPT and 77.5 in two-pill DAPT group, with no differences between them (p=0.499). The incidence of high on-treatment platelet reactivity at eight weeks, defined as PRU≥235 in Western people, was 34.8 % in one-pill DAPT group and 37.6 % in two-pill DAPT group (p=0.380), and that defined as PRU ≥275 in Oriental people was 17.7 vs 21.7 % (p=0.129). Independent predictors of high platelet reactivity on clopidogrel were female gender, increasing age, and diabetes. Study drugs were well tolerated. In conclusion, FDC one-pill DAPT showed similar efficacy to two-pill DAPT in terms of platelet reactivity in patients receiving DES in Korea.

Two-Year Safety and Efficacy of Biodegradable Polymer Drug-Eluting Stent Versus Second-Generation Durable Polymer Drug-Eluting Stent in Patients With Acute Myocardial Infarction: Data from the Korea Acute Myocardial Infarction Registry (KAMIR).

Despite improved long-term safety of biodegradable polymer (BP) drug-eluting stents (DES) compared to first-generation durable polymer (DP) DES, data on the safety and efficacy of BP-DES compared with second-generation (2G) DP-DES in patients with acute myocardial infarction (AMI) are limited.

Efficacy and Safety of DP-R202 in Patients with Chronic Artery Occlusive Disease: Multicenter Randomized Double-blind Active-controlled Parallel Group Phase III Clinical Study.

Sarpogrelate hydrochloride, a selective 5-hydroxytryptamine 2A antagonist, is a widely used antiplatelet agent for the treatment of peripheral arterial disease (PAD). DP-R202 is a new sarpogrelate hydrochloride product with an improved dosage regimen compared with the agent in current use. The aim of this study was to compare the efficacy and safety profile of DP-R202 and Anplag(⁎) Tab in patients with PAD.

Comparison of 2-year mortality according to obesity in stabilized patients with type 2 diabetes mellitus after acute myocardial infarction: results from the DIAMOND prospective cohort registry.

After acute myocardial infarction (AMI), the replicated phenomenon of obesity paradox, i.e., obesity appearing to be associated with increased survival, has not been evaluated in stabilized (i.e., without clinical events within 1 month post AMI) Asian patients with diabetes mellitus (DM).

Comparison of 12-month clinical outcomes in diabetic and nondiabetic patients with chronic total occlusion lesions: a multicenter study.

This study aimed to compare 1-year clinical outcomes in diabetic and nondiabetic patients with chronic total occlusion (CTO) lesions.

Clinical features of familial hypercholesterolemia in Korea: Predictors of pathogenic mutations and coronary artery disease - A study supported by the Korean Society of Lipidology and Atherosclerosis.

Proper screening and diagnosis of familial hypercholesterolemia (FH) is of critical importance for cardiovascular prevention. However, the clinical diagnosis of FH remains difficult partly because its phenotype can vary between different ethnicities. The aim of this study was to determine the clinical features and the best diagnostic approach in Korean FH patients. The predictors of putative pathogenic mutations and coronary artery disease (CAD) were also identified.

Comparison of Resolute zotarolimus-eluting stents versus everolimus-eluting stents in patients with metabolic syndrome and acute myocardial infarction: propensity score-matched analysis.

Despite common use of second-generation drug-eluting stents in treating patients with coronary artery disease, there is lack of data comparing these stents exclusively in patients with acute myocardial infarction (AMI), especially with metabolic syndrome (MetS), which is highly prevalent in AMI and potential to worsen clinical outcomes. The aim of this study was to compare clinical outcomes of everolimus-eluting stent (EES) and Resolute-zotarolimus-eluting stent (R-ZES) in AMI patients with MetS, in terms of stent-related and patient-related outcomes.

Evaluation of polygenic cause in Korean patients with familial hypercholesterolemia - A study supported by Korean Society of Lipidology and Atherosclerosis.

Familial hypercholesterolemia (FH) is an autosomal dominant disorder caused by mutations in LDLR, APOB, or PCSK9. Polygenicity is a plausible cause in mutation-negative FH patients based on LDL cholesterol (LDL-C)-associated single nucleotide polymorphisms (SNPs) identified by the Global Lipids Genetics Consortium (GLGC). However, there are limited data regarding the polygenic cause of FH in Asians.

Comparison of clinical outcomes between culprit vessel only and multivessel percutaneous coronary intervention for ST-segment elevation myocardial infarction patients with multivessel coronary diseases.

The clinical significance of complete revascularization for ST segment elevation myocardial infarction (STEMI) patients during admission is still debatable.

Genetic testing of Korean familial hypercholesterolemia using whole-exome sequencing.

Familial hypercholesterolemia (FH) is a genetic disorder with an increased risk of early-onset coronary artery disease. Although some clinically diagnosed FH cases are caused by mutations in LDLR, APOB, or PCSK9, mutation detection rates and profiles can vary across ethnic groups. In this study, we aimed to provide insight into the spectrum of FH-causing mutations in Koreans. Among 136 patients referred for FH, 69 who met Simon Broome criteria with definite family history were enrolled. By whole-exome sequencing (WES) analysis, we confirmed that the 3 known FH-related genes accounted for genetic causes in 23 patients (33.3%). A substantial portion of the mutations (19 of 23 patients, 82.6%) resulted from 17 mutations and 2 copy number deletions in LDLR gene. Two mutations each in the APOB and PCSK9 genes were verified. Of these anomalies, two frameshift deletions in LDLR and one mutation in PCSK9 were identified as novel causative mutations. In particular, one novel mutation and copy number deletion were validated by co-segregation in their relatives. This study confirmed the utility of genetic diagnosis of FH through WES.

The microRNA miR-34c inhibits vascular smooth muscle cell proliferation and neointimal hyperplasia by targeting stem cell factor.

The fine balance between proliferation and differentiation of vascular smooth muscle cells (VSMCs) is indispensable for the maintenance of healthy blood vessels, whereas an increase in proliferation participates in pathologic cardiovascular events such as atherosclerosis and restenosis. Here we report that microRNA-34c (miR-34c) targets stem cell factor (SCF) to inhibit VSMC proliferation and neointimal hyperplasia. In an animal model, miR-34c was significantly increased in the rat carotid artery after catheter injury. Transient transfection of miR-34c to either VSMCs or A10 cells inhibited cell survival by inducing apoptosis, which was accompanied by an increase in expression of p21, p27, and Bax. Transfection of miR-34c also attenuated VSMC migration. Bioinformatics showed that SCF is a target candidate of miR-34c. miR-34c down-regulated luciferase activity driven by a vector containing the 3'-untranslated region of SCF in a sequence-specific manner. Forced expression of SCF in A10 cells induced proliferation and migration, whereas knocking-down of SCF reduced cell survival and migration. miR-34c antagomir-induced VSMC proliferation was blocked by SCF siRNA. Delivery of miR-34c to rat carotid artery attenuated the expression of SCF and blocked neointimal hyperplasia. These results suggest that miR-34c is a new modulator of VSMC proliferation and that it inhibits neointima formation by regulating SCF.

One-year clinical outcomes of everolimus- versus sirolimus-eluting stents in patients with acute myocardial infarction.

In contrast to many studies comparing everolimus-eluting stent (EES) with paclitaxel-eluting stent (PES), data directly comparing EES with sirolimus-eluting stent (SES) are limited, especially in patients with acute myocardial infarction (AMI).

Impact of low level of high-density lipoprotein-cholesterol sampled in overnight fasting state on the clinical outcomes in patients with acute myocardial infarction (difference between ST-segment and non-ST-segment-elevation myocardial infarction).

Despite good treatment, there are residual risks in acute myocardial infarction (AMI) patients, and low level of high-density lipoprotein-cholesterol (HDL) has drawn attention as a possible cause. However, the impact of low HDL on ST-segment-elevation myocardial infarction (STEMI) compared with non-ST-segment-elevation myocardial infarction (NSTEMI) is not clear. Our aim was to evaluate the impact of low HDL on clinical outcomes in patients with STEMI or NSTEMI.

Association of beta-blocker therapy at discharge with clinical outcomes in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention.

This study sought to investigate the association of beta-blocker therapy at discharge with clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI) after primary percutaneous coronary intervention (PCI).

Relation of serum potassium level to long-term outcomes in patients with acute myocardial infarction.

Potassium plays a key role in normal myocardial function, and current guidelines recommend that serum potassium levels be maintained from 4.0 to 5.0 mEq/L in patients with acute myocardial infarction (AMI). However, the impact of serum potassium levels on long-term mortality has not been evaluated. We retrospectively studied 1,924 patients diagnosed with AMI. The average serum potassium levels measured throughout the hospitalization were obtained and statistically analyzed. Patients were categorized into 5 groups to determine the relation between mean serum potassium and long-term mortality: <3.5, 3.5 to <4.0, 4.0 to <4.5, 4.5 to <5.0, and ≥5 mEq/L. The long-term mortality was lowest in the group of patients with potassium levels of 3.5 to <4.0 mEq/L, whereas mortality was higher in the patients with potassium levels≥4.5 or <3.5 mEq/L. In a multivariate Cox-proportional regression analysis, the mortality risk was greater for serum potassium levels of >4.5 mEq/L (hazard ratio [HR] 1.71, 95% confidence interval [CI] 1.04 to 2.81 and HR 4.78, 95% CI 2.14 to 10.69, for patients with potassium levels of 4.5 to <5.0 mEq/L and ≥5.0, respectively) compared with patients with potassium levels of 3.5 to <4.0 mEq/L. The mortality risk was also higher for patients with potassium levels<3.5 mEq/L (HR 1.55, 95% CI 0.94 to 2.56). In contrast to the association with long-term mortality, there was no relation between serum potassium levels and the occurrence of ventricular arrhythmias. The results of the current analysis suggest that there is a need for change in our current concepts of the ideal serum potassium levels in patients with AMI.

Does gender influence the impact of impaired renal function on prognosis after ST-segment elevated myocardial infarction?

A limited number of studies have investigated the impact of gender on renal function and clinical outcomes after ST-segment elevated myocardial infarction (STEMI), and these studies have provided discrepant results.

Concomitant impact of high-sensitivity C-reactive protein and renal dysfunction in patients with acute myocardial infarction.

The present study aimed to investigate the impact of high-sensitivity C-reactive protein (hs-CRP) and renal dysfunction on clinical outcomes in acute myocardial infarction (AMI) patients.

Impact of patients' arrival time on the care and in-hospital mortality in patients with non-ST-elevation myocardial infarction.

Only a few studies have focused on the clinical characteristics and outcomes of non-ST-segment myocardial infarction (NSTEMI) during off-hours. The purpose of this study was to compare the impact of patients' arrival time on the care of NSTEMI and whether this pattern might affect hospital mortality. This study analyzed 4,736 NSTEMI patients included in the Korea Acute Myocardial Infarction Registry from November 2005 to January 2008. Patients' arrival time was classified into regular hours (weekdays, 9:00 a.m. to 6:00 p.m.) and off-hours (weekdays 18:01 p.m. to 8:59 a.m., weekends, and holidays). A subtotal of 2,225 (46.9%) patients was admitted during off hours, compared with 2,511 (53.1%) patients with regular-hour admission. A higher proportion of patients admitted during off-hours had a higher Killip class, had more frequent cardiopulmonary resuscitation, were less likely to receive percutaneous coronary intervention (PCI) (67.7% vs 72.7%, p <0.001), and had longer door-to-balloon times (28 hours, interquartile range: 11 to 63 vs 23 hours, interquartile range 4 to 67, p <0.001). Although unadjusted hospital mortality was associated with admission during off-hours (4.5% vs 3.3%, p = 0.023), after adjusting for all patients covariates, the difference in mortality was attenuated and was no longer statistically significant (odds ratio 0.94, 95% confidence interval 0.59 to 1.48, p = 0.793). In conclusion, despite receiving fewer PCIs and having substantially longer waiting times to PCI, patients admitted during off-hours may not be at risk for increased in-hospital mortality. If patients are treated within an appropriate reperfusion strategy according to their clinical risk, arrival time may not influence on mortality.