Abstract

Aims

To determine the safety and efficacy of a pharmaco-invasive reperfusion strategy utilizing half-dose fibrinolysis combined with transfer for immediate percutaneous coronary intervention (PCI) in ST-elevation myocardial infarction (STEMI) patients presenting to remote rural hospitals. Primary PCI is preferred for STEMI if performed in a timely manner. However, <20% of STEMI patients transferred for PCI in the USA have door-to-balloon times <2 h.

Methods and results

Prospective data from the Level 1 MI programme were analysed. All STEMI patients presenting to the Minneapolis Heart Institute or 31 referral hospitals received aspirin, clopidogrel, and unfractionated heparin (UFH) at the presenting hospital and those presenting to hospitals ≥60 miles away also received half-dose fibrinolytic with transfer for immediate PCI. From April 2003 through December 2009, we enrolled 2634 consecutive STEMI patients in the Level 1 MI database including 660 transferred from remote hospitals utilizing pharmaco-invasive therapy and 600 patients who presented directly to the PCI centre. There were no significant differences in 30-day mortality (5.5 vs. 5.6%; P= 0.94), stroke (1.1 vs. 1.3%; P= 0.66) or major bleeding (1.5 vs. 1.8%; P= 0.65), or re-infarction/ischaemia (1.2 vs. 2.5%; P= 0.088) in patients receiving a pharmaco-invasive strategy compared with patients presenting directly to the PCI centre, despite a significantly longer door-to-balloon time.

Conclusion

Within a regional STEMI system of care, half-dose fibrinolysis combined with immediate transfer for PCI may be a safe and effective option for STEMI patients with expected delays due to long-distance transfer.

Introduction

The optimal reperfusion strategy for ST-segment elevation myocardial infarction (STEMI) is primary percutaneous coronary intervention (PCI) if it can be performed in a timely manner by experienced providers.1,2 Only 25% of hospitals in the USA are capable of providing primary PCI and most are located in urban areas. To date, less than ideal treatment options exist for STEMI patients residing in rural areas located long distances from primary PCI-capable hospitals. These include fibrinolytic therapy (which restores normal coronary flow in only 50–55% of patients) or transfer to a PCI-capable hospital for primary PCI (which can result in significant delays to reperfusion). The most recent data from the National Cardiovascular Data Registry (2005–06) indicate that 82% of STEMI patients transferred for primary PCI had door-to-balloon times of >120 min.3

Recently, a strategy of combining fibrinolysis followed by transfer for early PCI (‘‘pharmaco-invasive PCI’’) has been shown to be an effective reperfusion strategy for STEMI patients presenting to non-PCI hospitals compared with fibrinolysis alone with an ischaemia-guided rescue PCI strategy based on current guidelines.4–7 We report the outcomes from a regional STEMI system in Minnesota utilizing a pharmaco-invasive reperfusion strategy in STEMI patients presenting to rural hospitals geographically remote from the primary PCI hospital.

Methods

The Minneapolis Heart Institute at Abbott Northwestern (MHI-ANW) Hospital in Minneapolis, Minnesota, is a tertiary, cardiovascular centre with referral relationships with 31 community hospitals throughout Minnesota and western Wisconsin. In 2003, a regional system for the management of STEMI, the ‘‘Level 1 MI programme’’ was initiated using a standardized protocol for transfer of STEMI patients for primary or pharmaco-invasive PCI from community hospitals up to 210 miles from the PCI hospital. Currently 11 referral hospitals are <60 miles from MHI-ANW (designated as Zone 1 hospitals) and 20 referral hospitals are 60–210 miles from MHI-ANW (designated as Zone 2 hospitals). The detailed design and early results of the Level 1 MI programme have been previously reported.8,9 Consecutive STEMI patients treated in the ‘‘Level 1 MI’’ regional STEMI system are enrolled in an extensive prospective registry called the ‘‘Level 1 MI’’ database.

A standardized protocol with pre-printed standing orders was implemented at each hospital. Each patient received aspirin 325 mg p.o., clopidogrel 600 mg p.o., unfractionated heparin (UFH) 60 U/kg i.v. load (maximum 4000 U), 12 U/kg/h i.v. infusion (max 1000 U/h), and a beta-blocker (unless contraindicated) in the emergency department at the presenting hospital. Patients who presented to the PCI hospital (MHI-ANW) or were transferred from a Zone 1 hospital (<60 miles away) underwent primary PCI as the reperfusion method. Patients transferred from Zone 2 hospitals (≥60 miles) received half-dose fibrinolytic followed by emergency transfer for immediate PCI (pharmaco-invasive PCI). The decision regarding which fibrinolytic to use was based on the individual hospital formulary but was tenecteplase (TNK) most frequently. Contraindications to fibrinolysis included: active bleeding, significant closed head injury within 3 months, suspected aortic dissection, ischaemic stroke within 3 months, known intracranial neoplasm or prior intracranial haemorrhage, and out of hospital cardiac arrest with prolonged CPR. Femoral access was used for coronary angiography in nearly all cases.

Patients with STEMI or new left bundle branch block within 24 h of symptom onset were included in the MHI Level 1 MI programme and database. No patients were excluded from the protocol unless the physician determined that reperfusion therapy was inappropriate due to an underlying co-morbid condition, such as advanced cancer or end-stage dementia. All patients (including those with advanced age, out-of-hospital cardiac arrest, and cardiogenic shock) were included in the data analysis. Data were prospectively entered into a registry and included clinical, laboratory, electrocardiogram, angiographic, and follow-up information. Clinical outcome data at 30 days and 1 year were abstracted from the electronic medical record. In addition, all patients were contacted by telephone at 1 year to inquire about clinical events. Angiographic data included the culprit coronary artery, number of vessels with coronary artery disease, thrombolysis in myocardial infarction (TIMI) flow before and after intervention, and ejection fraction using American College of Cardiology National Cardiovascular Data Registry definitions.10 All data collection forms, discharge summaries, and angiographic reports were reviewed by one of the authors (D.M.L. or T.D.H.) to ensure accuracy.

Recurrent ischaemia was defined as recurrent ischaemic pain at rest (believed to be cardiac in origin) associated with electrocardiographic changes. Recurrent infarction was defined according to the Joint European Society of Cardiology/American College of Cardiology definition of myocardial infarction.11 Major bleeding was defined according to the TIMI definitions for bleeding.10

For the purposes of comparison, we established five patient groups (Figure 1). Group A (n = 600)—primary PCI patients who presented directly to the PCI hospital (MHI-ANW). Group B (n = 1163)—primary PCI patients transferred from hospitals located <60 miles (Zone 1) from the PCI hospital. Group C (n = 32)—pharmaco-invasive PCI patients transferred from hospitals located <60 miles (Zone 1) from the PCI hospital with anticipated delays due to inclement weather. Group D (n = 660)—pharmaco-invasive PCI patients transferred from hospitals located ≥60 miles (Zone 2) from the PCI hospital. Group E (n = 179)—primary PCI patients transferred from ≥60 miles (Zone 2).

Figure 1

Distribution of ST-elevation myocardial infarction patients by initial hospital presentation and reperfusion strategy. Percutaneous coronary intervention Hosp: (Minneapolis Heart Institute at Abbott Northwestern Hospital). Zone 1 Hosp (referral hospitals located <60 miles from percutaneous coronary intervention hospital). Zone 2 Hosp (referral hospitals located ≥60 miles from the percutaneous coronary intervention hospital). PPCI, primary percutaneous coronary intervention. Ph-Inv, pharmaco-invasive.

Figure 1

Distribution of ST-elevation myocardial infarction patients by initial hospital presentation and reperfusion strategy. Percutaneous coronary intervention Hosp: (Minneapolis Heart Institute at Abbott Northwestern Hospital). Zone 1 Hosp (referral hospitals located <60 miles from percutaneous coronary intervention hospital). Zone 2 Hosp (referral hospitals located ≥60 miles from the percutaneous coronary intervention hospital). PPCI, primary percutaneous coronary intervention. Ph-Inv, pharmaco-invasive.

Statistics

The prespecified primary groups of comparison were patients presenting directly to the PCI hospital treated with primary PCI (Group A) and those transferred from hospitals >60 miles away who received pharmaco-invasive PCI (Group D). We also compared patients receiving primary PCI at both the PCI hospital and Zone 1 (Group A + B) with those receiving a pharmaco-invasive approach (Group C + D) in both Zone 1 and Zone 2. Categorical variables are reported as the number of patients (%) with the characteristic, except for door-to-balloon and length of stay (LOS) values which are reported as the median, and the 25 and 75th percentiles. χ2 or Fisher's exact tests were used to assess the statistical significance of categorical variables among combinations of groups. Length of stay and door-to-balloon values were transformed using ln(value + 1) to more closely approximate a normal distribution, and compared with t-tests.

A propensity-score method was used to identify comparable patients treated with the pharmaco-invasive approach and those receiving PPCI, in Groups A and D. Multivariable logistic regression analysis, including all baseline characteristics, was performed to calculate the predicted probability of receiving pharmaco-invasive (propensity score) for each patient. A nearest-neighbour 1:1 matching algorithm was used to match subjects on the basis of the logit of the propensity score.

A stepwise logistic multivariable analysis was performed to look for independent factors related to 30-day mortality. The model had a c-statistic of 0.88, indicating excellent discrimination and a Hosmer–Lemeshow test statistic of 12.77 (P = 0.12), indicating that the model had good fit.

A P-value of 0.05 or less was considered statistically significant and all reported P-values are two-sided. All analyses were performed with Stata Version 11.0 (College Station, TX, USA).

Results

From April 2003 to December 2009, we enrolled 2634 consecutive STEMI patients in the Level 1 MI database of whom 600 presented to the PCI hospital (MHI-ANW), 1195 to Zone 1 hospitals <60 miles, and 839 to Zone 2 hospitals ≥60 miles from the PCI hospital (Figure 1). Primary PCI was the reperfusion strategy for 1942 (73.7%) including the 600 patients who presented to the PCI hospital (MHI-ANW) directly, 1163 transferred from hospitals located <60 miles (Zone 1), and 179 transferred from hospitals located ≥60 miles (Zone 2) from the PCI hospital. A pharmaco-invasive reperfusion strategy with half-dose fibrinolysis (97% TNK, 3% reteplase) was used in 692 (26.3%) patients including 660 from Zone 2 hospitals located ≥60 miles away and 32 from Zone 1 hospitals with weather-related transfer delays.

Baseline clinical characteristics are shown in Table 1. Primary PCI-treated patients presenting directly to the PCI hospital or transferred from Zone 1 hospitals (Group A and B) were compared with pharmaco-invasive PCI-treated patients transferred from Zone 1 or 2 hospitals (Group C and D). The pharmaco-invasive-treated patients were slightly older; otherwise, there were no statistically significant differences in baseline clinical characteristics.

Table 1

Baseline clinical characteristics

 Group A, PPCI, PCI hospital, n= 600 Group B, PPCI, Zone 1, n = 1163 Total PPCI, A + B, n = 1763 Group C, PI, Zone 1, n = 32 Group D, PI, Zone 2, n = 660 Total, PI, C + D, n = 692 Group E, PPCI, Zone 2, n = 179 P-value, A vs. D P-value, PPCI vs. PI, A + B vs. C + D P-value, Zone 2, D vs. E 
Age 62.9 ± 14.7 61.2 ± 14.6 61.8 ± 14.6 61.7 ± 12.6 63.3 ± 13.5 63.2 ± 13.5 65.4 ± 14.5 0.65 0.025 0.073 
Patient ≥75 years 151 (25.2) 254 (21.8) 405 (23.0) 7 (21.9) 160 (24.2) 167 (24.1) 58 (32.4) 0.70 0.54 0.027 
Male 418 (69.7) 851 (73.2) 1269 (72.0) 27 (84.4) 484 (73.3) 511 (73.8) 116 (64.8) 0.15 0.35 0.025 
Hyperlidaemia 353 (60.7) 601 (53.3) 954 (55.8) 16 (51.6) 356 (56.0) 372 (55.8) 95 (55.6) 0.098 0.98 0.92 
Hypertension 361 (60.6) 636 (55.1) 997 (57.0) 16 (50.0) 368 (55.9) 384 (55.7) 117 (66.5) 0.096 0.55 0.012 
Diabetes 111 (18.6) 164 (14.2) 275 (15.7) 3 (9.4) 119 (18.1) 122 (17.7) 32 (18.0) 0.81 0.45 0.97 
Current smoker 201 (33.9) 475 (41.1) 676 (38.7) 10 (31.3) 270 (41.2) 280 (40.7) 56 (32.0) 0.008 0.36 0.027 
History of MI 137 (22.9) 207 (17.8) 344 (19.6) 2 (6.3) 131 (19.9) 133 (19.2) 46 (26.0) 0.19 0.85 0.076 
History of CABG 47 (8.9) 69 (6.0) 116 (6.6) 2 (6.3) 41 (6.2) 43 (6.2) 19 (10.7) 0.26 0.74 0.042 
History of PCI 144 (24.2) 217 (18.7) 361 (20.6) 5 (15.6) 122 (18.5) 127 (18.4) 47 (26.4) 0.013 0.22 0.019 
Cardiogenic shock 63 (10.5) 109 (9.4) 172 (9.8) 1 (3.1) 51 (7.7) 52 (7.5) 18 (10.1) 0.087 0.081 0.32 
Out of hospital cardiac arrest 36 (6.0) 125 (10.8) 161 (9.1) 2 (6.3) 46 (7.0) 48 (6.9) 21 (11.7) 0.49 0.079 0.037 
Anterior MI 212 (36.2) 378 (32.9) 590 (34.0) 16 (50.0) 230 (35.2) 246 (35.9) 57 (33.1) 0.71 0.38 0.61 
Killip Class 2–4 94 (15.7) 156 (13.4) 250 (14.2) 3 (9.4) 90 (13.6) 93 (13.4) 26 (14.5) 0.31 0.63 0.76 
New LBBB 14 (2.4) 44 (3.8) 58 (3.3) 0 (0) 17 (2.6) 17 (2.5) 10 (5.8) 0.81 0.27 0.035 
 Group A, PPCI, PCI hospital, n= 600 Group B, PPCI, Zone 1, n = 1163 Total PPCI, A + B, n = 1763 Group C, PI, Zone 1, n = 32 Group D, PI, Zone 2, n = 660 Total, PI, C + D, n = 692 Group E, PPCI, Zone 2, n = 179 P-value, A vs. D P-value, PPCI vs. PI, A + B vs. C + D P-value, Zone 2, D vs. E 
Age 62.9 ± 14.7 61.2 ± 14.6 61.8 ± 14.6 61.7 ± 12.6 63.3 ± 13.5 63.2 ± 13.5 65.4 ± 14.5 0.65 0.025 0.073 
Patient ≥75 years 151 (25.2) 254 (21.8) 405 (23.0) 7 (21.9) 160 (24.2) 167 (24.1) 58 (32.4) 0.70 0.54 0.027 
Male 418 (69.7) 851 (73.2) 1269 (72.0) 27 (84.4) 484 (73.3) 511 (73.8) 116 (64.8) 0.15 0.35 0.025 
Hyperlidaemia 353 (60.7) 601 (53.3) 954 (55.8) 16 (51.6) 356 (56.0) 372 (55.8) 95 (55.6) 0.098 0.98 0.92 
Hypertension 361 (60.6) 636 (55.1) 997 (57.0) 16 (50.0) 368 (55.9) 384 (55.7) 117 (66.5) 0.096 0.55 0.012 
Diabetes 111 (18.6) 164 (14.2) 275 (15.7) 3 (9.4) 119 (18.1) 122 (17.7) 32 (18.0) 0.81 0.45 0.97 
Current smoker 201 (33.9) 475 (41.1) 676 (38.7) 10 (31.3) 270 (41.2) 280 (40.7) 56 (32.0) 0.008 0.36 0.027 
History of MI 137 (22.9) 207 (17.8) 344 (19.6) 2 (6.3) 131 (19.9) 133 (19.2) 46 (26.0) 0.19 0.85 0.076 
History of CABG 47 (8.9) 69 (6.0) 116 (6.6) 2 (6.3) 41 (6.2) 43 (6.2) 19 (10.7) 0.26 0.74 0.042 
History of PCI 144 (24.2) 217 (18.7) 361 (20.6) 5 (15.6) 122 (18.5) 127 (18.4) 47 (26.4) 0.013 0.22 0.019 
Cardiogenic shock 63 (10.5) 109 (9.4) 172 (9.8) 1 (3.1) 51 (7.7) 52 (7.5) 18 (10.1) 0.087 0.081 0.32 
Out of hospital cardiac arrest 36 (6.0) 125 (10.8) 161 (9.1) 2 (6.3) 46 (7.0) 48 (6.9) 21 (11.7) 0.49 0.079 0.037 
Anterior MI 212 (36.2) 378 (32.9) 590 (34.0) 16 (50.0) 230 (35.2) 246 (35.9) 57 (33.1) 0.71 0.38 0.61 
Killip Class 2–4 94 (15.7) 156 (13.4) 250 (14.2) 3 (9.4) 90 (13.6) 93 (13.4) 26 (14.5) 0.31 0.63 0.76 
New LBBB 14 (2.4) 44 (3.8) 58 (3.3) 0 (0) 17 (2.6) 17 (2.5) 10 (5.8) 0.81 0.27 0.035 

PPCI, primary percutaneous coronary intervention; PCI, percutaneous coronary intervention; PI, pharmaco-invasive; MI, myocardial infarction; CABG, coronary artery bypass graft; LBBB, left bundle branch block.

Clinical outcome parameters are shown in Table 2. Median door-to-balloon times were 62 (44, 83) min for those presenting directly to the PCI hospital (Group A), 94 (80, 116) min for primary PCI patients transferred from Zone 1 hospitals (Group B), and 122 (100, 147) min for pharmaco-invasive-treated patients transferred from Zone 2 hospitals (Group D). The median door-to-needle time (arrival at the presenting hospital emergency department to administration of fibrinolytic) was 29 (20, 42) min for patients receiving fibrinolytic therapy prior to transfer.

Table 2

Clinical outcomes

 Group A, PPCI, PCI hospital, n = 600 Group B, PPCI, Zone 1, n = 1163 Total PPCI, A + B, n = 1763 Group C, PI, Zone 1, n = 32 Group D, PI, Zone 2, n = 660 Total, PI, C + D, n = 692 Group E, PPCI, Zone 2, n = 179 P-value, A vs. D P-value, PPCI vs. PI, A + B vs. C + D P-value, Zone 2, D vs. E 
Door-to-balloon 62 (44, 83) 94 (80, 116) 86 (68, 108) 112.5 (102, 141.5) 122 (100, 147) 121 (100, 146) 131 (107, 169) <0.001 <0.001 <0.001 
Chest pain-to-balloon 171.5 (118, 314) 190 (141, 304) 185 (135, 307) 238 (177.5, 379.5) 209.5 (160, 313.5) 210.5 (160.5, 316) 272 (192, 435) <0.001 <0.001 <0.001 
Mortality hospital 30 (5.0) 57 (4.9) 87 (4.9) 2 (6.3) 35 (5.3) 37 (5.4) 17 (9.5) 0.81 0.68 0.039 
Mortality 30 days 33 (5.5) 66 (5.7) 99 (5.6) 3 (9.4) 37 (5.6) 40 (5.8) 19 (10.6) 0.94 0.87 0.017 
Re-MI 30 days 10 (1.7) 10 (0.9) 20 (1.1) 1 (3.1) 7 (1.1) 8 (1.2) 2 (1.1) 0.35 0.96 0.95 
Re-MI/ischaemia 30 days 15 (2.5) 12 (1.0) 27 (1.5) 1 (3.1) 8 (1.2) 9 (1.3) 2 (1.1) 0.088 0.67 0.92 
Major bleeding 11 (1.8) 14 (1.2) 25 (1.4) 1 (3.1) 10 (1.5) 11 (1.6) 3 (1.7) 0.65 0.76 0.88 
Stroke 30 days 8 (1.3) 7 (0.6) 15 (0.9) 1 (3.1) 7 (1.1) 8 (1.2) 2 (1.1) 0.66 0.48 0.95 
Length of stay 3 (2, 5) 3 (2, 4) 3 (2, 4) 3 (2, 4) 3 (2, 4) 3 (2, 4) 3 (2, 5) 0.0017 0.050a 0.0334 
AICD implanted 18 (3.0) 54 (4.6) 72 (4.1) 0 (0) 19 (2.9) 19 (2.8) 6 (3.4) 0.90 0.11 0.74 
 Group A, PPCI, PCI hospital, n = 600 Group B, PPCI, Zone 1, n = 1163 Total PPCI, A + B, n = 1763 Group C, PI, Zone 1, n = 32 Group D, PI, Zone 2, n = 660 Total, PI, C + D, n = 692 Group E, PPCI, Zone 2, n = 179 P-value, A vs. D P-value, PPCI vs. PI, A + B vs. C + D P-value, Zone 2, D vs. E 
Door-to-balloon 62 (44, 83) 94 (80, 116) 86 (68, 108) 112.5 (102, 141.5) 122 (100, 147) 121 (100, 146) 131 (107, 169) <0.001 <0.001 <0.001 
Chest pain-to-balloon 171.5 (118, 314) 190 (141, 304) 185 (135, 307) 238 (177.5, 379.5) 209.5 (160, 313.5) 210.5 (160.5, 316) 272 (192, 435) <0.001 <0.001 <0.001 
Mortality hospital 30 (5.0) 57 (4.9) 87 (4.9) 2 (6.3) 35 (5.3) 37 (5.4) 17 (9.5) 0.81 0.68 0.039 
Mortality 30 days 33 (5.5) 66 (5.7) 99 (5.6) 3 (9.4) 37 (5.6) 40 (5.8) 19 (10.6) 0.94 0.87 0.017 
Re-MI 30 days 10 (1.7) 10 (0.9) 20 (1.1) 1 (3.1) 7 (1.1) 8 (1.2) 2 (1.1) 0.35 0.96 0.95 
Re-MI/ischaemia 30 days 15 (2.5) 12 (1.0) 27 (1.5) 1 (3.1) 8 (1.2) 9 (1.3) 2 (1.1) 0.088 0.67 0.92 
Major bleeding 11 (1.8) 14 (1.2) 25 (1.4) 1 (3.1) 10 (1.5) 11 (1.6) 3 (1.7) 0.65 0.76 0.88 
Stroke 30 days 8 (1.3) 7 (0.6) 15 (0.9) 1 (3.1) 7 (1.1) 8 (1.2) 2 (1.1) 0.66 0.48 0.95 
Length of stay 3 (2, 5) 3 (2, 4) 3 (2, 4) 3 (2, 4) 3 (2, 4) 3 (2, 4) 3 (2, 5) 0.0017 0.050a 0.0334 
AICD implanted 18 (3.0) 54 (4.6) 72 (4.1) 0 (0) 19 (2.9) 19 (2.8) 6 (3.4) 0.90 0.11 0.74 

PPCI, primary percutaneous coronary intervention; PCI, percutaneous coronary intervention; PI, pharmaco-invasive; MI, myocardial infarction AICD, automated implantable cardioverter defibrillator.

aPI group is significantly shorter.

Pre-PCI patency (TIMI 2 or 3 flow) was found in 73.6% of the pharmaco-invasive PCI-treated patients vs.40.3% in primary PCI patients (P< 0.001). Angiographic data comparing Group A vs. Group D are shown in Table 3. The time in minutes from fibrinolysis to angiography in Group D patients was <60 in 13%, 61–90 in 36%, 91–120 in 28%, 121–180 in 17%, and >180 in 6%.

Table 3

Angiographic characteristics

 Group A, ANW PPCI, (n= 600) Group D, Zone 2 PI, (n = 660) P-value 
Culprit artery 
 Left main 5 (0.8) 6 (0.9) 0.89 
 LAD 195 (32.5) 219 (33.2) 0.80 
 LCx 73 (12.2) 79 (12.0) 0.92 
 RCA 203 (33.8) 244 (37.0) 0.25 
 Graft 24 (4.0) 16 (2.4) 0.11 
 No culprit 53 (8.8) 55 (8.3) 0.75 
 No culprit and  negative markers 26 (4.3) 26 (3.9) 0.73 

 
TIMI flow pre 
 Flow: 0/1 354 (59.7) 171 (26.4) <0.001 
 Flow: 2/3 239 (40.3) 477 (73.6) 

 
TIMI flow post 
 Flow: 0/1 18 (3.0) 18 (2.8) 0.80 
 Flow: 2/3 576 (97.0) 629 (97.2) 
 Ejection fraction 46.6 ± 13.4 46.8 ± 13.5 0.81 
 Group A, ANW PPCI, (n= 600) Group D, Zone 2 PI, (n = 660) P-value 
Culprit artery 
 Left main 5 (0.8) 6 (0.9) 0.89 
 LAD 195 (32.5) 219 (33.2) 0.80 
 LCx 73 (12.2) 79 (12.0) 0.92 
 RCA 203 (33.8) 244 (37.0) 0.25 
 Graft 24 (4.0) 16 (2.4) 0.11 
 No culprit 53 (8.8) 55 (8.3) 0.75 
 No culprit and  negative markers 26 (4.3) 26 (3.9) 0.73 

 
TIMI flow pre 
 Flow: 0/1 354 (59.7) 171 (26.4) <0.001 
 Flow: 2/3 239 (40.3) 477 (73.6) 

 
TIMI flow post 
 Flow: 0/1 18 (3.0) 18 (2.8) 0.80 
 Flow: 2/3 576 (97.0) 629 (97.2) 
 Ejection fraction 46.6 ± 13.4 46.8 ± 13.5 0.81 

ANW, Abbott Northwestern Hospital; PPCI, primary percutaneous coronary intervention; PI, pharmaco-invasive; LAD, left anterior descending; LCx, left circumflex; RCA, right coronary artery.

A pre-specified prospective comparison of patients presenting directly to the PCI hospital, treated with primary PCI (Group A) with patients transferred from hospitals ≥60 miles from the PCI hospital (Zone 2) who received pharmaco-invasive PCI showed no significant differences with respect to 30-day mortality (5.5 vs. 5.6%; P = 0.94), stroke (1.3 vs. 1.1%; P = 0.66), recurrent ischaemia/myocardial infarction (2.5 vs. 1.2%; P = 0.088), or TIMI major bleeding (1.8 vs. 1.5%; P = 0.65). In addition, comparing the total group of patients treated with primary PCI (Group A and B) who presented to the PCI centre or were transferred from <60 miles (Zone 1) with the total group treated with pharmaco-invasive PCI (Group C and D) also showed no significant difference in 30-day mortality (5.6 vs. 5.8%; P = 0.87), stroke (0.9 vs. 1.2%; P = 0.48), recurrent ischaemia/myocardial infarction (1.5 vs. 1.3%; P = 0.67) or TIMI major bleeding (1.4 vs. 1.6%; P = 0.76).

In the propensity score matched cohort, all baseline characteristics exhibited excellent balance between Groups A and D. Of the 1260 patients, 75 were omitted due to an unknown baseline characteristic, with only 1 patient removed due to not achieving a suitable match. Of note, there was no difference in the 30-day mortality between the matched groups after adjustment for the propensity score, confirming our primary analyses. A multivariate analysis identified age, out-of-hospital cardiac arrest, and cardiogenic shock as independent predictors of 30-day mortality (Table 4).

Table 4

Multivariable model for predictors of death at 30 days (Group A + Group D)

 Coefficient (SE) Odds ratio (95% CI) P-value 
Intercept −8.327 (0.935) –  
Agea 0.064 (0.012) 1.89 (1.49, 2.40) <0.001 
Out of hospital cardiac arrest 2.002 (0.366) 7.40 (3.61, 15.17) <0.001 
Cardiogenic shock 2.512 (0.305) 12.33 (6.77, 22.43) <0.001 
 Coefficient (SE) Odds ratio (95% CI) P-value 
Intercept −8.327 (0.935) –  
Agea 0.064 (0.012) 1.89 (1.49, 2.40) <0.001 
Out of hospital cardiac arrest 2.002 (0.366) 7.40 (3.61, 15.17) <0.001 
Cardiogenic shock 2.512 (0.305) 12.33 (6.77, 22.43) <0.001 

aOdds ratio is per 10 year increment in age.

Kaplan–Meier 1-year survival curves comparing primary PCI (Group A and B) treated patients with pharmaco-invasive PCI (Group C and D)-treated patients are shown in Figure 2 and were nearly identical.

Figure 2

Kaplan–Meier survival curves comparing primary percutaneous coronary intervention treated ST-elevation myocardial infarction patients to pharmaco-invasive-treated ST-elevation myocardial infarction patients.

Figure 2

Kaplan–Meier survival curves comparing primary percutaneous coronary intervention treated ST-elevation myocardial infarction patients to pharmaco-invasive-treated ST-elevation myocardial infarction patients.

Intracranial haemorrhage occurred in two patients (0.3; 95% confidence interval, 0–0.7%) treated with half-dose fibrinolysis. Both patients survived neurologically intact. Although the LOS in the pharmaco-invasive group was statistically significant, the median LOS was 3 days for each group and, therefore, unlikely to be clinically relevant. There was also no difference in the requirement for automatic implantable cardiac defibrillators between any of the groups.

Of the 839 patients who presented initially to hospitals ≥60 miles (Zone 2) from the PCI hospital, 179 (21.3%) did not receive a fibrinolytic and were transferred for primary PCI. The median door-to-balloon time in this group was 131 (107, 169) min. Contraindication to fibrinolysis was the most common reason for exclusion from pharmaco-invasive therapy (Table 5). These patients had higher in-hospital (9.5 vs. 5.3%, P = 0.039) and 30-day mortality (10.6 vs. 5.6%, P = 0.17) compared with patients transferred from Zone 2 with pharmaco-invasive PCI. They were, however, higher risk patients as they were older with more risk factors (hypertension, prior history of MI, CABG, or PCI) and more likely to have had an out-of-hospital cardiac arrest (11.7 vs. 7.0%; P = 0.037), which was considered to be a relative contraindication to fibrinolysis.

Table 5

Reasons for no lytics in Zone 2 (n = 179)

Contraindication to lytics 100 (55.9%) 
Uncertain diagnosis 24 (13.4%) 
Reason not documented 20 (11.1%) 
Physician discretions 13 (7.3%) 
Delayed presentation 12 (6.7%) 
Post-cardiac arrest ‘Cool It’ 10 (5.6%) 
Contraindication to lytics 100 (55.9%) 
Uncertain diagnosis 24 (13.4%) 
Reason not documented 20 (11.1%) 
Physician discretions 13 (7.3%) 
Delayed presentation 12 (6.7%) 
Post-cardiac arrest ‘Cool It’ 10 (5.6%) 

Discussion

ST-elevation myocardial infarction patients who present to geographically isolated hospitals located long distances from a primary PCI-capable hospital frequently have delays to PCI of >120 min. For these patients, our results indicate that a pharmaco-invasive PCI strategy utilizing half-dose fibrinolysis, in addition to clopidogrel 600 mg and UFH, within the context of an organized regional network, maybe an equally effective and safe reperfusion strategy with results similar to those for patients presenting directly to a PCI-capable hospital.

Approximately 60 million people (20% of the US population) live >60 miles from a hospital capable of performing PCI.12 Within this population it is expected that ∼175 000 patients per year will have a STEMI and because of geographical location these patients may not have access to timely PCI. Even in Denmark with an organized transfer system and shorter transfer distances, 65% of transferred STEMI patients experienced a system delay to reperfusion of >120 min.13 Reperfusion options for this group of STEMI patients include the following: (i) full-dose fibrinolysis and admission to the non-PCI hospital with ischaemia-guided transfer for rescue PCI, (ii) full-dose fibrinolysis with routine transfer for ischaemia-guided rescue PCI, (iii) transfer for primary PCI, (iv) full- or reduced-dose fibrinolysis followed by immediate transfer for early or delayed PCI (pharmaco-invasive).14

Primary PCI is the preferred reperfusion strategy when compared with fibrinolysis in STEMI patients if it can be performed in a timely manner by experienced centres. However, most would agree that the benefit of primary PCI over fibrinolysis is reduced when there is a significant delay related to transfer.15–17 A recent study by Lambert et al.18 showed that STEMI patients, who are transferred for primary PCI, as recommended by guidelines, with delays to reperfusion >90 min have significantly greater 30-day mortality.

An alternative strategy, in principle, is combining the advantage of fibrinolysis availability with the improved reperfusion with PCI. The results of early randomized clinical trials, comparing the combination of fibrinolysis followed by immediate PCI with primary PCI alone, were disappointing.19–22 It is important to note that the majority of the patients enrolled in these trials was randomized at or within short distances to a PCI centre where primary PCI remains the optimal reperfusion strategy. However, a recent retrospective analysis of the two largest trials, ASSENT IV and FINESSE, offered new insights regarding this group of STEMI patients.14,23,24 Facilitated PCI seemed to show a benefit in certain subgroups such as high-risk patients who presented early to spoke hospitals.

Several recent randomized clinical trials have demonstrated the benefit of fibrinolysis followed by immediate transfer for an early PCI (pharmaco-invasive) strategy compared with fibrinolysis with an ischaemia-guided, rescue PCI strategy in STEMI patients presenting initially to non-PCI hospitals. The CARESS-in-AMI trial included high-risk STEMI patients (n = 600) who were admitted to non-PCI hospitals in France, Italy, or Poland.4 All patients received half-dose reteplase, abciximab, heparin, and aspirin and were randomized to immediate transfer for PCI or admission to the local hospital and transfer for rescue PCI if needed. The primary outcome, a composite of death, re-infarction or refractory ischaemia at 30 days, occurred in 4.4% of the immediate PCI group, compared with 10.7% in the standard care/rescue PCI group (hazard ratio, 0.4%; 95% CI, 0.21–0.76; P = 0.004). In the immediate PCI group the median time from fibrinolysis to PCI was 135 min.

In TRANSFER-AMI, high-risk STEMI patients (n = 1059) presenting to non-PCI hospitals in Canada were treated with full-dose fibrinolysis and then randomized to either immediate transfer to a PCI hospital with PCI performed within 6h vs. standard treatment with rescue PCI if needed or delayed angiography.5 In the early PCI group the median time from randomization to PCI was 2.8 h. The primary endpoint, a composite of death, re-infarction, recurrent ischaemia, new or worsening congestive heart failure, or cardiogenic shock within 30 days, occurred in 11% of the early routine PCI group compared with 17.2% in the standard treatment group (relative risk with early PCI, 0.64; 95% CI, 0.47–0.87; P = 0.004).

In the NORDISTEMI trial, STEMI patients (n = 266) living in rural areas with >90 min transfer delays were treated with full-dose TNK, aspirin, enoxaparin, and clopidogrel and then randomized to immediate transfer for PCI or to standard management in the local hospital with an ischaemia-guided rescue PCI strategy.6 The primary outcome, a composite of death, re-infarction, stroke, or new ischaemia at 12 months was 21% in the early PCI group vs. 27% in the standard treatment group (hazard ratio: 0.72; 95% CI: 0.44–1.18; P = 0.19). Even though the primary endpoint did not reach significance, the composite of death, re-infarction, or stroke at 12 months was significantly reduced in the early PCI group (6 vs. 16%, hazard ratio: 0.36, 95% CI: 0.16–0.81, P = 0.01).

In all three of these randomized trials there was no significant increase in major bleeding. These three trials were included in a recent meta-analysis which demonstrated that routine early PCI following fibrinolysis, in patients presenting to non-PCI hospitals, leads to a significant reduction in re-infarction, recurrent ischaemia, and the combined endpoint of death and re-infarction at 30 days with no significant increase in bleeding complications.7 Based on these results, the 2010 European Society of Cardiology and the European Association for Cardio-Thoracic Surgery (ESC-EACTS) guidelines on myocardial revascularization has made a class Ia recommendation for transfer of all post-fibrinolysis STEMI patients to a PCI-capable hospital for immediate rescue PCI if fibrinolysis is unsuccessful or coronary angiography within 3–24 h and delayed PCI as needed.25

The Strategic Reperfusion Early After Myocardial Infarction (STREAM) trail, currently enrolling patients, is an open label, prospective randomized international multicentre trial comparing primary PCI with a pharmaco-invasive strategy with full dose (patients < 75 years) or half-dose (patents > 75 years) TNK in STEMI patients presenting <3 h from symptom onset if PCI is not feasible within 60 min. In this protocol, patients who receive fibrinolysis undergo diagnostic angiography and PCI in 6–24 h if there is resolution of ST-elevation or rescue PCI if reperfusion fails within 90 min.26

Our data from real-world experience, which included all STEMI patients without exclusions, are consistent with these randomized clinical trials and confirm the safety and efficacy of a pharmaco-invasive PCI strategy for rural STEMI patients in the USA who do not have timely access to primary PCI. Our protocol differed from the ongoing STREAM trial in that we included patients with symptoms up to 24 h, and used half-dose fibrinolysis for all age groups, and PCI was performed as early as possible.

The exact pharmacologic regimen and timing of PCI following fibrinolysis remains unclear. As our regional STEMI network expanded in 2003 and 2004,8,9 it was uncertain whether patients transferred from non-PCI centres >60 miles from the PCI centre would achieve total door-to-balloon times <120 min. Therefore, after careful consideration of the available data including the design of the CARESS-in-AMI study, the MHI MI Committee elected to use one-half dose of TNK in addition to aspirin, clopidogrel, and IV UFH for patients in Zone 2 (61–120 miles from the PCI centre). This decision was based on the TNK patency results described in TIMI 10A and TIMI 10B27,28 and the synergistic effects of clopidogrel with fibrinolytic agents described in CLARITY and COMMIT.29,30 This decision was then followed by careful quality assurance, patient-by–patient, and month-to-month to monitor both the safety and efficacy results which have been reported here. With regard to the timing of PCI following fibrinolysis, ESC guidelines currently recommend angiography 3–24 h following fibrinolysis. Based on the design of our system, the majority (64%) of patients from Zone 2 receives angiography 60–120 min post-fibrinolysis. A significant number of patients in the randomized controlled trials comparing pharmaco-invasive PCI with standard therapy have also received PCI this early. For example, in TRANSFER-AMI ∼5% of patients receive PCI < 60 min and 25% < 120 min following fibrinolysis; In CARESS-in-AMI, ∼5% < 60 min, 22% < 90min, and 40% < 120 min following fibrinolysis. While our results do not provide new information regarding the ideal regimen or the timing of PCI, they do support the safety of this approach.

Study limitations

This study has several limitations. First of all, the results were obtained within the context of an organized STEMI system of care requiring significant resources, including physician and nurse training, and similar results may not be attainable in other regions that do not have such a system. Another limitation is that this is a registry investigation rather than a randomized, controlled trial. However, recent experience has shown that it is difficult to enroll STEMI patients in randomized trials because of the lack of research support in rural hospitals. In addition, registry data have the distinct advantage of including a higher risk patient population not included in randomized trials.31,32 The TIMI flow data were based on the interpretation by the interventional cardiologist and not independently reviewed by a core laboratory; however, this is not the main focus of this study and our results are consistent with many other randomized controlled trials demonstrating improved pre-PCI patency in patients receiving fibrinolysis prior to PCI.

Conclusion

Pharmaco-invasive therapy utilizing half-dose fibrinolysis, clopidogrel, and UFH, combined with emergent transfer for immediate PCI, may be a safe and effective reperfusion strategy for STEMI patients with expected delays due to long distances to a PCI centre. Using a standardized protocol within a regional STEMI system of care, we have effectively eliminated urban–rural disparities in the treatment of STEMI.

Funding

This work was supported by the Minneapolis Heart Institute Foundation. There were no relationships with industry.

Conflict of interest: none declared.

Acknowledgements

The authors are indebted to Jennifer Krech, BA for her assistance in the preparation of this manuscript.

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See page 1184 for the editorial comment on this article (doi:10.1093/eurheartj/ehr427)

Supplementary data

Comments

2 Comments
The pharmaco-invasive strategy - Why not just invasive...?
7 June 2012
Jacob T. Sorensen (with Christian J. Terkelsen)

Dear editor,

We read with great interest the paper by Larson et al. on utilization of a pharmaco-invasive strategy in Minnesota, USA(1) and the accompanying editorial by K Huber(2). We have a few reservations about the conclusions of the aforementioned paper and disagree with the recommendations of the editorial.

There is general consensus that primary percutaneous coronary intervention (PCI) is superior to facilitated PCI and that primary PCI is superior to a strategy of fibrinolysis combined with rescue PCI in those with failed reperfusion after fibrinolysis(3). Some believe that there is a window in between where a strategy of combining fibrinolysis with delayed PCI is superior to primary PCI - the so-called pharmaco-invasive strategy.

In the paper by Larson et al. the door-to-needle time was 29 minutes and the time from fibrinolysis to PCI was a median 90 minutes. When comparing with two of the major facilitated PCI trials (Finesse(4) and Assent-4(5)), the lessons learned were that delaying PCI for approximately 90 minutes, in spite of very aggressive antithrombotic/fibrinolytic therapy showed equal or even worse outcome compared to primary PCI.

It is very difficult to understand how the pharmaco-invasive strategy examined in the study by Larson et al. differ from the facilitated PCI approach used in Finesse and Assent-4, as the delay from lysis to PCI is a median 90-104 minutes in all studies. Most likely, the findings by Larson and colleagues are hampered by selection bias. Certainly, there was a higher frequency of patients in cardiogenic shock and patients with out-of-hospital cardiac arrest among those treated with primary PCI, i.e. primary PCI was chosen as the preferred strategy in the highest risk patients.

To this date the pharmaco-invasive approach has not been directly compared to primary PCI in randomized, controlled trials. Before we have convincing proof of this quite un-physiological concept it is our recommendation that great care is spent in diagnosing the patients as early as possible and triaging the STEMI patients directly for primary PCI from the field instead of delaying PCI for 90 minutes on purpose. Certainly, there is room for improvement in the door-to-balloon delays observed in the paper by Larson and colleagues, and the authors main concern should be that not a single patient is diagnosed in the prehospital phase. Prehospital diagnosis seems mandatory today, either to initiate fibrinolysis in the prehospital phase, or preferably, to field-triage patients to primary PCI if the extra delay associated with PCI is less than 120 minutes compared to a strategy of on-site fibrinolysis(6).

References

1. Larson DM, Duval S, Sharkey SW, Garberich RF, Madison JD, Stokman PJ, et al. Safety and efficacy of a pharmaco-invasive reperfusion strategy in rural ST-elevation myocardial infarction patients with expected delays due to long-distance transfers. Eur Heart J. 2012, May;33(10):1232-40.

2. Huber K. Optimizing reperfusion therapy in acute ST-elevation myocardial infarction by a pharmaco-invasive treatment approach in a well- organized network. Eur Heart J. 2012, May;33(10):1184-6.

3. Wijns W, Kolh P, Danchin N, Di Mario C, Falk V, Folliguet T, et al. Guidelines on myocardial revascularization. Eur Heart J. 2010, Oct;31(20):2501-55.

4. Ellis SG, Tendera M, de Belder MA, van Boven AJ, Widimsky P, Janssens L, et al. Facilitated PCI in patients with ST-elevation myocardial infarction. N Engl J Med. 2008, May 22;358(21):2205-17.

5. Primary versus tenecteplase-facilitated percutaneous coronary intervention in patients with ST-segment elevation acute myocardial infarction (ASSENT-4 PCI): randomised trial [Internet]. Lancet. 2006, Feb 18;367(9510):569-578.Available from: PM:10973764

6. Levine GN, Bates ER, Blankenship JC, Bailey SR, Bittl JA, Cercek B, et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol. 2011, Dec 6;58(24):e44-122.

Conflict of Interest:

None declared

Submitted on 07/06/2012 8:00 PM GMT
Reply to the letter of Drs. Sorensen and Terkelsen
12 July 2012
Timothy D Henry (with David M. Larson, Scott W. Sharkey)

Drs. Sorensen and Terkelsen raise important issues. We agree that primary percutaneous coronary intervention (PCI) is a superior strategy if performed in a timely manner (<120 minutes for transferred patients) based on both ACC/AHA and ESC guidelines.(1,2) The ideal reperfusion strategy for patients with delay >120 minutes remains controversial and is a common clinical problem throughout the world.(3) Even in Denmark, 52% of all EMS transported patients had a treatment delay of >120 minutes, including 65% of patients transferred from a non-PCI center.(4) Based on currently available evidence, we believe pharmaco-invasive PCI (PI-PCI) is an excellent strategy for these patients.(5)

From our perspective, facilitated PCI (F-PCI) and PI-PCI are similar with the major distinction being trial design. F-PCI trials compared fibrinolysis plus immediate PCI with PCI alone. In contrast, PI-PCI trials compared fibrinolysis followed by immediate (early) PCI with fibrinolysis followed by an ischemia guided (rescue) PCI strategy. The ideal pharmacologic regimen and timing of the PCI post-fibrinolysis remain uncertain. The majority of patients in the F-PCI trials were enrolled in PCI centers vs. non-PCI centers for PI-PCI trials. The CARESS-AMI trial was registered as a F-PCI trial on ClinicalTrials.gov, but published as a PI-PCI trial.(6)

The authors cite ASSENT-4 PCI (7) and FINESSE (8) as evidence that primary PCI is superior to F-PCI and ask how our PI-PCI protocol is different. In the MHI Level One Regional STEMI System, patients with an expected delay >120 minutes (distance >60 miles from the PCI hospital) received aspirin, unfractionated heparin (bolus and infusion), clopidogrel (600mg) and half dose fibrinolytic in the rural non-PCI hospital prior to transfer for immediate PCI.(5,9) In ASSENT-4, patients received either primary PCI alone or full-dose fibrinolytic followed by PCI.(7) ASSENT-4 patients received aspirin and heparin bolus without pre- procedure thienopyridines in either group and only PCI-treated patients received IIb/IIIa inhibitor therapy. Only 34% of patients were transferred from a non-PCI hospital. There was an insignificant trend towards higher mortality in patients who received F-PCI in the PCI hospital, and an insignificant trend towards lower mortality in patients receiving pre- hospital fibrinolysis.(7) In a follow-up manuscript, the ASSENT-4 authors note, "Few patients fit the target population, long delays to PCI for whom facilitated PCI was designed and an implied conclusion of our analysis is that the ASSENT-4 PCI trial should not be taken as grounds for conclusive rejection of facilitated PCI."(10) In fact, almost no patient in the MHI Level One Regional STEMI System would have met ASSENT-4 enrollment criteria.

In FINESSE, randomized STEMI patients received F-PCI (half dose reteplase + abciximab + PCI), (abciximab alone + PCI) or primary PCI alone.(8) There were no significant differences in the primary composite endpoint of death, ventricular fibrillation within 48 hours, cardiogenic shock, CHF during the first 90 days, or mortality among the three groups. The FINESSE investigators also published an important follow-up analysis.(11) Patients had a significant reduction in 1-year mortality with a F-PCI strategy compared to PCI alone when the following characteristics were present; TIMI risk score greater >3, presentation to a non-PCI hospital, and early presentation (<4 hours from symptom onset).(11) To our knowledge, this substudy is the only randomized clinical trial data which compared PCI alone with F-PCI or PI-PCI in patients with an expected delay to PCI. A number of PI-PCI trials and a subsequent meta-analysis of these trials,(6,12,13) indicate an unrestricted early invasive strategy after fibrinolysis is superior to a strategy of full dose fibrinolysis followed by ischemia guided rescue PCI.

The authors suggest primary PCI was chosen as the preferred strategy in the highest risk patients. Primary PCI was the only strategy for patients presenting to the PCI center or patients in Zone 1 (<60 miles from the PCI center).(5,9) Overall, 75% of our STEMI patients received primary PCI. The PI-PCI approach is reserved only for patients with expected delays due to distance from the PCI center (60-210 miles) or rarely weather. The authors are correct to note that more patients in the primary PCI arm had cardiogenic shock or out-of-hospital cardiac arrest, but these differences were not statistically significant. We agree with the authors regarding the importance of pre-hospital diagnosis, in fact it has become a component of our STEMI program. Pre-hospital STEMI diagnosis was made in the majority of patients who presented by EMS, contributing excellent treatment times.(9)

Until randomized, controlled clinical trial data comparing primary PCI to a PI-PCI approach in patients with delay to PCI are available, careful analysis from large regional STEMI networks and registries is necessary to inform real life, critical, day-to-day decisions.

References

1. Bashore TM, Balter S, Barac A, Byrne JG, Cavendish JJ, Chambers CE, Hermiller JB Jr, Kinlay S, Landzberg JS, Laskey WK, McKay CR, Miller JM, Moliterno DJ, Moore JW, Oliver-McNeil SM, Popma JJ, Tommaso CL. 2012 American college of cardiology foundation/society for cardiovascular angiography and interventions expert consensus document on cardiac catheterization laboratory standards update: a report of the American college of cardiology foundation task force on expert consensus documents. J Am Coll Cardiol 2012;59:2221-2305.

2. Van de Werf F, Bax J, Betriu A, Blomstrom-Lundqvist C, Crea F, Falk V, Filippatos G, Fox K, Huber K, Kastrati A, Rosengren A, Steg PG, Tubaro M, Verheugt F, Weidinger F, Weis M; ESC Committee for Practice Guidelines (CPG). Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation: the Task Force on the Management of ST-Segment Elevation Acute Myocardial Infarction of the European Society of Cardiology. Eur Heart J 2008;29:2909-2945.

3. Henry TD, Larson DM. The ideal reperfusion strategy for the ST- elevation myocardial infarction patient with expected delay to percutaneous coronary intervention. Paradise lost or paradise renamed? JACC Cardiovasc Interv 2009;2:931-933.

4. Terkelsen CJ, S?rensen JT, Maeng M, Jensen LO, Tilsted HH, Trautner S, Vach W, Johnsen SP, Thuesen L, Lassen JF. System delay and mortality among patients with STEMI treated with primary percutaneous coronary intervention. JAMA 2010;304:763-771.

5. Larson DM, Duval S, Sharkey SW, Garberich R, Madison JD, Stokman PJ, Dirks TG, Westin RK, Harris JL, Henry TD. Safety and efficacy of a pharmaco-invasive reperfusion strategy in rural ST-elevation myocardial infarction patients with expected delays due to long distance transfers. Eur Heart J 2012;33:1232-1240.

6. Di Mario C, Dudek D, Piscione F, Mielecki W, Savonitto S, Murena E, Dimopoulos K, Manari A, Gaspardone A, Ochala A, Zmudka K, Bolognese L, Steg PG, Flather M; CARESS-in-AMI (Combined Abciximab RE-teplase Stent Study in Acute Myocardial Infarction) Investigators. Immediate angioplasty versus standard therapy with rescue angioplasty after thrombolysis in the Combined Abciximab REteplase Stent Study in Acute Myocardial Infarction (CARESS-in-AMI): an open, prospective, randomised, multicentre trial. Lancet 2008;371:559-568.

7. Assessment of the Safety and Efficacy of a New Treatment Strategy with Percutaneous Coronary Intervention (ASSENT-4 PCI) investigators. Primary versus tenecteplase-facilitated percutaneous coronary intervention in patients with ST-segment elevation acute myocardial infarction (ASSENT- 4 PCI): randomised trial. Lancet 2006;367:569-578.

8. Ellis SG, Tendera M, de Belder MA, van Boven AJ, Widimsky P, Janssens L, Andersen HR, Betriu A, Savonitto S, Adamus J, Peruga JZ, Kosmider M, Katz O, Neunteufl T, Jorgova J, Dorobantu M, Grinfeld L, Armstrong P, Brodie BR, Herrmann HC, Montalescot G, Neumann FJ, Effron MB, Barnathan ES, Topol EJ; FINESSE Investigators. Facilitated PCI in patients with ST-elevation myocardial infarction. N Engl J Med 2008;358:2205-2217.

9. Henry TD, Sharkey SE, Burke MN, Chavez IJ, Graham KJ, Henry CR, Lips DL, Madison JD, Menssen KM, Mooney MR, Newell MC, Pedersen WR, Poulose AK, Traverse JH, Unger BT, Wang YL, Larson DM. A regional system to provide timely access to percutaneous coronary intervention for ST- elevation myocardial infarction. Circulation 2007;116:721-728.

10. Ross AM, Huber K, Zeymer U, Armstrong PW, Granger CB, Goldstein P, Bogaerts K, Van de Werf F. The impact of place of enrollment and delay to reperfusion on 90-day post-infarction mortality in the ASSENT-4 PCI trial: assessment of the safety and efficacy of a new treatment strategy with percutaneous coronary intervention. JACC Cardiovasc Interv 2009;2:925 -930.

11. Herrmann HC, Lu J, Brodie BR, Armstrong PW, Montalescot G, Betriu A, Neuman FJ, Effron MB, Barnathan ES, Topol EJ, Ellis SG; FINESSE Investigators. Benefit of facilitated percutaneous coronary intervention in high-risk ST-segment elevation myocardial infarction patients presenting to nonpercutaneous coronary intervention hospitals. JACC Cardiovasc Interv 2009;2:917-924.

12. Cantor WJ, Fitchett D, Borgundvaag B, Ducas J, Heffernan M, Cohen EA, Morrison LJ, Langer A, Dzavik V, Mehta SR, Lazzam C, Schwartz B, Casanova A, Goodman SG; TRANSFER-AMI Trial Investigators. Routine early angioplasty after fibrinolysis for acute myocardial infarction. N Engl J Med 2009;360:2705-2718.

13. Borgia F, Goodman SG, Halvorsen S, Cantor WJ, Piscione F, Le May MR, Fern?ndez-Avil?s F, S?nchez PL, Dimopoulos K, Scheller B, Armstrong PW, Di Mario C. Early routine percutaneous coronary intervention after fibrinolysis vs. standard therapy in ST-segment elevation myocardial infarction: a meta-analysis. Eur Heart J 2010;31:2156-2169.

Conflict of Interest:

None declared

Submitted on 12/07/2012 8:00 PM GMT