a b s t r a c t

Background: Timely transfer and percutaneous coronary intervention (PCI) with or without thrombolysis are recommended by the American Heart Association (AHA) to care for ST-segment elevation myocardial infarction patients who present first to a non-PCI-capable hospital. This study was to evaluate the impact on in- hospital mortality of the Compliance with guidelines regarding to the time of PCI for patients with STEMI who were transferred to a capable PCI hospital.

Methods: We used the CArdioVAscular disease surveillance data from November 2007 to December 2012 for this study. Adult patients who were diagnosed with STEMI and transferred from a primary hospital for PCI were in- cluded. Patients who underwent PCI or Coronary artery bypass graft surgery in the primary hospital and patients with an unknown emergency department disposition were excluded. The main exposure was the AHA recommen- dation for reperfusion therapy. We tested the association between compliance with AHA and hospital mortality. Results: A total of 2078 patients were analyzed, 30.0% of whom were treated in compliance with the guidelines, whereas the remaining 70.0% were not. Thrombolysis was performed in 7.9% and 0.8% (P value b .01) and hospital mortality was 5.0% and 6.8% (P value = .11) in the compliant and violence groups, respectively. The adjusted odds ratios (95% confidence intervals) of the compliant group for hospital mortality were 0.75 (0.46-1.21), respectively. A sensitivity analysis of symptom onset to arrival time was a trend for a beneficial effect in the compliant group.

Conclusions: Among the patients who were transferred for STEMI care, undergoing PCI as recommended by the AHA

was not associated with a Mortality benefit, but the patients whose symptom onset to hospital arrival time was within 30 minutes showed an association between compliance and lower mortality.

(C) 2016

Introduction

Background

? Funding acknowledgement: This study was supported by the National Emergency Management Agency of Korea and the Korean Centers for Disease Control and Prevention.

* Corresponding author at: Department of Emergency Medicine, National Medical Center, 245 Euljiro, jung-u, Seoul, Republic of Korea. Tel.: +82 10 7122 0448; fax: +82 2 2260 7420.

E-mail addresses: [email protected] (Y. Choi), [email protected] (Y.J. Lee), [email protected] (S.D. Shin), [email protected] (K.J. Song), [email protected] (K. Lee), [email protected] (E.J. Lee), [email protected] (Y.J. Kim), [email protected] (K.O. Ahn), [email protected] (K.J. Hong), [email protected] (Y.S. Ro).

Acute myocardial infarction (AMI) is still a leading cause of death in developed countries [1]. Despite recent improvements in the care and outcomes of patient with ST-segment elevation myocardial infarction , STEMI remains a major cause of death [2,3]. Reperfusion therapy is crucial to resolve the coronary artery pathology of a STEMI patient. Performing coronary interventions, including percutaneous coronary intervention (PCI) and coronary artery bypass graft surgery, in a timely manner is important in the management of STEMI patient [4]. Not all hospitals can provide coronary interventions; therefore, strategies to decrease Ischemic time, including designation of PCI

http://dx.doi.org/10.1016/j.ajem.2016.09.024

0735-6757/(C) 2016

centers and arranging Interhospital transfer after thrombolysis in primary emergency departments (EDs), are recommended [5-9].

It is known that the direct transfer of STEMI patients to PCI-capable centers by bypassing non-PCI-capable hospitals and taking STEMI patients directly to the catheterization laboratory by bypassing the ED are both strategies that are associated with better outcomes in STEMI patients [6]. However, approximately 28% of AMI patients still require interhospital transfer for definitive care [5,10]. For interhospital transfer STEMI patients who did not receive thrombolysis in primary hospital, the American Heart Association (AHA) guidelines recommend that the time from the first medical contact to balloon should be within 120 minutes. When the interhospital transfer STEMI patients receive thrombolysis in the primary hospital, the PCI should not be performed within the first 2 to 3 hours after the administration of Fibrinolytic therapy [11].

Performing Primary PCI within 120 minutes is likely to have better survival outcomes than thrombolysis at the scene [12], but previous studies have compared thrombolysis at the primary hospital with the Transfer of patients for PCI [12,13]. However, one study reported that patients who underwent PCI within 90 to 120 minutes after throm- bolysis showed no adverse effects when compared with patients who underwent primary PCI [14]. Furthermore, this study found limited evidence of benefit for the interhospital transfer of STEMI patients.

Goal of this study

We hypothesized that among transferred STEMI patients, the PCI care recommended by AHA would be associated with lower mortality. The goal of this study was to evaluate the impact on in-hospital mortality of the compliance with guidelines regarding the time of PCI for patients with STEMI who were transferred to a PCI-capable hospital.

Methods

Study setting

This study was a secondary analysis of the registry data of the Cardiovascular Disease Surveillance (CAVAS) program conducted by 29 EDs sponsored by the Korean Centers for Disease Control and Prevention. More [15] detailed information about the CAVAS program has been described in previously published articles [15,16].

Korea has a single-tier emergency medical service (EMS) system administered by the government and operated by the fire departments that serve a population of approximately 50 million[17]. The emergency medical technicians simply evaluate the patients and transport them to the nearest ED. In the ED, the emergency physician diagnoses the patient and provides reperfusion therapy; if the hospital is not equipped to perform PCI, the ED physician can transfer the patient to a PCI- capable hospital [18].

The level of care delivered in an ED is determined based on the personnel, equipment, and the availability of each Medical specialty. All EDs are categorized into levels 1 to 3. Level 1 EDs have the highest capability and capacity. As of December 2013, there were 20 level 1 EDs, 119 level 2 EDs, and 293 level 3 EDs in Korea. Almost all of the level 1 EDs had PCI team activation protocols before STEMI patients ar- rive at the ED; however, some of the level 2 EDs could only perform PCIs during the daytime. Most level 3 EDs could not perform PCIs during the day- and nighttime.

Level 1 or 2 ED conducted angiography and PCI to occlusive lesion as needed for almost all of STEMI patients. The quality of treatment process was controlled by Ministry of Health and Welfare.

There was no national standard protocol for the interhospital transfer of STEMI patients. Emergency physicians at the transferring hospital made the decision about whether to perform primary thrombolysis, and they selected the transfer hospital. The Emergency Medical Informa- tion Centers of each province gathered and provided the information on

the availability of PCI and coronary care units in real time. Private ambu- lance services were used to perform Interhospital transfers, and the accompanying physicians or nurses were designated by the emergency physician at the transferring hospital.

Study population

Adult patients older than 18 years who had final diagnosis of STEMI between November 2007 and December 2012 were identified in the database. The ED physicians of the final hospitals assigned the final diagnosis. The final diagnosis in the database was categorized as STEMI involving the anterior wall, STEMI involving the lateral or inferior wall, Non-ST-segment elevation myocardial infarction, bundle-branch block, sudden cardiac death, vasospasm-induced myocardial infarction, and others. This study included the patients who had STEMIs involving the anterior, lateral, or inferior wall.

Study eligibility was limited to adult patients who were diagnosed with STEMI and transferred from a primary hospital to a PCI-capable hospital for treatment.

Patients who underwent PCI or coronary artery bypass graft surgery in the primary hospital, who arrived to the primary hospital more than 12 hours after symptom onset, whose door to balloon time was more than 24 hours in the PCI-capable hospital, and whose ED disposition was unknown were excluded. Patients who presented after cardiac arrest and had undergone cardiopulmonary resuscitation were also excluded because their Reperfusion strategy may be dictated by another guideline and the time consumed by cardiopulmonary resuscitation could have affected the Transfer time.

Data collection

Data of patients admitted or discharged from the ED with acute cardiovascular from 29 participating EDs in 12 cities and provinces across Korea were prospectively collected through in-depth hospital medical record review. Trained reviewers from the Korea Centers for Disease Control and Prevention abstracted the data from medical records. Through the medical record review, the basic demographic data (age, sex); socioeconomic data (occupation, insurance status, and education); and risk factor data such as hypertension, diabetes, chronic renal failure, cardiovascular and cerebrovascular disease, previous history of PCI, smoking, and alcohol use were collected. Time data such as symptom onset, EMS call and arrival times, ED arrival, length of stay in the primary hospital, interhospital transfer times, and treat- ment times; information on initial diagnostic information such as ECG, cardiac biomarkers, and treatments; disposition (admission, discharge, transfer); and in-hospital mortality were also collected [19]. The primary ED length of stay was defined as the time from the arrival at the primary hospital to the departure from the primary hospital. Interhospital transfer time was defined as the time from the departure from the primary hospital to the arrival at the definite hospital.

Outcome measures

The primary outcome was in-hospital mortality. The main exposure was adherence with the AHA’s recommendations for reperfusion therapy. We defined the primary hospital as the first hospital where the patient presented and the definite hospital as the receiving hospital where the PCI was performed.

There are 4 groups that we analyzed that were determined by whether the patient received thrombolysis at the primary hospital and whether the patient underwent PCI at the definite hospital within 120 minutes from first medical contact to balloon inflation.

The compliant group included patients who received thrombolysis at the primary hospital, were transferred to a definite hospital, and then underwent PCI after 120 minutes from the first medical contact, as well as patients who did not receive thrombolysis at the primary

hospital, were transferred to a definite hospital, and underwent PCI within 120 minutes from the first medical contact.

The violation group included patients who received thrombolysis at the primary hospital, were transferred to a definite hospital, and underwent PCI within 120 minutes from the first medical contact, as well as patients who did not receive thrombolysis at the primary hospital, were transferred to a definite hospital, and underwent PCI after 120 minutes from the first medical contact.

Statistical analysis

Descriptive analysis was performed to examine the distributions of the categorical variables that were reported as percentages. The continuous variables that were not distributed normally are presented as medians with interquartile ranges (IQRs). The exposure groups were compared and tested for statistical significance using ?² test for categorical variables and Kruskal-Wallis test for continuous variables.

We tested the association between compliance with the Guideline recommendations (compliance vs violation group) on hospital mortality. The adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were calculated after adjustment using multivariable logistic regression analysis, including the potential confounders of age, sex, EMS use, shock, smoke, diabetes mellitus, hypertension, and chronic kidney disease.

Transferred N = 5,257

Not Transferred N = 4,722

Age? 19

N = 9,979

Age unknown or <19 N = 10

STEMI patient, Total N = 9,989

A sensitivity analysis was performed by examining multiple different symptom onset to arrival time criteria for the patients included in the multivariable logistic regression analysis model. There were 4 groups: those who arrived at the primary hospital within 30, 60, 120, and 360 minutes from the onset of symptoms.

All statistical analyses were performed using SAS software, version

9.4 (SAS institute Inc, Cary, NC).

Ethics statements

The study protocol was approved by the institutional review board of Seoul National university hospitals. The need for informed consent was waived by the board (IRB no. 1012-134-346).

Results

Demographic findings

Our sample was drawn from among the 9989 patients who were diagnosed with STEMI in the CAVAS database. We excluded patients who were not adults (n = 10), were not transferred or whose trans- fer status was unknown (n = 4722), received cardiopulmonary re- suscitation (n = 68), received PCI or coronary artery bypass

Excluded CPR, n = 68

PCI or CABG before transfer, n = 53 No PCI at definite hospital, n = 643 Time variable unknown, n = 1,770 Symptom to arrival > 12 hr, n = 342 Arrival to ballooning > 24 hr, n = 322

Discharge or transfer from final hospital, n = 23

N = 2,078

FMC to PCI? 120 12

FMC to PCI>120 1,442

Violation

Thrombolysis and FMC to PCI? 120, n = 12 No thrombolysis and FMC to PCI>120, n = 1,442

FMC to PCI? 120 575

FMC to PCI>120 49

Compliance

No thrombolysis and FMC to PCI? 120, n = 575 Thrombolysis and FMC to PCI>120, n = 49

Fibrinolysis at primary hospital 61

No Fibrinolysis at primary hospital 2,017

Figure. Study population.

surgery (n = 53), did not receive PCI at the definite hospital (n = 643), had a symptom onset to arrival time of more than 12 hours (n = 432), had an arrival to balloon time of more than 24 hours (n = 2002), and were discharged or transferred to a definite hospital (n = 23) (Figure).

A total of 2078 patients were analyzed, and 30.0% were compliant with the guidelines and 70.0% were not. Thrombolysis was performed in only 7.9% and 0.8% of the compliant and violation groups, respectively. Elderly patients were less likely to be in the compliant group (39.9%) than the violation group (49.6%) (P value b .01). The EMS was used for 14.8% of patients in the compliant group and 17.9%in the violation (P value = .95). Hospital mortality was 5.0% and 6.8% in the compliant and violation groups (P value = .11), respectively (Table 1).

Demographic finding of the excluded patients is presented (Appendix 1).

Table 2

Multivariable logistic regression of compliance vs violation group

Group	Total		Death		Unadjusted		Adjusted
	n		n %		OR 95% CI		OR 95% CI
All	2078		130 6.3
Violation	1454		99 6.8		1.00
Compliance	624		31 5.0		0.72 (0.47-1.08)		0.85 (0.55-1.33)

Adjusted for age, sex, EMS use, shock, smoke, diabetes mellitus, hypertension, and chronic kidney disease.

The symptom onset to arrival time was shorter in the compliant group (median, 50; IQR, 51-71) than the violation group (60; IQR, 30-150). The length of stay in the primary ED and the interhospital transfer time were

Table 1

Demographic and clinical characteristics of transferred STEMI patients classified by guideline compliance

	Total				Compliance				Violation
	n		%		n		%		n		%	P value
Total	2078				624		30.0		1454		70.0
Sex												b.01
Male	1505		72.4		486		77.9		1019		70.1
Female	573		27.6		138		22.1		435		29.9
Age												b.01
Elderly (65-100)	970		46.7		249		39.9		721		49.6
Adults (19-64)	1108		53.3		375		60.1		733		50.4
Median (IQR)		63 (52-73)			60 (51-71)				64 (53-74)			b.01
Medical history
DM	477		23.0		120		19.2		357		24.6	b.01
Hypertension	920		44.3		250		40.1		670		46.1	.01
CKD	38		1.8		10		1.6		28		1.9	.61
AMI	81		3.9		26		4.2		55		3.8	.68
PCI Hx	65		3.1		17		2.7		48		3.3	.49
Health behavior
Current smoker	972		46.8	316			50.6	656			45.1	.07
Ex-smoker	290		14.0	81			13.0	209			14.4
Alcohol drinking	764		36.8	267			42.8	497			34.2	b.01
Chief concern												b.01
Chest pain	1938		93.3	601			96.3	1337			92.0
Dyspnea	42		2.0	8			1.3	34			2.3
Syncope	27		1.3	4			0.6	23			1.6
Others	71		3.4	11			1.8	60			4.1
EMS use												.95
	308		14.8	92			14.7	216			14.9
Symptom to arrival												b.01
Median (IQR)		60 (27-143)				50 (20-130)				60 (30-150)
Primary hospital arrival to departure												b.01
Median (IQR)		55 (30-100)				30 (20-40)				70 (45-130)
Interhospital transfer time												b.01
		33 (20-51)				21 (13-31)				40 (26-58)
Cardiogenic shock												.63
	152		7.3	43			6.9	109			7.5
prehospital ECG												.12
ST elevation	1756		84.5	541			86.7	1215			83.6
Not ST elevation	163		7.8	38			6.1	125			8.6
Unknown	159		7.7	45			7.2	114			7.8
Thrombolysis	61		2.9	49			7.9	12			0.8	b.01
Initial ECG												.1
ST elevation	1954		94.0	595			95.4	1359			93.5
Not ST elevation	124		6.0	29			4.6	95			6.5
Unknown	1109		53.4	328			52.6	781			53.7
Door to balloon												b.01
		56 (40-83)				46 (35.5-59)				62.5 (45-97)
Diagnosis												.63
STEMI, ant	1109		53.4	328			52.6	781			53.7
STEMI, etc	969		46.6	296			47.4	673			46.3
ICU admission												.9
	1545		74.4	465			74.5	1080			74.3
Outcome												.11
Death	130		6.3	31			5.0	99			6.8

DM, diabetes mellitus; CKD, chronic kidney disease; ECG, electrocardiography; ICU, intensive care unit.

shorter in the compliant group (30; IQR, 20-40 and 21; IQR, 13-31) than the violation group (70; IQR, 45-130 and 40; IQR, 26-58). The door to balloon time was shorter in the compliant group (46; IQR, 35.5-59) than the violation group (62.5; IQR, 45-97) (Table 1).

multiple logistic regression analysis

The crude OR (95% CI) of the compliant group for hospital mortality was 0.72 (0.47-1.08), and the adjusted OR was 0.85 (0.55-1.33) (Table 2).

Sensitivity analysis

A sensitivity analysis was performed on the different inclusion criteria for the symptom onset to arrival time.

Multiple logistic regression was performed of the mortality in the different patient groups stratified by the symptom onset to arrival time. In the logistic model, as the symptom onset to arrival time shortened, there was a trend toward a beneficial effect in the compliant group.

A total of 753 patients arrived to the hospital within 30 minutes from symptom onset, and 34.4% and 65.6% were in compliant and violation groups, respectively. Hospital mortality was 3.5% and 6.9% in compliant and violation groups (P value = .06), respectively. Compared with the compliant group, the violation group was associated with higher in- hospital mortality only for patients who arrived to the hospital within 30 minutes from symptom onset (adjusted OR, 0.44 [0.19-0.98]), whereas there was no statistically significant association between guideline compliance and in-hospital mortality classified with symptom onset to arrival time (adjusted OR, 0.56 [0.29-1.06] for 1 hour; adjusted OR, 0.76 [0.44-1.28] for 2 hours; adjusted OR, 0.87 [0.54-1.39] for

6 hours, respectively) (Table 3).

Discussion

Using multicenter prospective data, we found that the compliance with AHA guideline regarding PCI care for interhospital-transferred STEMI patients was not associated with in-hospital mortality. In sensitivity analysis, the compliance with guideline was associated with higher in- hospital mortality only for patients who arrived to the hospital within 30 minutes from symptom onset. These results suggest that the AHA guideline may be followed to prevent in-hospital mortality, especially in patients with rapid progressive symptom.

The AHA guideline recommends either early PCI or late PCI after thrombolysis; these recommendations are based on previous studies that compared fibrinolysis to transfer for direct PCI [7,12,13]. These studies did not compare early PCI vs thrombolysis with later PCI. Further- more, in the real world, there may be more delays during the primary

hospital stay or the interhospital transfer. Future large-scale studies of transferred STEMI patient are needed to develop appropriate guidelines for this population of patients.

Although a previous study demonstrated that door to balloon time was more important than symptom to balloon time [20], another study revealed that symptom onset to balloon time was more important [21]. In this study, the in-hospital mortality was lower for patients who were admitted early after symptoms onset and who underwent PCI complying with the guideline.

In our study, only 2.9% of the patients received pretransfer throm- bolysis, but Vora et al [22] reported that 29.5% of patients received pretransfer thrombolysis in the United States. Korea had a relatively shorter interhospital transfer time, with a median interhospital transfer time of 33 minutes. Vora et al [22] reported a median interhospital transfer time of 57 minutes (IQR, 36-88 minutes) in United States. The short average transfer time may have contributed to the physicians’ decisions not to administer thrombolysis. A previous study about thrombolysis in stroke patients revealed that the symptomatic hemor- rhagic transformation was 7% [23].

The Transferred patients in our study had a higher mortality rate than those in a previous study (3.5%-3.9% compared with 6.3% in our study) [22,24]. The benefit of complying with the guideline was nulli- fied by the overall increase in mortality.

Korea has no regionalized protocol for EMS and hospitals to coordi- nate the transfer of STEMI patients. Our study showed that the median primary hospital arrival to departure time (55 minutes; IQR, 30-100 minutes) was longer than the median interhospital transfer time (33 minutes; IQR, 20-51 minutes). There was no detailed information available about delays at the primary hospitals, but the absence of a predesignatED referral center could have contributed. We believe that a regionalized protocol to limit transfer delays at the referring hospital is required.

These results suggest that the AHA guideline should be followed, especially in patients who present to the hospital early after symptom onset, to lower hospital mortality.

Our study had several limitations. First, all included hospitals were academic teaching hospitals. The CAVAS program was an observational study that involved hospitals that volunteered to participate in program, and these tended to be more specialized than the nonparticipating hospitals. Half of level 1 EDs and about 15% of level 2 EDs were selected considering geographical location. Second, we applied the 2013 AHA guidelines for AMI, but we included patients in our analysis who received treatment based on the 2005 and 2010 AHA guidelines. The previous guidelines suggested the transfer of STEMI patients from non-PCI- capable hospitals to PCI-capable hospitals as soon as possible, but it did not include a time-based protocol. Thus, some physicians applied the older guidelines. Third, this was not a controlled intervention trial. The

Table 3

Sensitivity analysis by multiple different symptom onset to arrival time criteria

	Group	Total		Death			Unadjusted		Adjusted
		n		n	%		OR 95% CI		OR	95% CI
	All	753		43	5.7
Symptom onset to arrival within 30 min	Violation	494		34	6.9		1.00
	Compliance	259		9	3.5		0.49 (0.23-1.03)		0.44	(0.19-0.98)
	All	1137		43	3.8
Symptom onset to arrival within 60 min	Violation	777		55	7.1		1.00
	Compliance	360		14	3.9		0.53 (0.29-0.97)		0.56	(0.3-1.07)
	All	1489		93	6.2
Symptom onset to arrival within 120 min	Violation	1033		72	7.0		1.00
	Compliance	456		21	4.6		0.64 (0.39-1.06)		0.77	(0.45-1.32)
	All	1767		107	6.1
Symptom onset to arrival within 240 min	Violation	1227		83	6.8		1.00
	Compliance	540		24	4.4		0.64 (0.4-1.02)		0.81	(0.49-1.32)

Adjusted for age, sex, EMS use, shock, smoke, diabetes mellitus, hypertension, and chronic kidney disease.

causes of death were not documented. The database did not capture in- formation about whether the patient had any contraindications to fibrinolysis.

Conclusions

In transferred STEMI patients, the PCI care recommended by the AHA did not demonstrate a difference in mortality or hospital length of stay between the compliant and violation groups. However, among the transferred STEMI patients who arrived to the hospital within 30 minutes of symptom onset, the PCI care recommended by the AHA was associated with lower mortality.

Appendix 1. Demographic and clinical characteristics of transferred STEMI patients included and excluded

Total Included Excluded

	n	%		n	%		n	%	P value
Total	5257			2078	39.5		3179	60.5
Sex									.02
Male	3714	70.6		1505	72.4		2209	69.5
Female	1543	29.4		573	27.6		970	30.5
Age									b.01
Elderly (65-100)	2629	50.0	970		46.7	1659		52.2
Adults (19-64)	2628	50.0	1108		53.3	1520		47.8
Median (IQR) 65 (53-74) 63 (52-73) 65 (54-74) b.01 Medical history
DM	1352	25.7	477		23.0	875		27.5	b.01
Hypertension	2437	46.4	920		44.3	1517		47.7	.01
CKD	147	2.8	38		1.8	109		3.4	b.01
AMI	262	5.0	81		3.9	181		5.7	b.01
PCI Hx	223	4.2	65		3.1	158		5.0	b.01
Health behavior Current smoker	2293	43.6	972		46.8	1321		41.6	b.01
Ex-smoker	737	14.0	290		14.0	447		14.1
Alcohol drinking	1786	34.0	764		36.8	1022		32.1	b.01
Chief concern									b.01
Chest pain	4675	88.9	1938		93.3	2737		86.1
Dyspnea	215	4.1	42		2.0	173		5.4
Syncope	78	1.5	27		1.3	51		1.6
Arrest	56	1.1	0		0.0	56		1.8
Others	233	4.4	71		3.4	162		5.1
EMS use									b.01
	609	11.6	308		14.8	301		9.5

Symptom to arrival b.01

Median (IQR) 60 (25-240) 60 (27-143) 120 (20-1095)

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    Primary hospital arrival to departure

    Median (IQR) 60 (30-120) 55 (30-100) 80 (37-195)

    b.01

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17. Shin SD, Ong ME, Tanaka H, Ma MH, Nishiuchi T, Alsakaf O, et al. Comparison of

    Interhospital transfer time b.01

    34 (21-54) 33 (20-51) 36 (23-62)

    Cardiogenic shock .28

    	410	7.8	152	7.3	258	8.1	Use and Inter-hospital Transfer on Time to Percutaneous Coronary Intervention in
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    Not ST elevation	484	9.2	163	7.8	321	10.1	[20] Cannon CP, Gibson CM, Lambrew CT, Shoultz DA, Levy D, French WJ, et al. Relation-
    Unknown	802	15.3	159	7.7	643	20.2	ship of symptom-onset-to-balloon time and Door-to-balloon time with mortality in
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    Not ST elevation	520	9.9	124	6.0	396	12.5	farction treated by primary angioplasty. J Am Coll Cardiol 2003;42(6):991-7.
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