International Journal of Cardiology 215 (2016) 193–200

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International Journal of Cardiology

journal homepage: www.elsevier.com/locate/ijcard

Comparison of short-term clinical outcomes between ticagrelor versus

clopidogrel in patients with acute myocardial infarction undergoing
successful revascularization; from Korea Acute Myocardial Infarction
Registry—National Institute of Health
Keun-Ho Park a, Myung Ho Jeong b,⁎,1, Youngkeun Ahn b, Tae Hoon Ahn c, Ki Bae Seung d, Dong Joo Oh e,
Dong-Joo Choi f, Hyo-Soo Kim g, Hyeon Cheol Gwon h, In Whan Seong i, Kyung Kuk Hwang j, Shung Chull Chae k,
Kwon-Bae Kim l, Young Jo Kim m, Kwang Soo Cha n, Seok Kyu Oh o, Jei Keon Chae p,
on behalf of KAMIR-NIH registry investigators:
a
Chosun University Hospital, Gwangju, Republic of Korea
b
Chonnam National University Hospital, Gwangju, Republic of Korea
c
Gachon University Gil Medical Center, Incheon, Republic of Korea
d
The Catholic University of Korea Seoul St. Mary's Hospital, Seoul, Republic of Korea
e
Korea University Guro Hospital, Seoul, Republic of Korea
f
Seoul National University Bundang Hospital, Seoul, Republic of Korea
g
Seoul National University Hospital, Seoul, Republic of Korea
h
Sungkyunkwan Universtiy Samsung Medical Center, Seoul, Republic of Korea
i
hungnam National Universtiy Hospital, Daejeon, Republic of Korea
j
Chungbuk National University Hospital, Cheongju, Republic of Korea
k
Kyungpook National University Hospital, Daegu, Republic of Korea
l
Keimyung University Dongsan Medical Center, Daegu, Republic of Korea
m
Yeungnam University Hospital, Daegu, Republic of Korea
n
Pusan National University Hospital, Busan, Republic of Korea
o
Wonkwang University Hospital, Iksan, Republic of Korea
p
Chonbuk National University Hospital, Jeonju, Republic of Korea

a r t i c l e i n f o a b s t r a c t

Article history: Background: Although ticagrelor has been well-known to improve clinical outcomes in patients with acute myo-
Received 19 February 2016 cardial infarction (AMI) without increased bleeding risk, its clinical impacts have not been well established in
Received in revised form 8 April 2016 East Asian patients.
Accepted 10 April 2016 Methods: Between November 2011 and June 2015, a total of 8010 patients (1377 patients were prescribed
Available online 14 April 2016
ticagrelor and 6633 patients clopidogrel) undergoing successful revascularization were analyzed from Korea
Acute Myocardial Infarction Registry—National Institute of Health. The patients who discontinued or occurred
Keywords:
Myocardial infarction
in-hospital switching between two antiplatelet agents were excluded.
Ticagrelor Results: After propensity score matching (1377 pairs), no difference in the composite of cardiac death, MI, stroke,
Hemorrhage or target vessel revascularization at 6 months was observed between two groups (4.2% vs. 4.9%, p = 0.499). How-
Far East ever, the incidences of in-hospital Thrombolysis In Myocardial Infarction (TIMI) major and minor bleeding were
higher in ticagrelor than clopidogrel (2.6% vs. 1.2%, p = 0.008; 3.8% vs. 2.5%, p = 0.051). The in-hospital mortality
was higher in patients with than those without TIMI major bleeding (11.3% vs. 0.9%, p b 0.001). In a subgroup
analysis, a higher risk for in-hospital TIMI major bleeding with ticagrelor was observed in patients ≥ 75 years
or with body weight b 60 kg (odd ratio [OR] = 3.209; 95% confidence interval [CI] = 1.356–7.592) and in
those received trans-femoral intervention (OR = 1.996; 95% CI = 1.061–3.754).
Conclusions: Our study shows that ticagrelor did not reduce ischemic events yet, however, was associated with
increased risk of bleeding complications compared with clopidogrel. Further large-scale, long-term, randomized
trials should be required to assess the outcomes of ticagrelor for East Asian patients with AMI.
© 2016 Elsevier Ireland Ltd. All rights reserved.

⁎ Corresponding author at: Chonnam National University Hospital, 671 Jaebongro, Dong-gu, Gwangju 501-757, Republic of Korea.
E-mail address: myungho@chollian.net (M.H. Jeong).
1
Principal investigator of Korea Acute Myocardial Infarction Registry.

http://dx.doi.org/10.1016/j.ijcard.2016.04.044
0167-5273/© 2016 Elsevier Ireland Ltd. All rights reserved.
194 K.-H. Park et al. / International Journal of Cardiology 215 (2016) 193–200
1. Introduction
Dual antiplatelet therapy is mandatory for prevention of thrombotic
events in patients undergoing percutaneous coronary intervention
(PCI) [1,2]. The stronger antiplatelet agents should be need for the pa-
tients with high risk of thromboembolic ischemic events, especially
those suffering acute myocardial infarction (AMI) [3,4]. Aspirin and
clopidogrel have been the most widely prescribed antiplatelet agents
so far. However, clopidogrel is an inactive pro-drug that requires 2-
step hepatic metabolism via several cytochrome P450 enzymes for gen-
eration of the active metabolite, therefore, it has a relatively slow onset
and low potency of platelet inhibition.
Ticagrelor, a cyclopentyl triazolopyrimidine is an oral, reversible,
direct-acting inhibitor of the adenosine diphosphate receptor P2Y12
that has a more rapid onset and more pronounced platelet inhibition
than clopidogrel [5,6]. The Platelet Inhibition and Patient Outcomes
(PLATO) study has shown that ticagrelor reduced adverse ischemic
events and all-cause mortality without a significant increase in overall
major bleeding complications [7].
However, there were a little data about the clinical impact of
ticagrelor in East Asian patients with AMI. Therefore, the purpose of
our study was to compare the short-term clinical outcomes between
ticagrelor and clopidogrel in East Asian patients with AMI undergoing
successful PCI.
2. Materials and methods
2.1. Study design and population
We consecutively selected patients with AMI who undergoing suc-
cessful PCI from the database of the Korea Acute Myocardial Infarction
Registry-National Institutes of Health (KAMIR-NIH). The KAMIR-NIH is
a prospective, multicenter, web-based observational cohort study to de-
velop the prognostic and surveillance index of Korean patients with AMI
from 15 center in Korea and has been performed to support by a grant of
Korea Centers for Disease Control and Prevention since November 2011.
The diagnosis of AMI was based on detection of a raise and/or fall of
cardiac biomarker (creatinine kinase-MB and troponin I or T) with at
least one value above the 99th percentile upper reference limit and
with at least one of the following: symptoms of ischemia., new or
presumed new significant ST-segment–T wave changes or new left
bundle branch block, development of pathological Q waves in the ECG,
and imaging evidence of new loss of viable myocardium or new regional
wall motion abnormality [8].
Among them, we excluded the patients receiving prasugrel, those
discontinued antiplatelet agents during hospitalization or those
occurred in-hospital switching between clopidogrel and ticagrelor
(Fig. 1). The study protocols were approved by the ethics committee
at each participating center, and followed the principles of the
Fig. 1. Study population flow chart. KAMIR-NIH, Korea Acute Myocardial Infarction
Registry—National Institute of Health; TIA, transient ischemic attack.
Declaration of Helsinki. All patients provided written, informed consent
for participation in the registry. Trained study coordinators at each
participating institution collected the data using a standardized format.
Standardized definitions of all variables were determined by the
steering committee board of KAMIR-NIH.
2.2. Interventional procedures and in-hospital medications
The choice of antiplatelet agents (clopidogrel or ticagrelor),
emergent or early invasive treatments strategies, vascular assess, pre-
dilatation or post-dilatation, type of stents, use of peri-procedural
glycoprotein IIb/IIIa inhibitors, and anti-thrombotic medication were
determined based on the clinical status of AMI patient according to
the clinical decision of operators in each institutes. PCI was performed
in a routine manner. Anti-platelet agents were administered to all
patients prior to the intervention, with aspirin 300 mg loading dose
(LD) and clopidogrel 300–600 mg LD or ticagrelor 180 mg LD. After
the intervention, the patients received aspirin 100 mg once daily
indefinitely and clopiodgrel 75 mg once daily or ticagrelor 90 mg
twice daily for at least one year. Other medical treatments were also
used based on the standard treatment regimen for patients with AMI
in a non-restrictive manner.
2.3. Study endpoints
The primary efficacy end-point was major adverse cardiac events
(MACE), defined as the composite of cardiac death, non-fatal MI, stroke,
and clinically-driven target vessel revascularization (TVR) at 6-month
follow-up. The secondary efficacy end-points were all-cause death,
cardiac death, non-fatal MI, stroke and definite stent thrombosis during
hospitalization. The safety end-points were the Thrombolysis in
Myocardial Infarction (TIMI) major and minor bleeding during hospital-
ization [9]. Clinically-driven TVR was defined as revascularization
performed on the treated lesion or vessel of a patient who complained
of clinical symptoms such as chest pain that had increased in frequency,
duration or intensity. Stroke defined as a medical condition where blood
flow to brain was interrupted, because of either ischemia or hemor-
rhage. The incidence of “definite” Stent thrombosis was recorded ac-
cording to the Academic Research Consortium of Circulatory System
Devices Panel Meeting, an advisory committee to the US Food and
Drug Administration (FDA) in 2006.
2.4. Statistical analysis
Categorical variables were expressed as frequencies and percentages
and continuous variables as mean ± SD. An analysis of categorical
variables was performed using chi-square test or Fisher's exact test, as
appropriate, and that of continuous ones using Student's t-test.
To minimalize the effect of selection bias in the direct comparison
between ticagrelor and clopidogrel, the propensity score was estimated
using a multivariable logistic regression model, in which treatment
status is regressed on observed baseline, clinical, angiographic, and pro-
cedural characteristics, such as age, gender, body weight, hypertension,
diabetes mellitus, dyslipidemia, previous history of MI or cerebrovascu-
lar accident (CVA), current smoker, family history of coronary artery
disease, creatinine clearance, Killip classification, use of glycoprotein
IIb/IIIa inhibitor, prescription of calcium channel blocker, beta-blocker,
angiotensin converting enzyme inhibitor or angiotensin II receptor
blocker, and statin, vascular access, target vessel, multi-vessel disease,
American College of Cardiology/American Heart Association (ACC/
AHA) lesion classification type B2 or C, procedure for target lesion, left
ventricular ejection fraction, and diagnosis of ST elevation MI or non-
ST elevation MI. Thereafter, the patients receiving clopidogrel were 1-
to-1 matched to the patients receiving ticagrelor on propensity scores
using the nearest available pair matching method [10].
 K.-H. Park et al. / International Journal of Cardiology 215 (2016) 193–200 195

In the propensity score-matched populations, the baseline clinical,
angiographic, and procedural covariates were compared between the
two groups we compared the baseline covariates between two groups.
Continuous variables were compared with the use of paired t test, and
categorical variables were compared using chi-square test or Fisher's
exact test, as appropriate. Cumulative event rates between the two pro-
pensity score-matched groups were estimated using the Kaplan–Meier
method. Time-to-event curves were compared using the log-rank tests.
Multiple logistic regression analysis with an “enter” method was used to
identify the independent predictors of in-hospital TIMI major bleeding.
Only variables with a p value b 0.05 in the univariate analysis were
included in the multivariate model. Cox proportional hazards regression
was used to compute hazard ratios (HRs) as estimates for each
endpoint. The HRs were adjusted for propensity score and important
risk covariables that had significant effects (p b 0.1) in the univariate
analysis for clinical outcomes.
All statistical tests were 2-tailed, and a p value b 0.05 was considered
statistically significant. All the statistical analyses were performed using
SPSS (Statistical Package for Social Science, SPSS Inc., Chicago, IL, USA)
for Windows, Version 21.0.
3. Results
3.1. Baseline characteristics
Between November 2011 and June 2015, there were 10,171 patients
with AMI who undergoing successful PCI in KAMIR-NIH. We excluded
1375 patients receiving prasugrel and 786 patients occurred in-
hospital switching between clopidogrel and ticagrelor, regardless of
the reason. Of these patients, 1377 patients received ticagrelor and
6633 patients did clopidogrel (Fig. l).
Before propensity score matching, patients received ticagrelor and
clopidogrel significantly differed in baseline clinical and procedural
characteristics and in-hospital medications (Table 1). The patients
with ≥ 75 years or b60 kg body weight, with previous history of
hypertension, diabetes, dyslipidemia, MI, and CVA, with a low Killip

Table 1
Baseline clinical, angiographic, and procedural characteristics and in-hospital medications of enrolled patients.

Ticagrelor (n = 1377) Clopidogrel (n = 6633) p-Value

Age, years 62.30 ± 12.06 64.80 ± 12.61 b0.001

Age ≥ 75 years (%) 259 (18.8) 1718 (25.9) b0.001
Body weight, kg 66.35 ± 11.92 64.51 ± 11.79 b0.001
Body weight b 60 kg (%) 382 (27.7) 2133 (32.2) 0.001
Male gender (%) 1070 (77.7) 4791 (72.2) b0.001
Hypertension (%) 635 (46.1) 3477 (52.4) b0.001
Diabetes (%) 327 (23.7) 1955 (29.5) b0.001
Dyslipidemia (%) 155 (11.3) 773 (11.7) 0.675
Current smoker (%) 581 (42.2) 2505 (37.8) 0.002
Family history of CAD (%) 83 (6.0) 442 (6.7) 0.385
Previous history of MI (%) 73 (5.3) 493 (7.4) 0.005
Previous history of CVA (%) 64 (4.6) 507 (7.6) b0.001
Killip class (%) b0.001
I 1174 (85.3) 5158 (77.8)
II to IV 203 (14.7) 1475 (22.2)
Final diagnosis (%) b0.001
Non-ST segment elevation MI 581 (42.2) 3395 (51.2)
ST segment elevation MI 796 (57.8) 3238 (48.8)
Left ventricular ejection fraction, % 52.90 ± 10.23 51.57 ± 11.15 b0.001
Left ventricular ejection fraction b 50% (%) 464 (33.7) 2634 (39.7) b0.001
Creatinine clearance, ml/min/1.73 m2 82.75 ± 40.32 74.03 ± 36.21 b0.001
Creatinine clearance b 60 ml/min/1.73 m2 (%) 368 (26.7) 2460 (37.1) b0.001
Vascular access (%) b0.001
Transradial approach 638 (46.3) 2074 (31.3)
Transfemoral approach 739 (53.7) 4559 (68.7)
Infarct-related artery (%) 0.877
Left anterior descending 631 (45.8) 3073 (46.3)
Left circumflex 255 (18.5) 1189 (17.9)
Right coronary 465 (33.8) 2228 (33.6)
Left main 26 (1.9) 143 (2.2)
Involved vessel number (%) 0.254
Single vessel 683 (49.6) 3178 (47.9)
Left main or multi-vessel disease 694 (50.4) 3455 (52.1)
ACC/AHA lesion classification (%) b0.001
Type A/B1 126 (9.2) 1039 (15.7)
Type B2/C 1251 (90.8) 5594 (84.3)
Procedure for target lesion 0.005
Only balloon angioplasty 93 (6.8) 485 (7.3)
Bare metal stent 30 (2.2) 260 (3.9)
Drug-eluting stent 1254 (91.1) 5888 (88.8)
Use of glycoprotein IIb/IIIa inhibitor (%) 242 (17.6) 869 (13.1) b0.001
In-hospital medications (%)
Aspirin 1376 (99.9) 6628 (99.9) 1.000
Cilostazol 7 (0.5) 1146 (17.3) b0.001
Beta-blocker 1165 (84.6) 5660 (85.3) 0.489
Calcium channel blockers 56 (4.1) 425 (6.4) 0.001
ACEi or ARB 1104 (80.2) 5427 (81.8) 0.153
Statin 1317 (95.6) 6117 (92.2) b0.001

Dichotomous variables are expressed as n (%); continuous variables are expressed as mean ± standard deviation.
CAD indicates coronary artery disease; MI, myocardial infarction; CVA, cerebrovascular accident; LV, left ventricular; ACC, American College of Cardiology; AHA, American Heart Associ-
ation; ACEi, angiotensin converting enzyme inhibitor; and ARB, angiotensin II receptor blocker.
196 K.-H. Park et al. / International Journal of Cardiology 215 (2016) 193–200

class, non-ST segment elevation MI and transfemoral approach were
more likely to receive clopidogrel. However, current smoker and the
patients diagnosed ST segment elevation MI and with receiving
glycoprotein IIb/IIIa inhibitor and statin were more likely to receive
ticagrelor.
After propensity score matching was performed for all patients,
1377 matched pairs of patients were selected (Table 2). In these
matched patients, there were no significant differences between
ticagrelor and clopidogrel for any baseline clinical and procedure
characteristics and in-hospital medication.
3.2. Clinical outcomes
With respect to the primary efficacy outcome, there was no signifi-
cant difference in the incidence of MACE between ticagrelor and
clopidogrel at 6-month follow-up (4.2% vs. 4.9%, p = 0.499) (Table 3,
Fig. 2). Also, no difference was observed in the composite of cardiac
death, non-fatal MI or stroke during hospitalization (1.3% vs. 1.6%,
p = 0.524). However, ticagrelor, compared with clopiodogrel, was
associated with higher incidences of in-hospital TIMI major and minor
bleeding (2.6% vs. 1.2%, p = 0.008; 3.8% vs. 2.5%, p = 0.051). In addition,
in-hospital TIMI major bleeding was strongly associated with in-
hospital mortality (11.3% vs. 0.9%, p b 0.001) and poor in-hospital
clinical outcomes (Fig. 3). However, there was no difference in in-
hospital mortality between ticagrelor and clopidogrel (1.2% vs. 1.0%,
p = 0.588).
Multivariate logistic regression analysis showed that the indepen-
dent predictors of in-hospital TIMI major bleeding were transfemoral
intervention (odds ratio [OR], 6.685; 95% confidence intervals [CI],
2.609–17.129), use of glycoprotein IIb/IIIa inhibitor (OR, 2.562; 95% CI,
1.394–4.708), and use of ticagrelor (OR, 1.971; 95% CI, 1.086–3.577)
(Table 4).

Table 2
Baseline clinical, angiographic, and procedural characteristics and in-hospital medications of propensity score matched patients.

Ticagrelor (n = 1377) Clopidogrel (n = 1377) p-Value

Age, years 62.30 ± 12.06 62.24 ± 12.53 0.895

Age ≥ 75 years (%) 259 (18.8) 272 (19.8) 0.530
Body weight, kg 66.35 ± 11.92 65.98 ± 11.59 0.402
Body weight b 60 kg (%) 382 (27.7) 385 (28.0) 0.865
Male gender (%) 1070 (77.7) 1086 (78.9) 0.460
Hypertension (%) 635 (46.1) 646 (46.9) 0.674
Diabetes (%) 327 (23.7) 314 (22.8) 0.558
Dyslipidemia (%) 155 (11.3) 156 (11.3) 0.952
Current smoker (%) 581 (42.2) 588 (42.7) 0.787
Family history of CAD (%) 83 (6.0) 82 (6.0) 0.936
Previous history of MI (%) 73 (5.3) 63 (4.6) 0.379
Previous history of CVA (%) 64 (4.6) 58 (4.2) 0.578
Killip class (%) 0.749
I 1174 (85.3) 1168 (84.8)
II to IV 203 (14.7) 209 (15.2)
Final diagnosis (%) 0.563
Non-ST segment elevation MI 581 (42.2) 596 (43.3)
ST segment elevation MI 796 (57.8) 781 (56.7)
Left ventricular ejection fraction, % 52.90 ± 10.23 53.19 ± 10.01 0.454
Left ventricular ejection fraction b 50% (%) 464 (33.7) 481 (34.9) 0.495
Creatinine clearance, ml/min/1.73 m2 82.75 ± 40.32 82.61 ± 36.85 0.924
Creatinine clearance b 60 ml/min/1.73 m2 (%) 368 (26.7) 373 (27.1) 0.830
Vascular access (%) 0.789
Transradial approach 638 (46.3) 645 (46.8)
Transfemoral approach 739 (53.7) 732 (53.2)
Infarct-related artery (%) 0.724
Left anterior descending 631 (45.8) 602 (43.7)
Left circumflex 255 (18.5) 264 (19.2)
Right coronary 465 (33.8) 486 (35.3)
Left main 26 (1.9) 25 (1.8)
Involved vessel number (%) 0.879
Single vessel 683 (49.6) 687 (49.9)
Left main or multi-vessel disease 694 (50.4) 690 (50.1)
ACC/AHA lesion classification (%) 0.947
Type A/B1 126 (9.2) 125 (9.1)
Type B2/C 1251 (90.8) 1.252 (90.9)
Procedure for target lesion 0.926
Only balloon angioplasty 93 (6.8) 89 (6.5)
Bare metal stent 30 (2.2) 32 (2.3)
Drug-eluting stent 1254 (91.1) 1256 (91.2)
Use of glycoprotein IIb/IIIa inhibitor (%) 242 (17.6) 225 (16.3) 0.388
In-hospital medications (%)
Aspirin 1376 (99.9) 1377 (100) 1.000
Cilostazol 7 (0.5) 226 (16.4) b0.001
Beta-blocker 1165 (84.6) 1150 (83.5) 0.435
Calcium channel blockers 56 (4.1) 65 (4.7) 0.403
ACEi or ARB 1104 (80.2) 1112 (80.8) 0.701
Statin 1317 (95.6) 1316 (95.6) 0.926

Dichotomous variables are expressed as n (%); continuous variables are expressed as mean ± standard deviation.
CAD indicates coronary artery disease; MI, myocardial infarction; CVA, cerebrovascular accident; LV, left ventricular; ACC, American College of Cardiology; AHA, American Heart Associ-
ation; ACEi, angiotensin converting enzyme inhibitor; and ARB, angiotensin II receptor blocker.
 K.-H. Park et al. / International Journal of Cardiology 215 (2016) 193–200 197

Table 3
In-hospital and 6-month cumulative clinical outcomes.

Ticagrelor Clopidogrel p-Value Risk for ticagrelor

In-hospital clinical outcomes, events (%) n = 1377 n = 1377 OR (95% CI)

All-cause death 17 (1.2) 14 (1.0) 0.588 1.241 (0.465–3.310)
Cardiac death 12 (0.9) 9 (0.7) 0.511 1.480 (0.484–4.527)
Non-fatal MI 6 (0.4) 5 (0.4) 0.763 1.237 (0.375–4.074)
Definite stent thrombosis 5 (0.4) 5 (0.4) 1.000 1.009 (0.291–3.496)
Stroke 1 (0.1) 11 (0.8) 0.006 0.084 (0.011–0.652)
Cardiac death, non-fatal MI or stroke 18 (1.3) 22 (1.6) 0.524 0.738 (0.372–1.465)
TIMI major bleeding 36 (2.6) 17 (1.2) 0.008 1.971 (1.086–3.577)
TIMI minor bleeding 53 (3.8) 35 (2.5) 0.051 1.480 (0.947–2.314)
TIMI major or minor bleeding 76 (5.5) 47 (3.4) 0.007 1.589 (1.081–2.338)
Cardiac death, non-fatal MI, stroke or TIMI major bleeding 52 (3.8) 34 (2.5) 0.049 1.480 (0.932–2.350)
At 6-month follow-up, events (%) n = 828 n = 1128 HR (95% CI)
All-cause death 25 (3.0) 36 (3.2) 0.829 0.915 (0.532–1.575)
Cardiac death 17 (2.1) 22 (2.0) 0.872 0.960 (0.482–1.913)
Non-fatal MI 10 (1.2) 15 (1.3) 0.812 0.851 (0.381–1.899)
Definite stent thrombosis 6 (0.7) 9 (0.8) 0.854 0.872 (0.312–2.476)
Stroke 7 (0.8) 17 (1.5) 0.189 0.481 (0.198–1.168)
Cardiac death, non-fatal MI or stroke 31 (3.7) 47 (4.2) 0.637 0.784 (0.491–1.253)
Cardiac death, non-fatal MI, stroke or TIMI major bleeding 64 (7.7) 59 (5.2) 0.026 0.749 (0.521–1.076)
Target lesion revascularization 8 (1.0) 13 (1.2) 0.693 0.819 (0.339–1.977)
Target vessel revascularization 10 (1.2) 16 (1.4) 0.688 0.812 (0.368–1.793)
MACE 35 (4.2) 55 (4.9) 0.499 0.784 (0.491–1.253)

OR, odd ratio; CI, confidence interval; MI, myocardial infarction; TIMI, the Thrombolysis in Myocardial Infarction; HR, hazard ratio; MACE, major adverse cardiac events defined as a com-
posite of cardiac death, non-fatal MI, stroke or target vessel revascularization.

3.3. Subgroup analysis
There were no significant interactions between anti-platelet agent and
in-hospital TIMI major bleeding in any subgroups, except the subgroup
regarding creatinine clearance. At subgroup analysis, the disfavoring of
ticagrelor for in-hospital TIMI major bleeding appeared consistent across
key prespecified covariates, especially female gender, the patients more
than 75 years of age or body weight less than 60 kg, those with hyperten-
sion, those with a low creatinine clearance, those received transfemoral
intervention, and those diagnosed non-ST elevation MI (Fig. 4).

Fig. 2. Kaplan–Meier curve for primary outcome between ticagrelor and clopiodgrel. (A) All-cause death, (B) a composite of cardiac death, non-fatal myocardial infarction or stroke, (C) a
composite of cardiac death, non-fatal myocardial infarction, stroke or target vessel revascularization, (D) a composite of cardiac death, non-fatal myocardial infarction, stroke or TIMI major
bleeding. MI, myocardial infarction; TVR, target vessel revascularization; TIMI, the Thrombolysis in Myocardial Infarction.
198 K.-H. Park et al. / International Journal of Cardiology 215 (2016) 193–200

Fig. 3. In-hospital clinical outcomes in patients with versus without in-hospital TIMI major bleeding.

4. Discussion platelets and the pro-thrombotic effect of transfusion of blood products,

Our study is conducted to compare the efficacy and safety between
ticagrelor versus clopidogrel in East Asian patients, especially Korean
patients with AMI. The major finding of our study is that ticagrelor
was associated with higher incidences of in-hospital major and minor
bleeding and similar to clopiodgrel for the prevention of ischemic
events. Therefore, our study suggests that ticagrelor should be required
to be carefully monitored for in-hospital bleeding complications, espe-
cially elderly patients or patients with low body weight. However, fur-
ther large scale, long-term, randomized should be needed to assess
the efficacy and safety of ticagrelor in East Asian patients with AMI.
Ticagrelor is a non-thienopyridine belonging to a new class known
as cyclopentyl triazolo-pyrimidines (CPTP), direct-acting, oral antago-
nist that binds reversibly to the P2Y12 receptor and also inhibits aden-
osine reuptake [11,12]. In PLATO study, as compared with clopidogrel,
ticagrelor was associated with a 16% relative risk reduction with regard
to the primary end point - a composite of death from cardiovascular
causes, MI, and stroke — but no significant increase in the overall risk
of major bleeding (11.6% vs. 11.2%, p = 0.43) [7]. The consistency of ef-
fects of ticagrelor was also observed in Asian patients of PLATO study
[13]. In addition, the benefits of reduction of mortality from any cause
and cardiovascular causes were more pronounced for patients treated
with bypass surgery [14]. The mechanisms for these reduction of
mortality still remain uncertain. However, the potential mechanisms
besides the more potent antiplatelet effect have been suggested includ-
ing the redistribution of ticagrelor to attenuate the reactivity of new
an increasing endogenous adenosine concentrations, anti-inflammatory
effect, and the differential effects on the responses to pulmonary events
and sepsis [15–18].
Even though previous data have demonstrated that potent anti-
platelet therapies could reduce ischemic events and mortality, our
study show no benefit of reduction of those in ticagrelor compared
with clopiodgrel. It could possibly explain that our study was a small-
scale, non-randomized study and the rate of the Korean AMI patients
receiving bypass surgery was very low compared to that of those from
West. In addition, we analyzed the short-term follow up between two
groups, therefore, a large-scale, long-term, randomized trial should be
needed to exactly assess the benefit of reduction of mortality of
ticagrelor in Korean patient with AMI.
In our study, the incidence of MACE was relatively lower compared
with previous published KAMIR or other AMI studies [19–21]. That is
because our study excluded the patients discontinued antiplatelet
agents, regardless of the reason or occurred in-hospital switching
between clopidogrel and ticagrelor, who might be confused to assess
the clinical outcomes of each antiplatelet agent. Accordingly, patients
who suffered ischemic or hemorrhagic events during hospitalization
tended to discontinue or switch anti-platelet agents, would have been
excluded, thus, relatively stable patients with AMI after successful
revascularization were mainly included in our study. Therefore, it
might have been underestimated the incidence of MACE in our study
compared with that in the real-world clinical practice in Korean patients
with AMI. Nevertheless, the incidence of TIMI major bleeding was

Table 4
The independent associates of TIMI major bleeding.

Variable Univariate analysis Multivariate analysis

OR (95% CI) p-Value OR (95% CI) p-Value

TFI vs. TRI 8.622 (3.422–21.724) b0.001 6.685 (2.609–17.129) b0.001

Glycoprotein IIb/IIIa inhibitor 3.056 (1.738–5.375) b0.001 2.562 (1.394–4.708) 0.002
Ticagrelor vs. clopidogrel 2.148 (1.200–3.842) 0.008 1.971 (1.086–3.577) 0.026
Dyslipidemia 0.148 (0.020–1.077) 0.026 0.141 (0.019–1.039) 0.055
Previous history of CVA 2.845 (1.192–6.789) 0.014 2.354 (0.937–5.912) 0.069
LV ejection fraction b 50% 2.017 (1.170–3.476) 0.010 1.692 (0.958–2.989) 0.070
Use of ACEi or ARB 0.426 (0.241–0.752) 0.002 0.642 (0.346–1.192) 0.161
Body weight b 60 kg 2.185 (1.264–3.777) 0.004 1.604 (0.803–3.205) 0.181
Age ≥ 75 years 2.193 (1.232–3.904) 0.006 1.600 (0.800–3.200) 0.184
Use of statin 0.348 (0.146–0.831) 0.013 0.589 (0.223–1.558) 0.286
Current smoker 0.529 (0.290–0.967) 0.035 0.707 (0.360–1.192) 0.316
Killip class II to IV vs. I 2.291 (1.248–4.204) 0.006 1.370 (0.706–2.659) 0.352
Female gender 2.226 (1.268–3.909) 0.004 1.276 (0.630–2.583) 0.498
Ccr b 60 ml/min/1.73 m2 1.956 (1.125–3.401) 0.015 0.849 (0.430–1.679) 0.638

TIMI, the Thrombolysis in Myocardial Infarction; OR, odd ratio; CI, confidence interval; TFI, trans-femoral intervention; TRI, trans-radial intervention; CVA, cerebrovascular accident; LV, left
ventricular; ACEi, angiotensin converting enzyme inhibitor; ARB, angiotensin II receptor blocker; Ccr, creatinine clearance.
 K.-H. Park et al. / International Journal of Cardiology 215 (2016) 193–200
Fig. 4. Forest plots for in-hospital TIMI major bleeding according to several key subgroups. TIMI, the Thrombolysis in Myocardial Infarction; CI, confidence interval; MI, myocardial
infarction.
significantly higher in patients with ticagrelor than those with
clopidogrel in our study, although fatal bleeding complications did not
occur. It means that the bleeding risk of ticagrelor might be much higher
than that of clopiodogrel in the real-world clinical practice in Korean
patients with AMI. Bleeding complications have been well known to
be associated with an increased risk of adverse outcomes and our
study also demonstrated similar in-hospital clinical results. Especially,
the subgroup analysis of our study showed that ticagrelor had a higher
bleeding complication in the patients more than 75 years of age or body
weight less than 60 kg than in the others. Therefore, the use of ticagrelor
should be considered carefully and needed to close monitoring for
bleeding complications in elderly and patients with a low body weight.
The result of the current Phase III (PHILO) study was consistent with
that of our study and showed that the incidences of the safety and
efficacy endpoints were higher in ticagrelor-treated patients compared
with clopidogrel-treated patients, in acute coronary syndrome (ACS)
patients from Japan, Taiwan and South Korea [22]. The East Asian
patients (Korean, Japanese, or Chinese, etc.) have well known to have
a lower body mass index, and the differences in thrombogenicity,
platelet P2Y12 receptor inhibition, and propensity for bleeding
complication and show the higher risk of warfarin-related hemorrhage
compared with western patients [23–25]. Furthermore, despite a higher
level of platelet reactivity during dual anti-platelet therapy, they tend to
have a similar or a lower rate of ischemic events after PCI compared
with Western patients [26–28]. Therefore, the different optimal
‘therapeutic window’ of platelet reactivity has been suggesting between
Western and East Asian patients, and the regional and national
guidelines should be necessary and required to develop for East Asian
patients with AMI or undergoing PCI [23]. The result of our study
would be a good reference to determine the appropriate antiplatelet
therapy strategies for East Asian patients.
199
In PRASugrel compared to clopidogrel For Japanese PatIenTs with
ACS undergoing PCI (PRASFIT-ACS) study, the low doses of prasugrel
(20/3.75 mg) was associated with a low incidence of ischemic events
and without increasing bleeding complications in Japanese patients
with ACS [29]. The usual dosage of prausgrel and ticagrelor might be
too high for East Asian in terms of the ischemic events as well as the
bleeding complications. The Prevention of Cardiovascular Events in Pa-
tients with Prior Heart Attack using Ticagrelor Compared to Placebo on
the Background of Aspirin - Thrombolysis in Myocardial Infarction 54
(PEGASUS-TIMI 54) study showed that the 60 mg of ticagrelor had a
lower rates of bleeding complication and a similar reduction of ischemic
events compared with the 90 mg of ticagrelor, therefore, suggested that
the 60-mg dose of ticagrelor may offer a more attractive benefit–risk
profile [30]. The potent antiplatelet agents can prevent ischemic events,
however, it will surely come at the expense of an increase of bleeding
complications [31]. Therefore, we have to pay attention to bleeding
complication as well as ischemic events in AMI patients receiving the
potent antiplatelet agents. According to the result of our study, we
think that a low dose of ticagrelor or prasugrel should be recommended
to prevent the bleeding risk outweighing the benefit in Korean patients,
furthermore East Asian patients, with AMI undergoing PCI.
5. Study limitations
Our study also has several limitations. First, our study was a non-
randomized study, but based on a prospective, observational registry,
therefore, selection bias was hardly avoidable, even though it was
partially compensated by propensity score matched analysis. Second,
as mentioned above, the mortality and ischemic event rates were very
low. Hence, our study was underpowered to assess the benefit of reduc-
tion of ischemic events of ticagrelor compared with clopiodgrel. Third,
200 K.-H. Park et al. / International Journal of Cardiology 215 (2016) 193–200
we could not accurately evaluate the bleeding complications and drug
adherence and persistence during follow-up, because of the limitation
of registry data. Fourth, there were few medical records about other
adverse effects of ticagrelor including dyspnea, heart block, or bruising.
6. Conclusions
Our study shows that ticagrelor did not reduce ischemic events yet,
however, was significantly associated with increased risk of in-hospital
bleeding complications compared with clopidogrel in Korean patients
with AMI. Therefore, ticagrelor should be required to be carefully
monitored for bleeding complications, especially in elderly or patients
with low body weight. However, further large-scale, long-term,
randomized should be required to assess the efficacy and safety of
ticagrelor in East Asian patients with AMI.
Disclosures
None.
Conflict of interest
The authors report no relationships that could be construed as a
conflict of interest.
Acknowledgments
This study was supported by grants of the Korea Centers for Disease
Control & Prevention (2013-E63005-01) and the Korean Health
Technology R&D Project, Ministry of Health & Welfare (HI13C1527),
Republic of Korea.
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