Download Pharmacoinvasive Strategy Versus Primary Percutaneous Coronary

Myocardial Infarction
Pharmacoinvasive Strategy Versus Primary Percutaneous
Coronary Intervention in Patients With ST-Segment–
Elevation Myocardial Infarction
A Propensity Score–Matched Analysis
Doo Sun Sim, MD, PhD; Myung Ho Jeong, MD, PhD; Youngkeun Ahn, MD, PhD;
Young Jo Kim, MD, PhD; Shung Chull Chae, MD, PhD; Taek Jong Hong, MD, PhD;
In Whan Seong, MD, PhD; Jei Keon Chae, MD, PhD; Chong Jin Kim, MD, PhD;
Myeong Chan Cho, MD, PhD; Seung-Woon Rha, MD, PhD; Jang Ho Bae, MD, PhD;
Ki Bae Seung, MD, PhD; Seung Jung Park, MD, PhD;
on behalf of the Korea Acute Myocardial Infarction Registry (KAMIR) Investigators
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Background—The Strategic Reperfusion Early After Myocardial Infarction trial and the French Registry of Acute STelevation or Non-ST-elevation Myocardial Infarction 2015 suggested that pharmacoinvasive strategy compares favorably
with primary percutaneous coronary intervention (PPCI). We sought to assess the clinical impact of pharmacoinvasive
strategy compared with PPCI in real-world patients with ST-segment–elevation myocardial infarction.
Methods and Results—We used the Korea Acute Myocardial Infarction Registry to identify ST-segment–elevation myocardial
infarction patients receiving either pharmacoinvasive strategy defined as fibrinolysis followed by percutaneous coronary
intervention (rescue/urgent or routine elective; n=708) or PPCI (n=8878). Patients receiving facilitated percutaneous
coronary intervention within 3 hours from fibrinolysis were excluded. Propensity-matched 12-month clinical outcome
was compared. In the propensity-matched cohort (n=706 in each group), the pharmacoinvasive group had shorter time
to reperfusion therapy (165 versus 241 minutes; P<0.001) and higher rate of pre-percutaneous coronary intervention
Thrombolysis in Myocardial Infarction grade 3 (50.4% versus 13.7%; P<0.001). Incidences of major bleeding and stroke
during hospitalization were not different. Twelve-month rates of death and major adverse cardiac events (composite of
death, recurrent myocardial infarction, target-vessel revascularization, and coronary artery bypass graft surgery) were
similar between pharmacoinvasive strategy and PPCI: 4.4% versus 4.1% and 7.5% versus 7.8%, respectively. Equipoise
between pharmacoinvasive strategy and PPCI for 12-month major adverse cardiac events occurred when percutaneous
coronary intervention–related delay was ≈100 minutes.
Conclusions—ST-segment–elevation myocardial infarction patients receiving pharmacoinvasive treatment, compared with
PPCI, had shorter time to reperfusion, higher culprit-vessel patency, and similar 12-month clinical outcome. (Circ Cardiovasc Interv. 2016;9:e003508. DOI: 10.1161/CIRCINTERVENTIONS.115.003508.)
Key Words: coronary artery bypass ◼ fibrinolysis ◼ myocardial infarction ◼ percutaneous coronary intervention
◼ stroke
P
rimary percutaneous coronary intervention (PPCI) is
the preferred reperfusion therapy for most patients with
ST-segment–elevation myocardial infarction (STEMI).1
However, many patients fail to receive timely PPCI because
of geographical or logistical issues. In such cases, pharmacoinvasive strategy where fibrinolysis is followed by immediate
Received October 29, 2015; accepted August 2, 2016.
From the Department of Cardiovascular Medicine, Chonnam National University Hospital, Gwangju, Republic of Korea (D.S.S., M.H.J., Y.A.); Division
of Cardiology, Yeungnam University Hospital, Daegu, Republic of Korea (Y.J.K.); Division of Cardiology, Kyungpuk National University Hospital, Daegu,
Republic of Korea (S.C.C.); Department of Cardiology, Busan National University Hospital, Republic of Korea (T.J.H.); Department of Cardiology,
Chungnam National University Hospital, Daejon, Republic of Korea (I.W.S.); Department of Cardiology, Chunbuk National University Hospital, Jeonju,
Republic of Korea (J.K.C.); Department of Cardiovascular Medicine, Kyung Hee University Hospital, Seoul, Republic of Korea (C.J.K.); Department of
Cardiology, Chungbuk National University Hospital, Cheongju, Republic of Korea (M.C.C.); Department of Cardiology, Korea University Guro Hospital,
Seoul (S.-W.R.); Division of Cardiology, Konyang University Hospital, Daejon, Republic of Korea (J.H.B.); Division of Cardiology, Catholic University
Hospital, Seoul, Republic of Korea (K.B.S.); and Department of Cardiology, Asan Medical Center, Seoul, Republic of Korea (S.J.P.).
A list of KAMIR Investigators is available in the Data Supplement.
The Data Supplement is available at http://circinterventions.ahajournals.org/lookup/suppl/doi:10.1161/CIRCINTERVENTIONS.115.003508/-/DC1.
Correspondence to Myung Ho Jeong, MD, PhD, Korea Acute Myocardial Infarction Registry, The Heart Research Center of Chonnam National
University Hospital Designated by Korea Ministry of Health, Welfare and Family Affairs, 671 Jaebong-ro, Dong-gu, Gwangju 501–757, Korea. E-mail
[email protected]
© 2016 American Heart Association, Inc.
Circ Cardiovasc Interv is available at http://circinterventions.ahajournals.org
1
DOI: 10.1161/CIRCINTERVENTIONS.115.003508
2 Sim et al Pharmacoinvasive Strategy in ST-Elevation Myocardial Infarction
WHAT IS KNOWN
• American
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College of Cardiology/American Heart
Association guidelines recommend primary percutaneous coronary intervention (PCI) for patients with
ST-segment–elevation myocardial infarction presenting ≤12 hours of symptom onset with a first medical
contact-to-device time goal of ≤120 minutes.
• Facilitated PCI consisting of fibrinolysis followed by
immediate planned PCI is not recommended because
of increased risk of death, intracranial hemorrhage,
and ischemic events.
• Pharmacoinvasive strategy where fibrinolysis is followed by immediate transfer to a PCI-capable hospital for either rescue PCI in case of failed fibrinolysis
or routine coronary angiography and PCI in case of
successful fibrinolysis may be a valid alternative to
primary PCI and part of the primary reperfusion in patients with ST-segment–elevation myocardial infarction in whom long PCI-related delay is anticipated.
WHAT THE STUDY ADDS
• ST-segment–elevation myocardial infarction patients
receiving pharmacoinvasive treatment, compared
with primary PCI, had shorter symptom-to-reperfusion time, higher culprit-vessel patency, and similar
12-month clinical outcome.
• In real practice, many transferred patients with STsegment–elevation myocardial infarction do not receive timely primary PCI, while fibrinolytic therapy
is underutilized. In such patients, pharmacoinvasive
strategy may be instrumental in reducing total ischemic time and improving outcomes.
transfer to a percutaneous coronary intervention (PCI)–capable
hospital for either rescue PCI, in case of failed fibrinolysis, or
routine coronary angiography and PCI, in case of successful
fibrinolysis, is a valid alternative.2,3 In contrast, facilitated PCI
consisting of fibrinolysis followed by immediate planned PCI
is not recommended because of increased risk of death, intracranial hemorrhage, and ischemic events.4,5
There are currently few large-scale studies that provide
data regarding the efficacy of pharmacoinvasive strategy compared with PPCI in real-world STEMI patients. In the present
study, we sought to evaluate the 12-month clinical outcome of
patients with STEMI undergoing pharmacoinvasive strategy
compared with PPCI using KAMIR (Korea Acute Myocardial
Infarction Registry).
setting, and of 881 patients receiving fibrinolysis, 843 patients (96%)
underwent coronary angiography and 726 patients underwent (82%)
subsequent PCI. The study flow diagram is shown in Figure 1.
The present study was conducted according to the Declaration
of Helsinki. The institutional review board of all participating centers approved the study protocol. The approval number was 05-49
of Chonnam National University Hospital. Written informed consent
was obtained from all participating patients.
Clinical End Points and Definitions
STEMI was defined as chest pain suggestive of myocardial ischemia
for ≈30 minutes, ST-segment elevation >0.1 mV in ≥2 contiguous
leads, or new or presumably new left bundle-branch block on the
12-lead ECG and elevated cardiac markers (creatine kinase-MB or
troponin I/T). PPCI was defined as PCI within 12 hours of symptom
onset in a patient not receiving fibrinolysis.7 Time to start of reperfusion therapy was defined as time to intravenous injection of fibrinolytics and time to balloon inflation in patients treated with fibrinolysis
and PPCI, respectively. Rescue PCI was defined as PCI mandated by
persisting symptoms or persisting ST-segment elevation (failure to
achieve ≈50% ST resolution) within 90 minutes after the administration of fibrinolysis.8 Urgent PCI was defined as PCI undertaken at any
time for worsening ischemia, hemodynamic instability, refractory ventricular arrhythmias, or recurrent ST-segment elevation that requires
immediate coronary intervention.8 Facilitated PCI was defined as fibrinolysis followed by immediate PCI (within 3 hours) irrespective
of fibrinolytic success.4,9 Pharmacoinvasive strategy was defined as
fibrinolysis followed by rescue or urgent PCI or by routine elective
PCI (beyond 3 hours of fibrinolytic administration).9 PCI-related delay was defined as the difference between the time from first medical
contact (FMC) to balloon inflation and the time from FMC to the start
of fibrinolytic therapy.3
The primary end point of the study was the occurrence of
major adverse cardiac events (MACE; composite of death from
any cause, recurrent MI, target-vessel revascularization, and coronary artery bypass graft surgery) at 12 months. The secondary
end points included death from any cause, recurrent MI, targetvessel revascularization, and coronary artery bypass graft surgery.
Recurrent MI was defined as the recurrence of symptoms or the
presence of ECG changes in association with a rise in cardiac
markers above the upper limit of normal. Target-vessel revascularization was defined as a repeat PCI of any segment within the
entire major coronary vessel proximal and distal to a target lesion,
including the target lesion itself. Major bleeding was defined as
type 3 or type 5 of the Bleeding Academic Research Consortium.10
Methods
Study Population and Data Collection
The study population was derived from KAMIR between November
2005 and December 2011. KAMIR is the first nationwide, multicenter
data-collection registry in Korea, designed to capture the outcomes of
patients with acute myocardial infarction (MI).6 We identified 9759 patients (≥18 years) with STEMI (<12 hours) eligible for either fibrinolysis
or PPCI. All fibrinolysis procedures were performed in the in-hospital
Figure 1. The study flow diagram of patients. KAMIR indicates
Korea Acute Myocardial Infarction Registry; NSTEMI, non-ST-segment–elevation myocardial infarction; PCI, percutaneous coronary
intervention; PI, pharmacoinvasive; PPCI, primary percutaneous
coronary intervention; and STEMI, ST-segment–elevation myocardial
infarction.
3 Sim et al Pharmacoinvasive Strategy in ST-Elevation Myocardial Infarction
Statistical Analysis
Continuous variables were expressed as mean±SD and compared
with the Student t test when normally distributed and as median
(quartiles) and compared with the Mann–Whitney U test when the
data did not fit to a normal distribution. Categorical variables were
reported as numbers and percentages and compared with the χ2 test
or Fisher exact test. Hazard ratios and 95% confidence intervals were
calculated for outcome variables using Cox regression analysis.
To adjust for the bias inherent to the decision of choosing pharmacoinvasive strategy or PPCI, propensity scores were used. The propensity
scores were estimated for the likelihood of receiving pharmacoinvasive
treatment using a multiple logistic regression model that contained 35
Table 1. Baseline Clinical Characteristics Between Pharmacoinvasive Strategy and Primary Percutaneous Coronary Intervention
Before and After Propensity Score Matching
All Patients
PI (n=708)
Age, years
Men
Propensity-Matched Patients
PPCI (n=8878)
P Value
PI (n=706)
PPCI (n=706)
P Value
58.5±11.4
62.0±12.8
<0.001
58.5±11.5
58.2±13.1
0.640
572 (80.8)
6568 (74.0)
<0.001
570 (80.7)
579 (82.0)
0.571
Body mass index, kg/m
24.6±2.9
24.0±3.1
<0.001
24.6±3.0
Smoking
496 (70.1)
5473 (61.6)
<0.001
494 (70.0)
498 (70.5)
0.854
Hypertension
298 (42.1)
4006 (45.1)
0.118
298 (42.2)
278 (39.4)
0.313
Diabetes mellitus
146 (20.6)
2134 (24.0)
0.040
146 (20.7)
152 (21.5)
0.751
Dyslipidemia
64 (9.0)
872 (9.8)
0.500
64 (9.1)
78 (11.0)
0.239
Myocardial infarction
11 (1.6)
231 (2.6)
0.087
11 (1.6)
10 (1.4)
1.000
Angina pectoris
24 (3.4)
276 (3.1)
0.679
23 (3.3)
16 (2.3)
0.337
PCI
26 (3.7)
409 (4.6)
0.250
26 (3.7)
24 (3.4)
0.883
2
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CABG
24.5±3.2
0.436
2 (0.3)
26 (0.3)
0.658
2 (0.3)
3 (0.4)
1.000
58 (8.2)
602 (6.8)
0.154
58 (8.2)
59 (8.4)
1.000
Typical chest pain
655 (92.5)
7943 (89.5)
0.010
653 (92.5)
652 (92.4)
1.000
Off-hour arrival*
589 (83.2)
5322 (59.9)
<0.001
587 (83.1)
584 (82.7)
0.868
Family history of CAD
First medical contact
0.069
0.196
PCI hospital
204 (28.8)
2752 (31.0)
204 (28.9)
187 (26.5)
Non-PCI hospital
372 (52.5)
4753 (53.5)
371 (52.5)
408 (57.8)
EMS
132 (18.6)
1373 (15.5)
131 (18.6)
111 (15.7)
Transfer admission
440 (62.1)
5203 (58.6)
0.065
438 (62.0)
456 (64.6)
0.345
14 (2.0)
250 (2.8)
0.189
14 (2.0)
14 (2.0)
1.000
Resuscitated cardiac arrest
129.8±26.4
124.6±30.7
<0.001
129.8±26.5
129.4±29.1
0.787
Diastolic blood pressure, mm Hg
80.0±16.6
76.9±18.9
<0.001
80.0±16.6
80.0±18.1
0.610
Heart rate, bpm
74.7±17.5
75.3±20.3
0.466
74.8±17.5
74.9±19.8
0.959
Systolic blood pressure, mm Hg
Killip class
0.003
0.263
1
545 (77.0)
6517 (73.4)
543 (76.9)
560 (79.3)
2
103 (14.5)
1218 (13.7)
103 (14.6)
82 (11.6)
3
35 (4.9)
524 (5.9)
35 (5.0)
33 (4.7)
4
25 (3.5)
619 (7.0)
25 (3.5)
31 (4.4)
GRACE score
143.8±31.2
154.9±38.2
<0.001
143.8±31.2
143.7±35.3
0.929
351 (49.6)
4659 (52.5)
0.137
351 (49.7)
359 (50.8)
0.700
Left bundle branch block
2 (0.3)
39 (0.4)
0.767
2 (0.3)
2 (0.3)
1.000
Second- or third-degree heart block
9 (1.3)
319 (3.6)
0.001
9 (1.3)
8 (1.1)
1.000
14 (2.0)
310 (3.5)
0.032
14 (2.0)
15 (2.1)
1.000
51.5±10.6
51.4±11.3
0.709
51.4±10.5
51.9±11.1
0.322
Anterior infarct
Atrial fibrillation
LVEF, %
Values are n (%) or mean±SD.
CABG indicates coronary artery bypass grafting; CAD, coronary artery disease; EMS, emergency medical system; GRACE, Global Registry of Acute Coronary Events;
LVEF, left ventricular ejection fraction; PCI, percutaneous coronary intervention; PI, pharmacoinvasive; and PPCI, primary percutaneous coronary intervention.
*Off-hours were defined as weeknights (Monday to Friday from 6:00 pm to 9:00 am), weekends, and holidays.
4 Sim et al Pharmacoinvasive Strategy in ST-Elevation Myocardial Infarction
Table 2. Characteristics of Procedures and Medical Treatment During Hospitalization Between Pharmacoinvasive Strategy and
Primary Percutaneous Coronary Intervention Before and After Propensity Score Matching
All Patients
PI (n=708)
PPCI (n=8878)
Tenecteplase
364 (51.4)
Alteplase
Urokinase
Propensity-Matched Patients
P Value
PI (n=706)
PPCI (n=706)
NA
364 (51.6)
NA
290 (41.0)
NA
288 (40.8)
NA
54 (7.6)
NA
54 (7.6)
NA
271 (38.3)
NA
271 (38.4)
NA
Urgent PCI after fibrinolysis
56 (7.9)
NA
56 (7.9)
NA
Elective PCI after fibrinolysis
381 (53.8)
NA
379 (53.7)
NA
P Value
Fibrinolytic agent
Rescue PCI after fibrinolysis
Infarct-related vessel
Left anterior descending artery
0.314
345 (48.7)
4557 (51.3)
0.167
345 (48.9)
350 (49.6)
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Left circumflex artery
70 (9.9)
859 (9.7)
70 (9.9)
92 (13.0)
Right coronary artery
288 (40.7)
3358 (37.8)
286 (40.5)
257 (36.4)
5 (0.7)
104 (1.2)
5 (0.7)
Left main coronary artery
ACC/AHA lesion type
7 (1.0)
<0.001
0.002
A
41 (5.8)
259 (2.9)
41 (5.8)
B1
158 (22.3)
1435 (16.2)
157 (22.2)
118 (16.7)
B2
242 (34.2)
2865 (32.3)
242 (34.3)
236 (33.4)
C
267 (37.7)
4319 (48.6)
266 (37.7)
326 (46.2)
No. of diseased vessels
26 (3.7)
0.860
0.199
1-vessel disease
353 (49.9)
4440 (50.0)
353 (50.0)
367 (52.0)
2-vessel disease
213 (30.1)
2579 (29.0)
212 (30.0)
192 (27.2)
3-vessel disease
135 (19.1)
128 (18.1)
1693 (19.1)
127 (18.0)
Left-main, complex
13 (1.8)
141 (1.6)
13 (1.8)
9 (1.3)
Left-main, isolated
1 (0.1)
25 (0.3)
1 (0.1)
3 (0.4)
Pre-PCI TIMI flow grade
<0.001
<0.001
0
126 (17.8)
5613 (63.2)
126 (17.8)
449 (63.6)
1
79 (11.2)
911 (10.3)
79 (11.2)
79 (11.2)
2
145 (20.5)
1148 (12.9)
145 (20.5)
81 (11.5)
3
358 (50.6)
1206 (13.6)
356 (50.4)
97 (13.7)
PCI with stenting
685 (96.8)
8334 (93.9)
0.002
683 (96.7)
676 (95.8)
0.401
612/685 (89.3)
7509/8334 (90.1)
0.564
608/683 (89.0)
615/676 (91.0)
0.275
Maximum stent diameter, mm
3.25±0.42
3.21±0.43
0.010
3.26±0.43
3.24±0.42
0.499
Total stent length, mm
23.3±7.4
24.1±7.0
0.002
23.3±7.4
24.1±6.6
0.032
No. of stents
1.48±0.80
1.39±0.72
0.003
1.49±0.80
1.40±0.81
0.054
Drug-eluting stenting
Post-PCI TIMI flow grade
0
0.080
8 (1.1)
118 (1.3)
0.267
8 (1.1)
6 (0.8)
1
3 (0.4)
87 (1.0)
3 (0.4)
5 (0.7)
2
21 (3.0)
410 (4.6)
21 (3.0)
36 (5.1)
3
676 (95.5)
8263 (93.1)
674 (95.5)
659 (93.3)
Aspirin
706 (99.7)
8831 (99.3)
0.238
704 (99.7)
704 (99.7)
1.000
Clopidogrel
702 (99.2)
8734 (98.4)
0.110
700 (99.2)
701 (99.3)
1.000
Medical treatment during hospitalization
(Continued )
5 Sim et al Pharmacoinvasive Strategy in ST-Elevation Myocardial Infarction
Table 2. Continued
All Patients
Propensity-Matched Patients
PI (n=708)
PPCI (n=8878)
P Value
PI (n=706)
PPCI (n=706)
P Value
56 (7.9)
1721 (19.4)
<0.001
56 (7.9)
131 (18.6)
<0.001
Unfractionated heparin
475 (67.1)
5974 (67.3)
0.913
475 (67.3)
505 (71.5)
0.094
Low molecular weight heparin
155 (21.9)
1387 (15.6)
<0.001
153 (21.7)
125 (17.7)
0.057
β-blocker
187 (26.4)
4291 (48.3)
<0.001
187 (26.5)
191 (27.1)
0.827
ACEI/ARB
610 (86.2)
7320 (82.5)
0.012
608 (86.1)
615 (87.1)
0.639
Diuretics
173 (24.4)
2325 (26.2)
0.306
172 (24.4)
183 (25.9)
0.533
Nitrates
559 (79.0)
5445 (61.3)
<0.001
557 (78.9)
555 (78.6)
0.943
Statin
564 (79.7)
6839 (77.0)
0.109
562 (79.6)
578 (81.9)
0.318
Glycoprotein IIb/IIIa inhibitor
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Values are n (%) or mean±SD.
ACC/AHA indicates American College of Cardiology/American Heart Association; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker;
PCI, percutaneous coronary intervention; PI, pharmacoinvasive; PPCI, primary percutaneous coronary intervention; and TIMI, Thrombolysis In Myocardial Infarction.
covariates shown in Tables 1 through 3: age, sex, body mass index,
smoking status, hypertension, diabetes mellitus, dyslipidemia, prior
history of MI, angina pectoris, PCI, and coronary artery bypass graft
surgery, family history of coronary artery disease, time from symptom
onset to FMC, typical chest pain at presentation, off-hour arrival, location of FMC, transfer admission, resuscitated cardiac arrest, systolic
blood pressure, diastolic blood pressure, heart rate, Killip class, infarct
location, left bundle branch block, second- or third-degree heart block,
atrial fibrillation, use of aspirin, clopidogrel, unfractionated heparin,
low molecular weight heparin, β-blocker, angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker, diuretics, nitrates, and
statin during hospitalization. The C statistic for the propensity model
was 0.73, indicating fair ability to discriminate treatment groups.
Matching was performed using a greedy matching protocol (1:1 nearest neighbor matching without replacement) with a caliper width of 0.2
of the SD.11 We were able to match 706 patients receiving pharmacoinvasive treatment to 706 patients receiving PPCI. We estimated standardized differences for all the 35 covariates before and after matching
to assess balance of the covariates between the matched groups. After
matching, none of the covariates showed a standardized difference
exceeding 10%, suggesting that all measured covariates were well
balanced.12 Differences between the matched pairs were evaluated using the paired t test or the Wilcoxon signed-rank test for continuous
variables and the McNemer test for categorical variables. The risks of
clinical end points in the matched cohort were compared using a Cox
proportional hazards regression model stratified on matched pairs, including factors deemed significant (P <0.1) by univariate analysis or
considered clinically important in the multivariate model. We further
tested the impact of pharmacoinvasive strategy on 12-month clinical
outcome in multiple subgroups. For subgroup analysis, we repeated the
same propensity score–matching process while matching on both the
score and the subgroup variable, forcing exact matches on the subgroup
characteristics. Conditional logistic regression was then used to identify treatment–subgroup interactions. PCI-related delay for a matched
pair was calculated as the difference between the FMC to needle time
and the FMC to balloon time in pharmacoinvasive and PPCI groups,
respectively. Relationship between PCI-related delay and 12-month
MACE was assessed as a linear regression model. All P values were
2 tailed, with statistical significance at <0.05. Statistical analyses were
conducted using SPSS version 21 (SPSS Inc., Chicago, IL) and R version 3.1.2 (R Foundation for Statistical Computing, Vienna, Austria).
Results
Baseline Clinical, Procedural Characteristics, and
Treatment During Hospitalization
In all patients (n=9586), pharmacoinvasive group (n=708)
was younger, more often men, smokers, more likely to have
typical chest pain, and off-hour arrival. PPCI group (n=8878)
was more likely to have higher Global Registry of Acute Coronary Events score, diabetes mellitus, lower blood pressure, and
higher Killip class (Table 1). Pharmacoinvasive group had less
complex lesions and higher rate of pre-PCI Thrombolysis In
Myocardial Infarction grade 3 and more often received PCI
with stenting, low molecular weight heparin, angiotensin inhibitors, and nitrates (Table 2). PPCI group more often received
glycoprotein IIb/IIIa inhibitor and β-blocker. The rate of postPCI Thrombolysis In Myocardial Infarction grade 3 was, however, similar between 2 groups. In propensity-matched cohort
(n=706 in each group), there were no significant differences
in baseline clinical characteristics. Still, pharmacoinvasive
group showed lower lesion complexity, higher rate of pre-PCI
Thrombolysis In Myocardial Infarction grade 3 (13.7% versus
50.4%; P<0.001) and similar rate of post-PCI Thrombolysis In
Myocardial Infarction grade 3 (Table 2).
Time Delays
In all patients, time from symptom to FMC was significantly
shorter in pharmacoinvasive group (Table 3). Time from symptom onset to the initiation of reperfusion therapy and time from
FMC to the start of reperfusion therapy were also shorter in
pharmacoinvasive group. In propensity-matched cohort, time
from symptom onset to FMC was no longer different. However,
time from symptom onset to the start of reperfusion therapy
(median 165 versus 241 minutes; P<0.001) and time from FMC
to start of reperfusion therapy (median 80 versus 145 minutes;
P<0.001) were still shorter in pharmacoinvasive groups.
Clinical Outcomes
In all patients, in-hospital mortality was lower in pharmacoinvasive group (Table 4). Incidences of major bleeding and
stroke during hospitalization were not different. Pharmacoinvasive group had lower rates of 12-month death and MACE.
In propensity-matched cohort, there were no significant differences in in-hospital adverse event rates. Twelve-month
mortality and MACE were not different between pharmacoinvasive strategy and PPCI—4.4% versus 4.1% and 7.5% versus
7.8%, respectively (Table 4; Figure 2).
6 Sim et al Pharmacoinvasive Strategy in ST-Elevation Myocardial Infarction
Table 3. Time Delays in Pharmacoinvasive Strategy and Primary Percutaneous Coronary Intervention Before and After Propensity
Score Matching
All Patients
Symptom to first medical contact, min
Symptom to start of reperfusion therapy, min
First medical contact to start of reperfusion therapy, min
Door to balloon, h
Propensity-Matched Patients
PI (n=708)
PPCI (n=8878)
P Value
PI (n=706)
PPCI (n=706)
P Value
60 (30–132)
80 (30–222)
<0.001
60 (30–132)
60 (30–150)
0.965
165 (92–281)
255 (158–464)
<0.001
165 (92–283)
241 (160–378)
<0.001
80 (30–145)
132 (77–220)
<0.001
80 (30–145)
145 (88–235)
<0.001
40.1 (8.7–75.9)
1.2 (0.9–1.7)
<0.001
40.1 (8.7–75.8)
1.3 (1.0–1.9)
<0.001
PCI-related delay, min
105 (51–215)
Values are median (quartiles).
PCI indicates percutaneous coronary intervention; PI, pharmacoinvasive strategy; and PPCI, primary percutaneous coronary intervention.
Downloaded from http://circinterventions.ahajournals.org/ by guest on May 8, 2017
Subgroup analysis in propensity-matched cohort showed
that the treatment effects of pharmacoinvasive strategy and
PPCI for 12-month MACE in all subgroups were similar
to those in the overall population (Figure 3). Relationship
between PCI-related delay and clinical outcome was assessed
as a linear regression model in propensity-matched cohort.
For 12-month MACE, the point of equipoise between pharmacoinvasive strategy and PPCI was ≈100 minutes (Figure 4).
Discussion
The present study showed that STEMI patients receiving pharmacoinvasive treatment, compared with PPCI, had shorter
symptom-to-reperfusion time, higher culprit-vessel patency,
and similar 12-month clinical outcome, suggesting that pharmacoinvasive strategy may be a reasonable alternative to PPCI
when long PCI-related delay is expected.
Currently, PPCI is the preferred treatment for STEMI
patients who present within 12 hours of symptom onset. In
case PPCI cannot be performed ≤120 minutes from the arrival
to a non-PCI capable hospital, fibrinolysis should be administered ≤30 minutes of hospital arrival.2,3
Pharmacoinvasive strategy refers to fibrinolytic therapy
either in a prehospital setting or at a non-PCI–capable hospital, followed by immediate transfer to a PCI capable hospital
for early PCI. The rationale for this pharmacoinvasive approach
is that initial fibrinolytic treatment is implemented to permit the
Table 4. Unadjusted and Adjusted Clinical Outcomes Between Pharmacoinvasive Strategy and Primary Percutaneous Coronary
Intervention Before and After Propensity Score Matching
All Patients
PI (n=708) PPCI (n=8878) Unadjusted HR (95% CI)
Propensity-Matched Patients
P Value
PI (n=706)
PPCI (n=706) Adjusted HR (95% CI) P Value
In-hospital
Death from any cause
14 (2.0)
388 (4.4)
0.44 (0.26–0.74)
0.002
14 (2.0)
18 (2.5)
0.65 (0.21–2.01)
0.456
Stroke
4 (0.6)
46 (0.5)
1.09 (0.39–3.04)
0.868
4 (0.6)
2 (0.3)
2.01 (0.37–10.99)
0.422
Major bleeding
5 (0.7)
28 (0.3)
2.25 (0.87–5.84)
0.096
5 (0.7)
1 (0.1)
5.03 (0.59–43.15)
0.141
20 (2.8)
460 (5.2)
0.51 (0.32–0.79)
0.003
20 (2.8)
24 (3.4)
0.83 (0.35–1.98)
0.681
1 (0.1)
34 (0.4)
0.30 (0.04–2.19)
0.234
1 (0.1)
1 (0.1)
0.91 (0.06–14.57)
0.947
30 d
Death from any cause
MI
Death from any cause or MI
21 (3.0)
494 (5.6)
0.49 (0.32–0.76)
0.001
21 (3.0)
25 (3.5)
0.81 (0.34–1.90)
0.623
TVR
2 (0.3)
19 (0.2)
1.06 (0.25–4.57)
0.933
2 (0.3)
1 (0.1)
1.92 (0.17–21.21)
0.593
CABG
1 (0.1)
5 (0.1)
1.97 (0.23–16.84)
0.537
1 (0.1)
1 (0.1)
0.85 (0.05–13.55)
0.907
MACE
24 (3.4)
517 (5.8)
0.53 (0.35–0.80)
0.002
24 (3.4)
27 (3.8)
0.92 (0.41–2.06)
0.832
31 (4.4)
568 (6.4)
0.64 (0.44–0.92)
0.015
31 (4.4)
29 (4.1)
1.37 (0.59–3.16)
0.468
2 (0.3)
65 (0.7)
0.33 (0.08–1.35)
0.124
2 (0.3)
4 (0.6)
0.33 (0.04–3.21)
0.341
Death from any cause or MI
33 (4.7)
628 (7.1)
0.61 (0.43–0.86)
0.005
33 (4.7)
33 (4.7)
1.15 (0.52–2.53)
0.725
TVR
19 (2.7)
211 (2.4)
0.89 (0.55–1.45)
0.646
19 (2.7)
21 (3.0)
0.87 (0.39–1.91)
0.721
CABG
2 (0.3)
13 (0.1)
1.67 (0.38–7.39)
0.501
2 (0.3)
1 (0.1)
2.18 (0.20–24.20)
0.524
MACE
53 (7.5)
845 (9.5)
0.69 (0.52–0.92)
0.010
53 (7.5)
55 (7.8)
0.96 (0.65–1.41)
0.831
12 mo
Death from any cause
MI
Values are n (%).
CABG indicates coronary artery bypass graft surgery; CI, confidence interval; HR, hazard ratio; MACE, major adverse cardiac events; MI, myocardial infarction; PCI,
percutaneous coronary intervention; PI, pharmacoinvasive; PPCI, primary percutaneous coronary intervention; and TVR, target-vessel revascularization.
7 Sim et al Pharmacoinvasive Strategy in ST-Elevation Myocardial Infarction
Figure 2. Adjusted cumulative major
adverse cardiac events at 12 months
between pharmacoinvasive (PI) and primary
percutaneous coronary intervention (PPCI)
groups after propensity score matching.
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early restoration of coronary blood flow and subsequent invasive
strategy to reopen the infarct-related artery with rescue PCI in
case of failed fibrinolysis or to improve the initial results achieved
and obviate reocclusion with routine elective PCI in case of successful fibrinolysis.9 In the FASTMI2015 (French Registry of
Acute ST-elevation or Non-ST-elevation Myocardial Infarction
2015), 1714 patients with STEMI (<48 hours) received PPCI,
fibrinolysis followed by PCI, or no reperfusion.13 Time to reperfusion was significantly shorter with fibrinolysis followed by
PCI than by PPCI (median, 130 versus 300 minutes). In-hospital
or 1- and 5-year mortalities were not different between pharmacoinvasive strategy and PPCI.13,14 Recently, the STREAM trial
(Strategic Reperfusion Early after Myocardial Infarction)15 randomly assigned 1892 patients with STEMI within 3 hours of
symptom onset and unable to undergo PPCI within 1 hour to
either PPCI or fibrinolysis with tenecteplase followed by early
coronary angiography within 6 to 24 hours. Thirty-day rates of
composite death, shock, congestive heart failure, or reinfarction
were similar between fibrinolysis and PPCI arms (12.4% versus
14.3%). At 1 year, mortality rates were similar in both groups.16
These results suggest that pharmacoinvasive strategy may be an
effective alternative option for STEMI treatment when PPCI is
not readily available, especially in early presenters. Our results
in an Asian population confirm the FASTMI2015 results in a
European population and the STREAM results in a North
American population.
It is important, however, to note that in pharmacoinvasive
strategy the time window between fibrinolysis and PCI is crucial. Facilitated PCI, which refers to pharmacological therapy
(usually fibrinolysis or half-dose fibrinolysis plus glycoprotein IIb/IIIa inhibitor) followed by immediate (within 3 hours)
planned PCI, was associated with worse outcomes, compared
with PPCI.4,5 Failure of facilitated PCI may have been attributed to fibrinolysis-induced platelet activation, intraplaque
hemorrhage of the culprit lesion, and increased bleeding risk.
In addition, the use of suboptimal antithrombotic cotherapy
without up-front clopidogrel may have resulted in increased
ischemic events.17 The optimal timing of routine angiography and PCI for pharmacoinvasive strategy has not been
determined, but it seems reasonable to perform a coronary
angiogram within 3 to 24 hours after successful fibrinolysis
in most patients.2,3 In the present study, the median time from
fibrinolysis and routine elective PCI was 41.5 hours (quartiles,
9.4–77.4 hours). Only 20.5% underwent routine elective PCI
within 3 to 24 hours, reflecting a real-world practice of routine
elective PCI after successful fibrinolysis performed before the
suggested time frame was derived from randomized trials.
The time from symptom onset to reperfusion therapy plays
an important role in determining outcomes in STEMI patients.
The acceptable time limit for PCI-related delay, beyond which
outcomes of PPCI may be less favorable than fibrinolysis with
respect to mortality, seems to vary between 60 and 120 minutes.18–20 Similarly, in the present study, the equipoise between
pharmacoinvasive strategy and PPCI for 12-month MACE
occurred when PCI-related delay was ≈100 minutes.
Recent registry data show that the guideline-recommended
time goals from FMC to reperfusion in STEMI are often difficult to meet in real practice. An observational study using
the Acute Coronary Treatment and Intervention Outcomes
Network Registry–Get With the Guidelines database between
2008 and 201221 showed that only 51.3% of patients with
STEMI (≤12 hours) transferred for PPCI achieved the FMCto-balloon time of ≤120 minutes and 34.3% of fibrinolysis-eligible patients received pretransfer fibrinolysis with only 43.8%
achieving a door-to-needle time of ≤30 minutes. Similarly, in
the present study, only 45.8% of patients (26.1% of transferred
patients) in the PPCI group achieved the FMC-to-balloon time
of ≤120 minutes, even though the median door-to-balloon
time at STEMI-receiving hospitals (80 minutes) was within
the recommended 90 minutes. In the pharmacoinvasive group,
the FMC-to-needle time (median, 80 minutes) was much longer than the guideline-recommended 30 minutes. Only 25%
of patients achieved a FMC-to-needle time of ≤30 minutes.
These findings go to show that the number of STEMI patients
8 Sim et al Pharmacoinvasive Strategy in ST-Elevation Myocardial Infarction
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Figure 3. Hazard ratios (HR) for 12-month major adverse cardiac events in propensity-matched cohort according to subgroup. CI indicates confidence interval; EMS, emergency medical system; GRACE, Global Registry of Acute Coronary Events; HR, hazard ratio; PI,
pharmacoinvasive; and PPCI, primary percutaneous coronary intervention.
treated with delays >120 minutes still remains substantial in
real-world circumstances. Fibrinolytic therapy is, however,
underutilized among eligible patients, and its administration
is often delayed. In the present study, the majority of STEMI
patients (70%) had symptom onset-to-FMC ≤3 hours and
more than half of the patients (60.4%) have high-risk features
(Global Registry of Acute Coronary Events risk score >140).
Given that only 23% of transferred patients receiving PPCI in
the propensity-matched cohort achieved FMC-to-balloon time
≤120 minutes, as many as 3 quarters of fibrinolysis-eligible
patients being transferred in our STEMI network would benefit from pharmacoinvasive strategy.
9 Sim et al Pharmacoinvasive Strategy in ST-Elevation Myocardial Infarction
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Figure 4. Relationship between percutaneous coronary intervention (PCI)-related delay and 12-month major adverse cardiac
events (MACE) as a linear regression model. The y axis displays
the log hazard ratio of 12-month MACE with pharmacoinvasive
relative to primary percutaneous coronary intervention (PPCI),
whereas the x axis is PCI-related delay in minutes. Dotted lines
represent 95% confidence intervals. Equipoise between pharmacoinvasive and PPCI occurred at ≈100 min (vertical dashed line).
HR indicates hazard ratio; PCI, percutaneous coronary intervention; PI, pharmacoinvasive; and PPCI, primary percutaneous
coronary intervention.
The present study has the usual limitations inherent in
observational studies. Although these results come from
a large cohort and adjustment was made using propensity
score analysis for a large number of confounding variables,
unmeasurable factors may still exist. Patients receiving PPCI
had higher estimated mortality risk than patients treated with
pharmacoinvasive strategy based on comparisons of measured
clinical characteristics, indicating that treating physicians may
have preferred PPCI for higher-risk patients, even when longer FMC-to-balloon times were expected.
In conclusion, in this large observational study with propensity-matched analysis, STEMI patients receiving pharmacoinvasive strategy, compared with PPCI, had shorter
symptom-to-reperfusion time, higher culprit-vessel patency,
and similar 12-month clinical outcome. Still, many transferred
patients with STEMI fail to undergo timely PPCI but fibrinolysis is being underutilized. With the growing number of
high-risk STEMI patients presenting early, pharmacoinvasive
strategy seems to have a crucial part to play and is probably
a realistic alternative to reduce total ischemic time and infarct
mortality.
Sources of Funding
This study was performed with the support of the Korean Circulation
Society in commemoration of its 50th anniversary.
Disclosures
None.
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Pharmacoinvasive Strategy Versus Primary Percutaneous Coronary Intervention in
Patients With ST-Segment−Elevation Myocardial Infarction: A Propensity Score−
Matched Analysis
Doo Sun Sim, Myung Ho Jeong, Youngkeun Ahn, Young Jo Kim, Shung Chull Chae, Taek
Jong Hong, In Whan Seong, Jei Keon Chae, Chong Jin Kim, Myeong Chan Cho, Seung-Woon
Rha, Jang Ho Bae, Ki Bae Seung and Seung Jung Park
on behalf of the Korea Acute Myocardial Infarction Registry (KAMIR) Investigators
Circ Cardiovasc Interv. 2016;9:
doi: 10.1161/CIRCINTERVENTIONS.115.003508
Circulation: Cardiovascular Interventions is published by the American Heart Association, 7272 Greenville
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KAMIR Investigators
Myung Ho Jeong, Young Keun Ahn, Shung Chull Chae, Jong Hyun Kim, Seung Ho Hur, Young Jo Kim,
In Whan Seong, Dong Hoon Choi, Jei Keon Chae, Taek Jong Hong, Jae Young Rhew, Doo Il Kim, In Ho
Chae, Jung Han Yoon, Bon Kwon Koo, Byung Ok Kim, Myoung Yong Lee, Kee Sik Kim, Jin Yong
Hwang, Myeong Chan Cho, Seok Kyu Oh, Nae Hee Lee, Kyoung Tae Jeong, Seung Jea Tahk, Jang Ho
Bae, Seung-Woon Rha, Keum Soo Park, Chong Jin Kim, Kyoo Rok Han, Tae Hoon Ahn, Moo Hyun
Kim, Ki Bae Seung, Wook Sung Chung, Ju Young Yang, Chong Yun Rhim, Hyeon Cheol Gwon, Seong
Wook Park, Young Youp Koh, Seung Jae Joo, Soo Joong Kim, Dong Kyu Jin, Jin Man Cho, Yang Soo
Jang, Jeong Gwan Cho, and Seung Jung Park.