Myocardial Infarction

No Benefit of Ticagrelor Pretreatment Compared With

Treatment During Percutaneous Coronary Intervention in
Patients With ST-Segment–Elevation Myocardial Infarction
Undergoing Primary Percutaneous Coronary Intervention
Sasha Koul, MD, PhD; J. Gustav Smith, MD, PhD; Matthias Götberg, MD, PhD;
Elmir Omerovic, MD, PhD; Joakim Alfredsson, MD, PhD; Dimitrios Venetsanos, MD;
Jonas Persson, MD, PhD; Jens Jensen, MD, PhD; Bo Lagerqvist, MD, PhD;
Björn Redfors, MD, PhD; Stefan James, MD, PhD; David Erlinge, MD, PhD

Background—The effects of ticagrelor pretreatment in patients with ST-segment–elevation myocardial infarction

undergoing primary percutaneous coronary intervention (PCI) is debated. This study investigated the effects of ticagrelor
pretreatment on clinical outcomes in this patient group.
Methods and Results—Patients with ST-segment–elevation myocardial infarction undergoing primary PCI were included
from October 2010 to October 2014 in Sweden. Screening was done using the SWEDEHEART register (Swedish
Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to
Recommended Therapies). A total of 7433 patients were included for analysis with 5438 patients receiving ticagrelor
pretreatment and 1995 patients with ticagrelor given only in the catheterization laboratory. The primary end point of the
study was 30-day event rates of a composite of all-cause mortality, myocardial infarction (MI), and stent thrombosis.
Secondary end points were mortality, MI, or stent thrombosis alone and major in-hospital bleeding. Crude event rates
showed no difference in 30-day composite end point (6.2% versus 6.5%; P=0.69), mortality (4.5% versus 4.7%; P=0.86),
MI (1.6% versus 1.7%; P=0.72), or stent thrombosis (0.5% versus 0.4%; P=0.80) with ticagrelor pretreatment. Three
different statistical models were used to correct for baseline differences. No difference in the composite end point,
Downloaded from http://ahajournals.org by on November 15, 2018

mortality, MI, or stent thrombosis was seen between the 2 groups after statistical adjustment. No increase in in-hospital
major bleeding rate was observed with ticagrelor pretreatment.
Conclusions—Ticagrelor pretreatment versus ticagrelor given in the catheterization laboratory in patients with ST-segment–
elevation myocardial infarction undergoing primary PCI did not improve the composite end point of all-cause mortality
or MI or stent thrombosis or its individual components at 30 days.  (Circ Cardiovasc Interv. 2018;11:e005528. DOI:
10.1161/CIRCINTERVENTIONS.117.005528.)

Key Words: myocardial infarction ◼ percutaneous coronary intervention ◼ ST-elevation myocardial infarction

◼ stents ◼ thrombosis

M odern P2Y12 inhibitors constitute a cornerstone in

the treatment of ST-segment–elevation myocardial
infarction (STEMI).1,2 Early P2Y12 inhibition for patients
with STEMI administered before coronary angiography
may decrease stent thrombosis and ischemic events but may
increase bleeding complications. Furthermore, patients with
other complicating diseases (aortic dissection, aortic rupture,
cardiac tamponade, etc) could, thus, be subjected to a treatment
See Editorial by Huber
that might worsen their clinical condition, and administra-
tion of irreversible early P2Y12 inhibitors may complicate or
delay emergent surgery. Pretreatment with P2Y12 inhibitors in
patients with acute coronary syndromes, especially in patients
with STEMI, before coronary angiography and percutaneous
coronary intervention (PCI) has, thus, been debated.3–8 The

Received May 21, 2017; accepted February 15, 2018.

From the Department of Cardiology (S.K., J.G.S., M.G., D.E.) and Department of Clinical Sciences (S.K., J.G.S., M.G., D.E.), Skane University
Hospital Lund, Lund University, Sweden; Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden (E.O., B.R.); Department of
Cardiology (J.A., D.V.) and Department of Medical and Health Sciences (J.A., D.V.), Linköping University, Sweden; Division of Cardiovascular Medicine,
Department of Clinical Sciences, Danderyd University Hospital (J.P.) and Department of Medicine, Capio Saint Göran Hospital (J.J.), Karolinska Institute,
Stockholm, Sweden; and Uppsala Clinical Research Institute, Uppsala University, Sweden (B.L., S.J.).
The Data Supplement is available at http://circinterventions.ahajournals.org/lookup/suppl/doi:10.1161/CIRCINTERVENTIONS.117.005528/-/DC1.
Correspondence to Sasha Koul, MD, PhD, Department of Cardiology, Skane University Hospital, Lund University, Lund, Sweden. E-mail sashamkoul@
gmail.com
© 2018 American Heart Association, Inc.
Circ Cardiovasc Interv is available at http://circinterventions.ahajournals.org DOI: 10.1161/CIRCINTERVENTIONS.117.005528

1
 2   Koul et al   Ticagrelor Pretreatment in STEMI Undergoing PCI
WHAT IS KNOWN
• Chronic P2Y12 inhibition with ticagrelor decreases
mortality and reinfarction in patients with acute cor-
onary syndromes.
• However, pretreatment with ticagrelor in patients
with ST-segment–elevation myocardial infarction is
debated.
• In a previous randomized trial (n=1862), pretreat-
ment with ticagrelor in patients with ST-segment–
elevation myocardial infarction did not improve
myocardial flow at angiography or ST resolution.
There was, in addition, a trend toward increased
mortality in patients receiving ticagrelor pretreat-
ment. Potential benefits or harm with ticagrelor
pretreatment in patients undergoing primary percu-
taneous coronary intervention is, thus, still unclear.
WHAT THE STUDY ADDS
• This registry study (n=7433) evaluated ticagrelor
pretreatment compared with treatment given in the
catheterization laboratory in patients with ST-seg-
ment–elevation myocardial infarction undergoing
primary percutaneous coronary intervention in the
SWEDEHEART register (The Swedish Web-system
for Enhancement and Development of Evidence-
based care in Heart disease Evaluated According to
Recommended Therapies).
• The results indicated overall no benefit of ticagrelor
Downloaded from http://ahajournals.org by on November 15, 2018
pretreatment on a composite end point of mortality,
myocardial infarction, and stent thrombosis or the
individual components of this end point at 30 days.
• Delaying ticagrelor administration until after the cor-
onary anatomy is known and a diagnosis of ST-seg-
ment–elevation myocardial infarction is confirmed
could avoid potent platelet inhibition to patients with
other life-threatening disorders, such as aortic dissec-
tion, where platelet inhibition could be deleterious.
2013 American College of Cardiology Foundation/American
Heart Association guidelines for STEMI recommend usage of
P2Y12 inhibitors as early as possible in patients presenting
with STEMI undergoing primary PCI, which is also endorsed
by the 2014 European Society of Cardiology guidelines for
myocardial revascularization and is currently practiced in
many countries worldwide.1,2 However, there is limited ran-
domized data on this matter.4
In the ATLANTIC study (Administration of Ticagrelor
in the Cath Lab or in the Ambulance for New ST Elevation
Myocardial Infarction to Open the Coronary Artery), ticagre-
lor was randomized in patients with STEMI and planned
primary PCI to either administration before arrival at the cath-
eterization laboratory or administration at the coronary cathe-
terization laboratory.4 Ticagrelor pretreatment did not improve
TIMI (Thrombolysis in Myocardial Infarction) flow grade 3
or ST resolution before PCI. However, ticagrelor pretreatment
decreased the rate of definite stent thrombosis both within 24
hours and within 30 days. Mortality trended unfavorably with
ticagrelor pretreatment (3.3% in pretreatment group compared
with 2.0% in standard-care group; P=0.08). The absence of
benefit of ticagrelor pretreatment in ATLANTIC study has
been discussed as maybe attributed to the short time delay
between ticagrelor pretreatment and administration in the
catheterization laboratory.4
The purpose of this study was to investigate the effects of
pretreatment with ticagrelor in patients with STEMI undergoing
primary PCI compared with ticagrelor given at the catheteriza-
tion laboratory in a real-life setting using the SWEDEHEART
register (Swedish Web-System for Enhancement and
Development of Evidence-Based Care in Heart disease
Evaluated According to Recommended Therapies).
Methods
The data, analytic methods, and study materials are available to other
researchers for purposes of reproducing the results or replicating the
procedure and can be acquired by submitting request to the corre-
sponding author. The corresponding author is responsible for main-
taining availability of the data. Pretreatment was defined as treatment
before arrival at the catheterization laboratory. This includes pretreat-
ment in the ambulance (majority of patients), referring hospital, coro-
nary care unit, or local emergency department. The study design is a
retrospective cohort study.
National Registers
The SWEDEHEART register includes all patients with myocardial
infarction (MI) and those undergoing coronary angiography, PCI,
cardiac surgery, or percutaneous valve implantations in Sweden.
Using each patient’s unique personal identification, the register can
be merged with other national registers. The SWEDEHEART sub-
registers used in this study were the SCAAR (Swedish Coronary
Angiography and Angioplasty Register) and the RIKS-HIA (Swedish
Register of Information and Knowledge about Swedish Heart
Intensive care Admissions). These registers were merged with the
national Swedish Hospital Discharge Register and the National
Population Register. Patient screening was performed using SCAAR.
Data on PCI and pretreatment or treatment in the catheterization lab-
oratory with platelet inhibitors or anticoagulants and definite stent
thrombosis were also obtained from the SCAAR. Information on
discharge medications, in-hospital bleeding events, and ejection frac-
tion was obtained from RIKS-HIA. Data on medical history and new
MI were obtained from the Swedish Hospital Discharge Register.
Information on death was obtained from the National Population
Register.
Study Sample
A total of 105 242 patients were identified from October 24, 2010, to
October 10, 2014, with a first-time inclusion in SCAAR during this
time period. Data on death and stent thrombosis were collected up to
November 14, 2014. Data on myocardial reinfarctions were collected
to December 14, 2014 (maximum follow-up time).
Patients with no STEMI were excluded leaving 17 166 patients
for further analysis. Patients without PCI treatment were excluded
(n=2099), leaving 15 067 patients for analysis. Patients with no in-
formation on ticagrelor pretreatment and ticagrelor administration in
the catheterization laboratory were excluded (n=2528+257). Patients
not having received either ticagrelor pretreatment or ticagrelor in
the catheterization laboratory (n=4757) were excluded. A further 68
patients who received both ticagrelor pretreatment and ticagrelor in
the catheterization laboratory were excluded, leaving a total of 7457
patients for analysis, who received either ticagrelor pretreatment or ti-
cagrelor in the catheterization laboratory. Out of these, 5457 patients
received ticagrelor pretreatment and no ticagrelor in the catheteriza-
tion laboratory and 2000 patients received no ticagrelor pretreatment
 3   Koul et al   Ticagrelor Pretreatment in STEMI Undergoing PCI
but ticagrelor in the catheterization laboratory. Patients undergoing
primary PCI in hospitals with <20 patients on ticagrelor were exclud-
ed from the analysis leading to final patient pool of 5438 patients with
ticagrelor pretreatment and 1995 patients with ticagrelor given only
in the catheterization laboratory (ticagrelor no pretreatment group).
End Points
The main end points of the study were 30-day composite cardio-
vascular outcome (all-cause mortality/MI/stent thrombosis) and the
individual components of the composite end point alone. The second-
ary end point was major in-hospital bleeding rate defined as fatal,
cerebral, or requiring surgery/blood transfusion. The definition of MI
was rehospitalization for MI at a cardiac intensive care unit. Stent
thrombosis was defined as angiographically verified stent thrombosis.
Statistical Methods
Crude survival rate was estimated using the Kaplan–Meier estima-
tor. Unadjusted clinical events were compared using the log-rank test.
Adjusted analyses were performed using 3 different statistical models
to balance out baseline confounding differences: (1) direct multivari-
able regression, (2) propensity score covariate adjustment, and (3)
propensity score matching. Covariate selection differed a bit between
the models (see below). In general, covariates that based on clinical
experience were judged a priori to be potentially confounding were
screened for inclusion in the models. Furthermore, variables showing
a baseline difference of P<0.20 and deemed as potential confounders
were also screened for inclusion.
Discharge medications were not used as covariates because that
could impart potential immortal time bias. Glycoprotein IIB/IIIA
(GPIIB/IIIA) inhibitor pretreatment was not included as a covariate
because the usage was low (0.1%–0.2%). Proportionality of hazards
assumption was assessed using Schoenfeld residuals for the primary
composite end point.
Downloaded from http://ahajournals.org by on November 15, 2018
Direct Multivariable Regression Model
Using the criteria above, the following variables were used in the direct
multivariable regression model for the composite end point and mor-
tality: age, sex, current smoking status, aspirin pretreatment, aspirin
during PCI, clopidogrel pretreatment, heparin pretreatment, heparin
during PCI, GPIIB/IIIA inhibitors during PCI, bivalirudin during PCI,
diabetes mellitus, hyperlipidemia, hypertension, previous MI, stroke,
heart failure, chronic obstructive pulmonary disease, tertiary center
versus nontertiary center, usage of drug-eluting stent, inotropic sup-
port during hospital stay, usage of intra-aortic balloon pump, usage
of intravenous nitroglycerin, time delay from symptom-to-PCI, year
of procedure, access site (femoral versus nonfemoral), and number of
stents used. These variables were then used in Cox regression analyses.
For the direct multivariable regression model for MI, because of
low event rate (n=112), fewer variables could be included in direct
multivariable regression. Using a logistic regression analyses, the
following factors were deemed of most importance for the develop-
ment of subsequent MI at 30 days and were included in the model:
clopidogrel pretreatment, heparin pretreatment, age, bivalirudin dur-
ing PCI, GPIIB/IIIA inhibitors during PCI, previous stroke, previous
heart failure, usage of drug-eluting stents, usage of intravenous nitro-
glycerin, usage of inotropic support during hospital stay, tertiary cen-
ter versus nontertiary center. These variables were then used in Cox
regression analyses. Cardiogenic shock was later added in the models
or excluded from the patient population as sensitivity analyses.
Propensity Score Covariate Adjustment
Propensity scoring was done by including factors that were deemed
most important for the propensity of receiving treatment at the time of
treatment decision in a logistic regression model. Propensity scoring
was performed for smoking status, aspirin pretreatment, clopidogrel
pretreatment, heparin pretreatment, age, sex, diabetes mellitus, hyper-
tension, hyperlipidemia, previous MI, bypass surgery, stroke, heart
failure, cancer, chronic obstructive pulmonary disease, year of proce-
dure, time delay from symptom-to-PCI, specific hospital where PCI
was performed, access site (femoral versus nonfemoral), and treated
vessel. The propensity score was then used in a Cox regression analy-
sis to achieve a propensity score covariate adjustment. In a separate
model, cardiogenic shock was also included in the propensity score.
Propensity Score Matching
Propensity score matching was performed in a 1:1 fashion based on
smoking status, aspirin pretreatment, heparin pretreatment, age, sex,
diabetes mellitus, hypertension, hyperlipidemia, previous MI, bypass
surgery, stroke, heart failure, cancer, chronic obstructive pulmonary
disease, symptom-to-PCI time delay, specific hospital where PCI was
performed, and treated vessel. Majority of variables were balanced
after matching. However, additional adjustment using Cox regression
analyses was done for variables that were deemed of importance and
were residually unmatched for (femoral access versus nonfemoral
access, year of procedure, tertiary center versus nontertiary center,
symptom-to-PCI, GPIIB/IIIA inhibitors, and heparin during PCI).
Matching was performed using a caliper of 0.02 in the propensity
score for the maximum allowed difference in propensity score to
closest neighbor.
Multiple Imputation
Results are presented for complete case analysis; however, end points
were also analyzed by using multiple imputation for missing data.
Multiple imputation was done by using 10 imputations with 100 it-
erations for every imputation.
Other Statistical Methods
For patient demographics, categorical variables were compared, strat-
ified by ticagrelor pretreatment or not, using Pearson χ2 test. For con-
tinuous variables with normal distribution, Student t test was used.
For continuous variables without normal distribution, groups were
compared using the Mann–Whitney U test.
All tests were 2 sided with a P value for significance 0.05. All anal-
yses were performed in SPSS (SPSS version 22; SPSS, Inc, Chicago,
IL) and STATA (STATA version 14; StataCorp, TX).
Ethical Approval
This study was ethically approved by the regional scientific ethics
committee of Lund University. Since all patients were anonymized in
the study (with their social security number substituted by a unique
SWEDEHEART specific ID-number) no informed consent was
deemed necessary by the scientific ethics committee.
Results
Baseline Demographics
The degree of pretreatment increased gradually with sub-
sequent years with rates of 47% (2011), 64% (2012), 76%
(2013), and 78% (2014).
Patients with ticagrelor pretreatment were significantly
older than patients with no ticagrelor pretreatment (Table 1).
Patients with ticagrelor pretreatment received significantly
more heparin and aspirin pretreatment, compared with
patients with no ticagrelor pretreatment, who instead received
more clopidogrel pretreatment. Consequently, patients with
no ticagrelor pretreatment received more aspirin and heparin
during the PCI procedure. Ticagrelor pretreatment patients
received less GPIIB/IIIA inhibitors during PCI but more drug-
eluting stents (Table 1).
After propensity score matching, both groups were overall
considerably better matched with 1115 patients included in
the ticagrelor pretreatment group and 1115 patients in the no
ticagrelor pretreatment group.
After propensity score matching, baseline differences were
evened out for age, sex, cardiogenic shock at arrival, diabetes
mellitus, previous MI, hyperlipidemia, heparin pretreatment,
 4   Koul et al   Ticagrelor Pretreatment in STEMI Undergoing PCI

Table 1.  Baseline Demographics

Ticagrelor No Ticagrelor Ticagrelor No Ticagrelor
Sample Pretreatment, Pretreatment, Sample Pretreatment Pretreatment
Size n (%) n (%) P Value Size (PSM) (PSM), n (%) (PSM), n (%) P Value
Age, mean (SD) 7433 66.9 (12.1) 65.4 (12.0) <0.001 2230 65.9 (11.8) 65.5 (11.8) 0.244
Male sex 7433 3800 (69.9) 1459 (73.1) 0.006 2223 847 (75.8) 863 (77.3) 0.402
Year of procedure 7433 <0.001 2230 0.003
 2011 34 (0.6) 38 (1.9) 24 (2.2) 21 (1.9)
 2012 1299 (23.9) 743 (37.2) 503 (45.0) 535 (47.9)
 2013 2244 (41.3) 694 (34.8) 342 (30.6) 261 (34.1)
 2014 1861 (34.2) 520 (26.1) 248 (22.2) 180 (16.1)
PCI performed at tertiary center 7433 3393 (62.4) 1278 (64.1) 0.19 2230 732 (65.6) 865 (77.4) <0.001
Body mass index, mean (SD) 5607 27.1 (7.9) 27.0 (6.5) 0.54 1566 27.7 (12.8) 27.0 (7.4) 0.197
Smoking status 7433 0.912 2230 0.271
 Never smoked 3856 (70.9) 1412 (70.8) 742 (66.5) 767 (68.7)
 Current smoker 1582 (29.1) 583 (29.2) 374 (33.5) 350 (31.3)
Cardiogenic shock upon arrival 7431 81 (1.5) 47 (2.4) 0.03 2230 11 (1.0) 18 (1.6) 0.193
Inotropic support during hospital stay 7273 266 (5.0) 97 (5.0) 0.64 2227 45 (4.0) 45 (4.1) 0.990
Use of aortic balloon pump 7429 37 (0.7) 16 (0.8) 0.58 2230 9 (0.8) 5 (0.5) 0.283
Intravenous nitroglycerin 7273 444 (8.3) 140 (7.2) 0.22 2230 90 (8.1) 80 (7.2) 0.425
Symptom to PCI, h, median and IQR 7096 3.25 (2.1–5.6) 2.8 (1.8–4.6) <0.001 2230 2.9 (2.0–4.8) 2.7 (1.8–4.6) 0.0179
History
 Known cancer 7433 95 (1.7) 45 (2.3) 0.12 2230 31 (2.8) 26 (2.3) 0.50
Downloaded from http://ahajournals.org by on November 15, 2018

 Diabetes mellitus 7433 746 (13.7) 312 (15.6) 0.04 2230 178 (16.0) 175 (15.7) 0.855
 MI 7433 140 (2.6) 36 (1.8) 0.05 2230 28 (2.5) 29 (2.6) 0.896
 Heart failure 7433 108 (2.0) 37 (1.9) 0.72 2230 20 (1.8) 21 (1.9) 0.887
 Hypertension 7433 1047 (19.3) 359 (18.0) 0.22 2230 217 (19.4) 212 (19.0) 0.780
 COPD 7433 203 (3.7) 94 (4.7) 0.06 2230 49 (4.4) 49 (4.4) 0.996
 Kidney failure 7433 88 (1.6) 29 (1.5) 0.61 2230 21 (1.9) 11 (1.0) 0.075
 PCI 7433 7 (0.1) 1 (0.1) 0.36 2230 2 (0.1) 1 (0.2) 0.563
 Stroke 7433 248 (4.6) 77 (3.9) 0.19 2230 66 (5.9) 52 (4.7) 0.184
 Dementia 7433 18 (0.3) 7 (0.4) 0.90 2230 3 (0.3) 4 (0.4) 0.706
 Peripheral vascular disease 7433 48 (2.4) 133 (2.4) 0.92 2230 35 (3.1) 31 (2.8) 0.615
 Hyperlipidemia 7432 767 (14.1) 265 (13.3) <0.001 2230 196 (17.6) 176 (15.8) 0.252
Antithrombotic medication
 Heparin pretreatment 7433 2984 (54.9) 267 (13.4) <0.001 2230 220 (19.7) 240 (21.5) 0.300
 Heparin during PCI 7433 2891 (53.2) 1655 (83.0) <0.001 2230 759 (68.0) 885 (79.2) <0.001
 Clopidogrel pretreatment 7433 211 (3.9) 758 (38.0) <0.001 2230 105 (9.4) 700 (62.7) <0.001
 Aspirin pretreatment 7433 5332 (98.1) 1123 (56.3) <0.001 2230 1042 (93.4) 1051 (94.1) 0.482
 Aspirin during PCI 7433 28 (0.5) 873 (43.8) <0.001 2230 14 (1.3) 85 (7.6) <0.001
 Warfarin treatment 7433 50 (0.9) 19 (1.0) 0.90 2230 11 (1.0) 6 (0.5) 0.223
 Bivalirudin during PCI 7433 4241 (78) 1530 (76.7) 0.23 2230 452 (64) 501 (71) 0.587
 GPIIB/IIIA-inhibitor pretreatment 7433 13 (0.2) 1 (0.1) 0.10 2230 6 (0.5) 1 (0.1) 0.058
 GPIIB/IIIA inhibitor during PCI 7433 536 (9.9) 324 (16.2) <0.001 2230 150 (13.4) 195 (17.5) 0.09

(Continued )
 5   Koul et al   Ticagrelor Pretreatment in STEMI Undergoing PCI

Table 1.  Continued

Ticagrelor No Ticagrelor Sample Ticagrelor No Ticagrelor
Sample Pretreatment, Pretreatment, Size Pretreatment Pretreatment
Size n (%) n (%) P Value (PSM) (PSM), n (%) (PSM), n (%) P Value
Angiographic characteristics
 Stent implanted 7433 5150 (94.7) 1905 (95.5) 0.17 2230 1064 (95.3) 1073 (96.1) 0.401
 Insertion of drug-eluting stent 7058 4286 (83.2) 1466 (76.9) <0.001 2230 718 (64.3) 725 (64.9) 0.779
 No. of stents implanted, median 6636 1 (1–2) 1 (1–2) 0.10 2230 1 (1–2) 1 (1–2) 0.110
and IQR
 Vessel treated 7427 0.58 2230 0.88
  
LM 62 (1.1) 31 (1.6) 15 (1.3) 17 (1.5)
  
RCA 2038 (37.5) 750 (37.6) 446 (40.0) 426 (38.1)
  
LAD 2386 (43.9) 875 (43.9) 462 (41.4) 479 (42.9)
  
Cx 789 (14.5) 289 (14.5) 168 (15.1) 166 (14.9)
Discharge medications
 ACE inhibitors 7113 3789 (72.9) 1378 (71.8) 0.46 2183 807 (74.2) 800 (73.0) 0.508
 Angiotensin II receptor blockers 7113 687 (13.2) 217 (11.3) 0.09 2183 153 (14.1) 127 (11.6) 0.082
 Aspirin 7113 4883 (94.0) 1842 (96.0) 0.005 2183 1017 (93.6) 1070 (97.6) <0.001
 Ticagrelor 7113 4353 (83.8) 1593 (83.0) 0.30 2230 882 (79.0) 924 (82.7) 0.027
 Clopidogrel 7113 542 (10.4) 220 (11.5) 0.22 2230 134 (12.0) 119 (10.7) 0.313
β-Blockers
  7113 4611 (88.8) 1766 (92.0) <0.001 2183 974 (89.6) 1016 (92.7) 0.011
 Statins 7113 4921 (94.7) 1828 (95.3) 0.56 2185 1038 (95.5) 1058 (96.5) 0.214
Values are indicated as n (%) unless otherwise specified. ACE indicates angiotensin converting enzyme; Cx, circumflex artery; GPIIB/IIIA, glycoprotein IIB/IIIA inhibitor; IQR,
interquartile range; LAD, left anterior descending artery; LM, left main artery; MI, myocardial infarction; PSM, propensity score matching; and RCA, right coronary artery.
Downloaded from http://ahajournals.org by on November 15, 2018

aspirin pretreatment, and usage of drug-eluting stents. One
factor was not significantly different before matching but sig-
nificantly different after matching (PCI performed at tertiary
center). This covariate and the remaining few covariates that
were still unbalanced after matching (a minority) and deemed
of importance to adjust for were fitted in a Cox regression
analysis.
Composite End Point (Death/MI/Stent Thrombosis)
A total of 338 events in the composite end point occurred in
the ticagrelor pretreatment group and 130 events in the no pre-
treatment group. Kaplan–Meier curves for unadjusted event
rates of the composite end point are presented in Figure 1A
with no observed difference at 30 days (6.2% in pretreatment
group versus 6.5% in no pretreatment group; Table 2). Direct
multivariable Cox regression showed no difference in adjusted
rates of the composite end point (hazard ratio [HR], 1.00; 95%
confidence interval [CI], 0.71–1.41). Propensity score covari-
ate adjustment and propensity score matching did not either
show any difference in the adjusted rates of the composite end
point (Table 2).
but propensity score covariate adjustment yielded a trend with
a HR of 0.78 (95% CI, 0.51–1.19) for 30-day mortality. How-
ever, the results for 30-day mortality were neutral with either
propensity score matching (HR, 0.88; 95% CI, 0.56–1.38) or
direct multivariable regression analysis (HR, 0.92; 95% CI,
0.62–1.38; Table 2).
Myocardial Infarction
A total of 83 MIs occurred in the ticagrelor pretreatment group
and 33 in the no pretreatment group at 30 days. Kaplan–Meier
curves for MI are presented in Figure 1C with no difference
observed in new MI at 30 days (1.6% in pretreatment group
versus 1.7% in no pretreatment group, log-rank test P=0.72).
Direct multivariable Cox regression analysis showed no asso-
ciation between ticagrelor pretreatment and lower rate of MI
at 30 days (HR, 0.91; 95% CI, 0.57–1.47; Table 2). Similar
results were obtained using propensity score covariate adjust-
ment (HR, 0.94; 95% CI, 0.46–1.92), whereas propensity
score matching suggested a trend, however, with wide CIs
toward increased MI with ticagrelor pretreatment (HR, 1.39;
95% CI, 0.67–2.9; Table 2).

Mortality Stent Thrombosis

A total of 247 deaths occurred in the ticagrelor pretreatment
group and 93 in the no pretreatment group at 30 days. Kaplan–
Meier curves for crude mortality are presented in Figure 1B
with no difference observed at 30 days (4.5% in pretreatment
group versus 4.7% in no pretreatment group, Table 2). No
model showed a statistically significant effect on mortality,
A total of 24 stent thromboses occurred in the ticagrelor pre-
treatment group and 8 cases in the no pretreatment group at
30 days. Kaplan–Meier curves for stent thrombosis are pre-
sented in Figure 1D with no difference observed in stent
thrombosis at 30 days (0.5% in pretreatment group versus
0.4% in no pretreatment group, log-rank test P=0.80). Direct
 6   Koul et al   Ticagrelor Pretreatment in STEMI Undergoing PCI
Downloaded from http://ahajournals.org by on November 15, 2018

Figure 1. Unadjusted Kaplan-Meier event curves for 30-day clinical outcomes. A, Kaplan–Meier curve of 30-day event rate of composite
end point (all-cause death, myocardial infarction [MI], and stent thrombosis). B, Kaplan–Meier curve of 30-day event rate of all-cause mor-
tality. C, Kaplan–Meier curve of 30-day event rate of MI. D, Kaplan–Meier curve of 30-day event rate of stent thrombosis. E, Kaplan–Meier
curve of 30-day event rate of the composite end point in the propensity score–matched population.

multivariable Cox regression analysis and analysis using pro-
pensity score matching were not performed because of low
event rates of stent thrombosis. Propensity score covariate
adjustment showed no statistically significant association
between ticagrelor pretreatment and decreased rate of definite
stent thrombosis at 30 days (HR, 0.90; 95% CI, 0.22–3.69).
Cardiogenic Shock
A lower incidence of cardiogenic shock on arrival to the cath-
eterization laboratory was noted in the pretreatment group
(2.4% in no pretreatment group versus 1.5% in pretreatment
group; P=0.03; Table 1). When accounting for total cardio-
genic shock, including cardiogenic shock during hospital stay,
 7   Koul et al   Ticagrelor Pretreatment in STEMI Undergoing PCI

Table 2.  Summary of Clinical Event Rates at 30 Days

Composite End Point Death MI Stent Thrombosis
Unadjusted event rate (KM)* P=0.69 P=0.86 P=0.72 P=0.80
 Ticagrelor pretreatment, % 6.2 4.5 1.6 0.5
 No ticagrelor pretreatment, % 6.5 4.7 1.7 0.4
Direct multivariable regression model, hazard 1.00 (0.71–1.41); P=1.0 0.92 (0.62–1.38); P=0.70 0.91 (0.57–1.47); P=0.71 Not performed
ratio and 95% CI
Propensity score covariate adjustment model, 0.83 (0.58–1.19); P=0.26 0.78 (0.51–1.19); P=0.25 0.94 (0.46–1.92); P=0.87 0.90 (0.22–3.69); P=0.88
hazard ratio and 95% CI
Propensity score matching, hazard ratio and 95% CI 1.00 (0.69–1.44); P=0.98 0.88 (0.56–1.38); P=0.57 1.39 (0.67–2.9); P=0.37 Not performed
CI indicates confidence interval; KM, Kaplan–Meier; and MI, myocardial infarction.
*Estimated from KM event rates.

there was a nonsignificant but borderline association between
less cardiogenic shock in the pretreatment group compared
with the no pretreatment group (3.4% in no pretreatment
group versus 3.0% in pretreatment group; P=0.054). When
adjusting for cardiogenic shock in our main models, similar
results were obtained for 30-day composite end point, mortal-
ity, MI, and stent thrombosis as without cardiogenic shock in
the models (Table 3). Sensitivity analyses where patients with
cardiogenic shock were excluded yielded similar results.
Major In-Hospital Bleeding Events
Major in-hospital bleeding events occurred in 1.0% of patients
receiving ticagrelor pretreatment and in 0.9% of patients not
receiving ticagrelor pretreatment (P=not significant).
Downloaded from http://ahajournals.org by on November 15, 2018
The C statistic for the propensity score matching was 0.90
without and 0.91 with cardiogenic shock in the propensity
score matching model.
All results are presented as complete case analyses, with
91.9% % of cases being complete cases. Multiple imputation
was performed to correct for variables with >20 missing cases
and did not alter any of the results significantly.
Discussion
Main Findings
Our study constitutes, to our knowledge, the largest published
study examining the effects of ticagrelor pretreatment com-
pared with ticagrelor given in the coronary catheterization lab-

oratory in the setting of STEMI and primary PCI. Our findings

Other Subgroups Analyses
χ2 analyses showed no difference between the ticagrelor pretreat-
ment group and no pretreatment group concerning left ventricu-
lar ejection fraction at discharge (Pearson χ2 P=0.42). Further
subgroup analyses showed no differences in mortality depending
on sex, hypertension, diabetes mellitus, high age, low weight,
and so on (Figure 2), with no P values for interaction reaching
statistical significance. Adjusted analyses were also performed
where all patients with clopidogrel pretreatment were removed
and showed similar overall neutral results, however, with wider
CIs because of smaller sample size, especially in the no ticagre-
lor pretreatment group (Table I in the Data Supplement).
Propensity Scoring and Multiple Imputation
The C statistic for the propensity score was 0.95 both with and
without cardiogenic shock in the propensity scoring model.
The Nagelkerke R2 was 0.70 without and 0.71 with cardio-
genic shock included in the propensity score.
suggest no significant difference in a composite end point of
all-cause mortality/MI/stent thrombosis and mortality, MI, or
stent thrombosis alone with ticagrelor pretreatment in patients
with STEMI undergoing primary PCI. These findings, in con-
junction with the neutral results of the previously published
randomized ATLANTIC trial,4 suggest that routine adminis-
tration of ticagrelor pretreatment should be reevaluated in this
patient group.
Previous Studies on Antiplatelet Pretreatment
Strategies in STEMI and Primary PCI
Pretreatment with antiplatelet agents for patients with STEMI
scheduled for acute PCI has been debated. Several random-
ized trials using GPIIB/IIIA-inhibitor pretreatment have
shown conflicting results concerning hard clinical end points,
where some studies have suggested benefit and others not.9–11
Although some data support usage of GPIIB/IIIA inhibitors in
patients with STEMI that are early presenters,11 many centers

Table 3.  Summary of Adjusted Clinical Event Rates at 30 Days With Cardiogenic Shock Included in Statistical Models
Cardiogenic Shock Included in Statistical Model
Composite End Point Death MI Stent Thrombosis
Direct multivariable regression model, hazard 1.02 (0.72–1.45); P=0.91 0.94 (0.62–1.42); P=0.77 0.87 (0.54–1.41); P=0.58 Not performed
ratio and 95% CI
Propensity score covariate adjustment model, 0.87 (0.60–1.25); P=0.44 0.83 (0.54–1.28); P=0.40 0.93 (0.45–1.91); P=0.84 0.91 (0.22–3.85); P=0.90
hazard ratio and 95% CI
Although not specifically balanced for cardiogenic shock, the propensity score–matched population became automatically balanced for it after matching and therefore
the model already accounts for it in Table 2. CI indicates confidence interval; and MI, myocardial infarction.
 8   Koul et al   Ticagrelor Pretreatment in STEMI Undergoing PCI
have switched from GPIIB/IIIA-inhibitor–based strategies
because of excess bleeding risk.12 Clopidogrel pretreatment
has in several registry studies showed promise as a pretreat-
ment option in STEMI patients undergoing primary PCI.13,14
The only prospective and randomized trial evaluating clopi-
dogrel pretreatment in this setting was vastly underpowered
because of slow inclusion rate (n=337), however, showed
strong trends toward reduction in major adverse clinical
events with clopidogrel pretreatment.15
Although both American and European guidelines recom-
mend as early P2Y12 inhibition as possible in patients with
STEMI undergoing primary PCI, there is limited data on this
Downloaded from http://ahajournals.org by on November 15, 2018
matter using modern P2Y12 inhibitors. Ticagrelor is the only
modern P2Y12 inhibitor to have been evaluated in this setting
in a prospective and randomized fashion in the ATLANTIC
study.4
Comparisons With ATLANTIC
Our study shared the same purpose as the ATLANTIC study.
Although this study was an observational study, the patients
included were all-comer patients, representative of a real-life
population and with a considerably larger sample size. Three
statistical models were used, each with its advantage and dis-
advantages, to more adequately shed light on this issue. The
choice of usage of multiple statistical models was based on a
stricter epidemiological approach; rather than publish a single
model that could deviate in any untoward direction, all 3 mod-
els were a priori required to show similar findings in order for
the data to be considered credible.
Our study indicated no benefit of ticagrelor pretreatment
in a 30-day composite cardiovascular end point (mortality/MI/
stent thrombosis) or its individual components. We did not see
any trend toward increased mortality or a decrease in stent
thrombosis at 30 days, in contrast to the ATLANTIC study.
However, the overall rate of stent thrombosis was lower in our
study than in the ATLANTIC study, more drug-eluting stents
were used in our study, and other concomitantly used anti-
platelet and anticoagulant agents differed between the studies
as well.4
The exact timing of ticagrelor administration is not
known in the SCAAR. However, practice in Sweden has
been to give ticagrelor pretreatment at first medical contact,
Figure 2. Forrest plot of 30-day mortal-
ity stratified by ticagrelor pretreatment or
treatment in catheterization laboratory. No
P values of interaction <0.05 were noted.
after a diagnosis of STEMI has been ascertained by 12-lead
ECG. In the recently published prospective and randomized
VALIDATE-SWEDEHEART (Bivalirudin versus Heparin
in ST-Segment and Non–ST-Segment Elevation Myocardial
Infarction in Patients on Modern Antiplatelet Therapy in the
Swedish Web-System for Enhancement and Development of
Evidence-based Care in Heart Disease Evaluated according
to Recommended Therapies Registry Trial), randomization
and background demographics were taken from the SCAAR,
where additional trial-specific information was added (that
is not normally part of the registry). This included time
delay from ticagrelor administration to angiography.16 In the
VALIDATE trial, representing an all-comer population in
Sweden and also using the SWEDEHEART register/SCAAR
on which this study is based, >40% of STEMI patients
received ticagrelor >1 hour before PCI.16 This time delay in
ticagrelor pretreatment is considerably longer than the median
of 31 minutes between the 2 ticagrelor loading doses in the
ATLANTIC study.4
Cardiogenic shock represents a special case of cause and
effect. Antiplatelet agents could potentially have an effect on
the hemodynamics, and it would, thus, constitute a part of
the causality chain and should not be adjusted for. In fact, in
the ATLANTIC study, the trend toward excess death in the
pretreatment group consisted of cardiogenic shock, cardiac
arrest, mechanical complications, and heart failure.4 However,
cardiogenic shock could also represent a potential confounder.
Therefore, cardiogenic shock was analyzed in separate mod-
els. The results were similar with or without cardiogenic
shock in our statistical models and when removing cardio-
genic shock patients from the models.
Low rates of bleeding in general were observed, and no
increased bleeding rate was noted in the ticagrelor pretreat-
ment group. This could be because of the fact that a majority
of patients with STEMI with ticagrelor pretreatment do not
have a substantial ticagrelor effect at the initiation of PCI and
no greater risk of bleeding during PCI (access-site bleeding,
cardiac tamponade, etc).17,18 Subgroup analyses did not show
any significant P values for interaction in any subgroup, sug-
gestive of uniform results across multiple subgroups.
 9   Koul et al   Ticagrelor Pretreatment in STEMI Undergoing PCI
Causality
Physiological reasons for the neutral results in our study
are purely speculative but deserve mention. The time delay
between ticagrelor administration and PCI could be insuf-
ficient for ticagrelor effect, in particular when taking into
account the morphine interaction with a slower uptake of
ticagrelor in STEMI patients compared with healthy volun-
teers. We have previously published STEMI data (where a
majority of patients have received morphine) indicating that
only 50% of ticagrelor pretreatment patients have sufficient
platelet inhibition at completion of PCI, leaving a majority
of patients not sufficiently inhibited during PCI.17 Further-
more, pretreatment perhaps might not be necessary because
the cause of mortality and morbidity could be postprocedural
thrombotic problems rather than intraprocedural. Patients
often receive peri-procedural antithrombotic treatments like
heparin, bivalirudin, or GPIIB/IIIA inhibitors, and thus in-
catheterization laboratory administration of ticagrelor might
be sufficient.
Limitations
We do not have data on patients undergoing coronary angi-
ography because of an indication of STEMI but with no PCI
performed. In the SCAAR, information on pretreatment is
available only when PCI is performed. Patients receiving
ticagrelor pretreatment but with other diagnoses such as aortic
dissection are, thus, likely to not be represented in our study
material. Furthermore, the exact timing of ticagrelor admin-
istration is not known. Although 40% of patients in the VAL-
Downloaded from http://ahajournals.org by on November 15, 2018
IDATE-SWEDEHEART trial had more than 1 hour of time
delay between ticagrelor and PCI, in 60% of patients, there
was <1 hour of time delay between ticagrelor pretreatment to
PCI, suggesting that there might not have been adequate time
for absorption in several patients.16 Morphine intake and dos-
age is not known because morphine has been shown to interact
with ticagrelor in subgroup analyses of the ATLANTIC study.4
Our study is an observational study, and all results have,
thus, to be interpreted with care and serve only as hypoth-
esis generating and cannot provide definite evidence of cau-
sality. Although multiple adjusted modeling was performed
to decrease confounding, a certain degree of residual con-
founding cannot be ruled out. Clinical events were registered
according to treating physician discretion and not centrally
adjudicated.
Our study represents, to our knowledge, the largest study
to date examining the effects of ticagrelor pretreatment in
patients with STEMI undergoing primary PCI. However, a
larger sample size would have increased the statistical power
of our observations. Information on TIMI flow grade post PCI
was not available and would have added more information. A
total of 969 patients also received clopidogrel pretreatment,
with the majority of these patients being in the no ticagre-
lor pretreatment group. Although we have tried to statistically
adjust for this, it remains a limitation.
Conclusions
Our results indicate that ticagrelor pretreatment did not
improve cardiovascular composite outcomes (death/MI/stent
thrombosis) or the individual components of the composite
outcome, compared with ticagrelor administered in the cath-
eterization laboratory in patients with STEMI undergoing
primary PCI. Our findings cast a doubt on the regular prac-
tice of ticagrelor pretreatment in the setting of STEMI and
primary PCI. Delaying ticagrelor administration till after the
coronary anatomy is known and a diagnosis of STEMI is con-
firmed, could avoid potent platelet inhibition to patients with
other life-threatening disorders, like aortic dissection, where
platelet inhibition could be deleterious.6 Furthermore, it could
potentially improve outcomes in the subset of patients that
require emergency surgery instead of PCI. Our results rein-
force the neutral results of the randomized ATLANTIC study.
However, a more definite answer on ticagrelor pretreatment in
patients with STEMI and primary PCI would require a larger
prospective randomized trial.
Acknowledgments
We would like to greatly thank Rebecca Rylance, MS in statistics, for
her invaluable help in statistical revision of this article.
Sources of Funding
This study was supported by unrestricted grants from the Swedish
Heart-Lung Foundation and TOTAL-AMI. The funders had no role in
any part of the study or in any decision about publication.
Disclosures
Drs Koul, Omerovic, Persson, Alfredsson, and Erlinge have received
speakers honoraria from Astra Zeneca. Drs Omerovic, James, and
Alfredsson have received research grants from Astra Zeneca for other
research projects. The other authors report no conflicts
References
1. Windecker S, Kolh P, Alfonso F, Collet JP, Cremer J, Falk V, Filippatos
G, Hamm C, Head SJ, Juni P, Kappetein AP, Kastrati A, Knuuti J,
Landmesser U, Laufer G, Neumann FJ, Richter DJ, Schauerte P, Sousa
Uva M, Stefanini GG, Taggart DP, Torracca L, Valgimigli M, Wijns W,
Witkowski A; Authors/Task Force Members. 2014 ESC/EACTS guide-
lines on myocardial revascularization: the task force on myocardial re-
vascularization of the European Society of Cardiology (ESC) and the
European Association for Cardio-Thoracic Surgery (EACTS) developed
with the special contribution of the European Association of Percutaneous
Cardiovascular Interventions (EAPCI). Eur Heart J. 2014;35:2541–619.
doi: 10.1093/eurheartj/ehu278.
2. O’Gara PT, Kushner FG, Ascheim DD, Casey DE Jr, Chung MK, de
Lemos JA, Ettinger SM, Fang JC, Fesmire FM, Franklin BA, Granger
CB, Krumholz HM, Linderbaum JA, Morrow DA, Newby LK, Ornato JP,
Ou N, Radford MJ, Tamis-Holland JE, Tommaso CL, Tracy CM, Woo
YJ, Zhao DX, Anderson JL, Jacobs AK, Halperin JL, Albert NM, Brindis
RG, Creager MA, DeMets D, Guyton RA, Hochman JS, Kovacs RJ,
Kushner FG, Ohman EM, Stevenson WG, Yancy CW; American College
of Cardiology Foundation/American Heart Association Task Force on
Practice Guidelines. 2013 ACCF/AHA guideline for the management
of ST-elevation myocardial infarction: a report of the American College
of Cardiology Foundation/American Heart Association Task Force on
practice guidelines. Circulation. 2013;127:e362–e425. doi: 10.1161/
CIR.0b013e3182742cf6.
3. Bellemain-Appaix A, Kerneis M, O’Connor SA, Silvain J, Cucherat M,
Beygui F, Barthélémy O, Collet JP, Jacq L, Bernasconi F, Montalescot
G; ACTION Study Group. Reappraisal of thienopyridine pretreatment in
patients with non-ST elevation acute coronary syndrome: a systematic re-
view and meta-analysis. BMJ. 2014;349:g6269.
4. Montalescot G, van ‘t Hof AW, Lapostolle F, Silvain J, Lassen JF,
Bolognese L, Cantor WJ, Cequier A, Chettibi M, Goodman SG, Hammett
CJ, Huber K, Janzon M, Merkely B, Storey RF, Zeymer U, Stibbe
O, Ecollan P, Heutz WM, Swahn E, Collet JP, Willems FF, Baradat C,
Licour M, Tsatsaris A, Vicaut E, Hamm CW; ATLANTIC Investigators.
 10   Koul et al   Ticagrelor Pretreatment in STEMI Undergoing PCI
Prehospital ticagrelor in ST-segment elevation myocardial infarction. N
Engl J Med. 2014;371:1016–1027. doi: 10.1056/NEJMoa1407024.
5. Montalescot G, Bolognese L, Dudek D, Goldstein P, Hamm C, Tanguay
JF, ten Berg JM, Miller DL, Costigan TM, Goedicke J, Silvain J, Angioli P,
Legutko J, Niethammer M, Motovska Z, Jakubowski JA, Cayla G, Visconti
LO, Vicaut E, Widimsky P; ACCOAST Investigators. Pretreatment with
prasugrel in non-ST-segment elevation acute coronary syndromes. N Engl
J Med. 2013;369:999–1010. doi: 10.1056/NEJMoa1308075.
6. Hansson EC, Dellborg M, Lepore V, Jeppsson A. Prevalence, indications
and appropriateness of antiplatelet therapy in patients operated for acute
aortic dissection: associations with bleeding complications and mortality.
Heart. 2013;99:116–121. doi: 10.1136/heartjnl-2012-302717.
7. Redfors B, Angerås O, Petursson P, Råmunddal T, Omerovic E. The
ATLANTIC trial does not support the safety of prehospital ticagrelor treat-
ment for patients with ST-elevation myocardial infarction. Int J Cardiol.
2015;190:157–158. doi: 10.1016/j.ijcard.2015.04.135.
8. Capodanno D, Angiolillo DJ. Pretreatment with antiplatelet drugs in inva-
sively managed patients with coronary artery disease in the contemporary
era: review of the evidence and practice guidelines. Circ Cardiovasc Interv.
2015;8:e002301. doi: 10.1161/CIRCINTERVENTIONS.114.002301.
9. Mehilli J, Kastrati A, Schulz S, Früngel S, Nekolla SG, Moshage W,
Dotzer F, Huber K, Pache J, Dirschinger J, Seyfarth M, Martinoff
S, Schwaiger M, Schömig A; Bavarian Reperfusion Alternatives
Evaluation-3 (BRAVE-3) Study Investigators. Abciximab in patients with
acute ST-segment-elevation myocardial infarction undergoing primary
percutaneous coronary intervention after clopidogrel loading: a random-
ized double-blind trial. Circulation. 2009;119:1933–1940. doi: 10.1161/
CIRCULATIONAHA.108.818617.
10. 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. doi: 10.1056/NEJMoa0706816.
11. Van’t Hof AW, Ten Berg J, Heestermans T, Dill T, Funck RC, van Werkum
W, Dambrink JH, Suryapranata H, van Houwelingen G, Ottervanger
Downloaded from http://ahajournals.org by on November 15, 2018
JP, Stella P, Giannitsis E, Hamm C; Ongoing Tirofiban In Myocardial
Infarction Evaluation (On-TIME) 2 Study Group. Prehospital initiation
of tirofiban in patients with ST-elevation myocardial infarction under-
going primary angioplasty (On-TIME 2): a multicentre, double-blind,
randomised controlled trial. Lancet. 2008;372:537–546. doi: 10.1016/
S0140-6736(08)61235-0.
12. Stone GW, Witzenbichler B, Guagliumi G, Peruga JZ, Brodie BR, Dudek
D, Kornowski R, Hartmann F, Gersh BJ, Pocock SJ, Dangas G, Wong SC,
Kirtane AJ, Parise H, Mehran R; HORIZONS-AMI Trial Investigators.
Bivalirudin during primary PCI in acute myocardial infarction. N Engl J
Med. 2008;358:2218–2230. doi: 10.1056/NEJMoa0708191.
13. Koul S, Smith JG, Scherstén F, James S, Lagerqvist B, Erlinge D. Effect
of upstream clopidogrel treatment in patients with ST-segment elevation
myocardial infarction undergoing primary percutaneous coronary inter-
vention. Eur Heart J. 2011;32:2989–2997. doi: 10.1093/eurheartj/ehr202.
14. Dörler J, Edlinger M, Alber HF, Altenberger J, Benzer W, Grimm G,
Huber K, Pachinger O, Schuchlenz H, Siostrzonek P, Zenker G, Weidinger
F; Austrian Acute PCI Investigators. Clopidogrel pre-treatment is associ-
ated with reduced in-hospital mortality in primary percutaneous coronary
intervention for acute ST-elevation myocardial infarction. Eur Heart J.
2011;32:2954–2961. doi: 10.1093/eurheartj/ehr360.
15. Zeymer U, Arntz HR, Mark B, Fichtlscherer S, Werner G, Schöller R,
Zahn R, Diller F, Darius H, Dill T, Huber K. Efficacy and safety of a
high loading dose of clopidogrel administered prehospitally to improve
primary percutaneous coronary intervention in acute myocardial infarc-
tion: the randomized CIPAMI trial. Clin Res Cardiol. 2012;101:305–312.
doi: 10.1007/s00392-011-0393-1.
16. Erlinge D, Omerovic E, Fröbert O, Linder R, Danielewicz M, Hamid
M, Swahn E, Henareh L, Wagner H, Hårdhammar P, Sjögren I, Stewart
J, Grimfjärd P, Jensen J, Aasa M, Robertsson L, Lindroos P, Haupt J,
Wikström H, Ulvenstam A, Bhiladvala P, Lindvall B, Lundin A, Tödt T,
Ioanes D, Råmunddal T, Kellerth T, Zagozdzon L, Götberg M, Andersson
J, Angerås O, Östlund O, Lagerqvist B, Held C, Wallentin L, Scherstén F,
Eriksson P, Koul S, James S. Bivalirudin versus heparin monotherapy in
myocardial infarction. N Engl J Med. 2017;377:1132–1142. doi: 10.1056/
NEJMoa1706443.
17. Koul S, Andell P, Martinsson A, Smith JG, Scherstén F, Harnek J, Götberg
M, Norström E, Björnsson S, Erlinge D. A pharmacodynamic comparison
of 5 anti-platelet protocols in patients with ST-elevation myocardial in-
farction undergoing primary PCI. BMC Cardiovasc Disord. 2014;14:189.
doi: 10.1186/1471-2261-14-189.
18. Franchi F, Rollini F, Cho JR, Bhatti M, DeGroat C, Ferrante E, Dunn
EC, Nanavati A, Carraway E, Suryadevara S, Zenni MM, Guzman LA,
Bass TA, Angiolillo DJ. Impact of escalating loading dose regimens of
ticagrelor in patients with ST-segment elevation myocardial infarction
undergoing primary percutaneous coronary intervention: results of a
prospective randomized pharmacokinetic and pharmacodynamic inves-
tigation. JACC Cardiovasc Interv. 2015;8:1457–1467. doi: 10.1016/j.
jcin.2015.02.030.