CLINICAL RESEARCH
European Heart Journal (2012) 33, 1232–1240
doi:10.1093/eurheartj/ehr403
Acute coronary syndromes
Safety and efficacy of a pharmaco-invasive
reperfusion strategy in rural ST-elevation
myocardial infarction patients with expected
delays due to long-distance transfers
David M. Larson 1,2*, Sue Duval 1,3, Scott W. Sharkey 1, Ross F. Garberich 1,
James D. Madison 1, Peter J. Stokman 1, Timothy G. Dirks 1, Robert K. Westin4,
James L. Harris 5, and Timothy D. Henry 1
1
Minneapolis Heart Institute Foundation at Abbott Northwestern Hospital, 920 East 28th Street, Suite 100, Minneapolis, MN 55407, USA; 2Department of Emergency Medicine,
Ridgeview Medical Center, Waconia, MN, USA; 3Lillehie Clinical Research Unit, University of Minnesota, MN, USA; 4Cuyuna Regional Medical Centre, Crosby, MN, USA; and
5
Riverwood Healthcare Centre, Aitkin, MN, USA
Received 19 April 2011; revised 8 May 2011; accepted 10 October 2011; online publish-ahead-of-print 31 October 2011
See page 1184 for the editorial comment on this article (doi:10.1093/eurheartj/ehr427)
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
Prospective data from the Level 1 MI programme were analysed. All STEMI patients presenting to the Minneapolis
and results
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 ¼ 0.94), stroke (1.1 vs. 1.3%; P ¼ 0.66) or major bleeding (1.5 vs. 1.8%; P ¼ 0.65), or re-infarction/ischaemia (1.2 vs. 2.5%; P ¼ 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.
----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords
STEMI † Reperfusion † Transfer † Fibrinolysis † Pharmaco-invasive
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)
* Corresponding author. Tel: +1 612 863 7372, Fax: +1 612 863 3801, Email: [email protected]
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2011. For permissions please email: [email protected]
1233
Safety and efficacy of a pharmaco-invasive reperfusion
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 endstage 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 ¼ 600)—primary PCI patients who presented
directly to the PCI hospital (MHI-ANW). Group B (n ¼ 1163)—
primary PCI patients transferred from hospitals located ,60 miles
(Zone 1) from the PCI hospital. Group C (n ¼ 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 ¼ 660)—pharmaco-invasive
PCI patients transferred from hospitals located ≥60 miles (Zone 2)
from the PCI hospital. Group E (n ¼ 179)—primary PCI patients transferred from ≥60 miles (Zone 2).
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. x2 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 ¼ 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
1234
D.M. Larson et al.
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.
,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 pharmacoinvasive-treated patients were slightly older; otherwise, there
were no statistically significant differences in baseline clinical
characteristics.
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.
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%.
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 ¼ 0.94), stroke (1.3 vs. 1.1%; P ¼ 0.66), recurrent ischaemia/myocardial infarction (2.5 vs. 1.2%; P ¼ 0.088), or TIMI major
bleeding (1.8 vs. 1.5%; P ¼ 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 ¼ 0.87), stroke (0.9 vs. 1.2%; P ¼ 0.48), recurrent ischaemia/myocardial infarction (1.5 vs. 1.3%; P ¼ 0.67) or
TIMI major bleeding (1.4 vs. 1.6%; P ¼ 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).
Kaplan–Meier 1-year survival curves comparing primary PCI
(Group A and B) treated patients with pharmaco-invasive PCI
Group A, PPCI,
PCI hospital,
n 5 600
Group B, PPCI,
Zone 1,
n 5 1163
Total PPCI,
A 1 B,
n 5 1763
Group C, PI,
Zone 1,
n 5 32
Group D, PI,
Zone 2,
n 5 660
Total, PI,
C 1 D,
n 5 692
Group E,
PPCI, Zone 2,
n 5 179
P-value,
A vs. D
P-value, PPCI
vs. PI, A 1 B
vs. C 1 D
P-value,
Zone 2,
D vs. E
Age
Patient ≥75 years
62.9 + 14.7
151 (25.2)
61.2 + 14.6
254 (21.8)
61.8 + 14.6
405 (23.0)
61.7 + 12.6
7 (21.9)
63.3 + 13.5
160 (24.2)
63.2 + 13.5
167 (24.1)
65.4 + 14.5
58 (32.4)
0.65
0.70
0.025
0.54
0.073
0.027
Male
418 (69.7)
851 (73.2)
1269 (72.0)
27 (84.4)
484 (73.3)
511 (73.8)
Hyperlidaemia
Hypertension
353 (60.7)
361 (60.6)
601 (53.3)
636 (55.1)
954 (55.8)
997 (57.0)
16 (51.6)
16 (50.0)
356 (56.0)
368 (55.9)
372 (55.8)
384 (55.7)
116 (64.8)
0.15
0.35
0.025
95 (55.6)
117 (66.5)
0.098
0.096
0.98
0.55
0.92
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
History of MI
201 (33.9)
137 (22.9)
475 (41.1)
207 (17.8)
676 (38.7)
344 (19.6)
10 (31.3)
2 (6.3)
270 (41.2)
131 (19.9)
280 (40.7)
133 (19.2)
56 (32.0)
46 (26.0)
0.008
0.19
0.36
0.85
0.027
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
Cardiogenic
shock
Out of hospital
cardiac arrest
144 (24.2)
63 (10.5)
217 (18.7)
109 (9.4)
361 (20.6)
172 (9.8)
5 (15.6)
1 (3.1)
122 (18.5)
51 (7.7)
127 (18.4)
52 (7.5)
47 (26.4)
18 (10.1)
0.013
0.087
0.22
0.081
0.019
0.32
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
Killip Class 2 –4
212 (36.2)
94 (15.7)
378 (32.9)
156 (13.4)
590 (34.0)
250 (14.2)
16 (50.0)
3 (9.4)
230 (35.2)
90 (13.6)
246 (35.9)
93 (13.4)
57 (33.1)
26 (14.5)
0.71
0.31
0.38
0.63
0.61
0.76
14 (2.4)
44 (3.8)
58 (3.3)
17 (2.6)
17 (2.5)
10 (5.8)
0.81
0.27
0.035
New LBBB
0 (0)
Safety and efficacy of a pharmaco-invasive reperfusion
Table 1 Baseline clinical characteristics
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.
1235
1236
Table 2 Clinical outcomes
Group A, PPCI,
PCI hospital,
n 5 600
Group B, PPCI, Total PPCI,
Zone 1,
A 1 B,
n 5 1163
n 5 1763
Group C, PI, Zone Group D, PI,
1, n 5 32
Zone 2, n 5 660
Total, PI, C 1 D, Group E, PPCI, P-value,
n 5 692
Zone 2, n 5 179 A vs. D
P-value,
P-value,
PPCI vs. PI, Zone 2, D
A 1 B vs.
vs. E
C1D
.............................................................................................................................................................................................................................................
Door-to-balloon
62 (44, 83)
Chest
171.5 (118, 314)
pain-to-balloon
Mortality hospital
30 (5.0)
94 (80, 116)
190 (141, 304)
86 (68, 108)
185 (135, 307)
112.5 (102, 141.5)
238 (177.5, 379.5)
122 (100, 147)
209.5 (160, 313.5)
121 (100, 146)
210.5 (160.5, 316)
131 (107, 169)
272 (192, 435)
,0.001
,0.001
,0.001
,0.001
,0.001
,0.001
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
Re-MI/ischaemia
30 days
Major bleeding
10 (1.7)
15 (2.5)
10 (0.9)
12 (1.0)
20 (1.1)
27 (1.5)
1 (3.1)
1 (3.1)
7 (1.1)
8 (1.2)
8 (1.2)
9 (1.3)
2 (1.1)
2 (1.1)
0.35
0.088
0.96
0.67
0.95
0.92
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
3 (2, 5)
18 (3.0)
3 (2, 4)
54 (4.6)
3 (2, 4)
72 (4.1)
3 (2, 4)
0 (0)
3 (2, 4)
19 (2.9)
3 (2, 4)
19 (2.8)
3 (2, 5)
6 (3.4)
0.0017
0.90
0.050a
0.11
0.0334
0.74
Length of stay
AICD implanted
PPCI, primary percutaneous coronary intervention; PCI, percutaneous coronary intervention; PI, pharmaco-invasive; MI, myocardial infarction AICD, automated implantable cardioverter defibrillator.
a
PI group is significantly shorter.
D.M. Larson et al.
1237
Safety and efficacy of a pharmaco-invasive reperfusion
Table 3
Angiographic characteristics
Group D, Zone P-value
2 PI, (n 5 660)
Group A,
ANW PPCI,
(n 5 600)
................................................................................
Culprit artery
Left main
5 (0.8)
6 (0.9)
0.89
LAD
195 (32.5)
219 (33.2)
0.80
LCx
RCA
73 (12.2)
203 (33.8)
79 (12.0)
244 (37.0)
0.92
0.25
Graft
24 (4.0)
16 (2.4)
0.11
No culprit
No culprit and
negative markers
53 (8.8)
26 (4.3)
55 (8.3)
26 (3.9)
0.75
0.73
................................................................................
TIMI flow pre
Flow: 0/1
354 (59.7)
171 (26.4)
Flow: 2/3
239 (40.3)
477 (73.6)
Flow: 0/1
Flow: 2/3
18 (3.0)
576 (97.0)
18 (2.8)
629 (97.2)
0.80
Ejection fraction
46.6 + 13.4
46.8 + 13.5
0.81
,0.001
................................................................................
TIMI flow post
ANW, Abbott Northwestern Hospital; PPCI, primary percutaneous coronary
intervention; PI, pharmaco-invasive; LAD, left anterior descending; LCx, left
circumflex; RCA, right coronary artery.
Table 4 Multivariable model for predictors of death at
30 days (Group A 1 Group D)
Coefficient
(SE)
Odds ratio (95%
CI)
28.327 (0.935)
–
P-value
................................................................................
Intercept
Agea
Out of hospital
cardiac arrest
Cardiogenic shock
1.89 (1.49, 2.40)
7.40 (3.61, 15.17)
,0.001
,0.001
2.512 (0.305) 12.33 (6.77, 22.43)
,0.001
0.064 (0.012)
2.002 (0.366)
a
Odds ratio is per 10 year increment in age.
(Group C and D)-treated patients are shown in Figure 2 and were
nearly identical.
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 ¼ 0.039)
and 30-day mortality (10.6 vs. 5.6%, P ¼ 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 ¼ 0.037), which was considered to be a
relative contraindication to fibrinolysis.
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 ischaemiaguided 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.
1238
D.M. Larson et al.
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.
Table 5
Reasons for no lytics in Zone 2 (n 5 179)
Contraindication to lytics
100 (55.9%)
Uncertain diagnosis
24 (13.4%)
Reason not documented
Physician discretions
20 (11.1%)
13 (7.3%)
Delayed presentation
12 (6.7%)
Post-cardiac arrest ‘Cool It’
10 (5.6%)
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 ¼ 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 ¼ 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 ¼ 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 6 h 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 ¼ 0.004).
In the NORDISTEMI trial, STEMI patients (n ¼ 266) living in
rural areas with .90 min transfer delays were treated with fulldose 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 ¼ 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 ¼ 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
1239
Safety and efficacy of a pharmaco-invasive reperfusion
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.
Acknowledgements
The authors are indebted to Jennifer Krech, BA for her assistance
in the preparation of this manuscript.
Funding
This work was supported by the Minneapolis Heart Institute Foundation. There were no relationships with industry.
Conflict of interest: none declared.
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