- Email: [email protected]
Ticagrelor versus clopidogrel in acute myocardial infarction patients with multivessel disease; From Korea Acute Myocardial Infarction Registry-National Institute of Health
G Model
JJCC 1958 1–7 Journal of Cardiology xxx (2019) xxx–xxx
Contents lists available at ScienceDirect
Journal of Cardiology journal homepage: www.elsevier.com/locate/jjcc 1 2 3 4 5
6 7 8 9 10 11 12 13 14 15 16
Original article
Ticagrelor versus clopidogrel in acute myocardial infarction patients with multivessel disease; From Korea Acute Myocardial Infarction Registry-National Institute of Health Joon Ho Ahn (MD)a, Youngkeun Ahn (MD, PhD, FACC, FSCAI)a,*, Myung Ho Jeong (MD, PhD, FACC, FAHA, FESC, FASCAI)a, Ju Han Kim (MD, PhD)a, Young Joon Hong (MD, PhD)a, Doo Sun Sim (MD, PhD)a, Min Chul Kim (MD, PhD)a, Jin Yong Hwang (MD, PhD)b, Jung Han Yoon (MD, PhD)c, In Whan Seong (MD, PhD)d, Seung-Ho Hur (MD, PhD)e, Seok Kyu Oh (MD, PhD)f, other KAMIR-NIH Registry Investigators a
Chonnam National University Hospital, Gwangju, South Korea Gyeongsang National University Hospital, Jinju, South Korea Yonsei University Wonju College of Medicine, Wonju Severance Christian Hospital, Wonju, South Korea d Chungnam National University Hospital, Daejeon, South Korea e Keimyung University Dongsan Medical Center, Daegu, South Korea f Wonkwang University Hospital, Iksan, South Korea b c
A R T I C L E I N F O
A B S T R A C T
Article history: Received 17 June 2019 Received in revised form 24 October 2019 Accepted 17 November 2019 Available online xxx
Background: The clinical efficacy of ticagrelor is questionable in East Asian populations. Patients with acute myocardial infarction (AMI) with multivessel disease (MVD) are considered as high risk patients who might benefit from ticagrelor treatment. The purpose of this study is to compare the clinical effect of ticagrelor and clopidogrel in AMI patients with MVD in Korea. Methods and results: A total of 2275 patients between November 2011 and June 2015, diagnosed with AMI with MVD after successful percutaneous coronary intervention who were registered in the Korea Acute Myocardial Infarction Registry – National Institute of Health (KAMIR-NIH) were enrolled. Patients were divided into ticagrelor (n = 837) and clopidogrel group (n = 1438). The primary endpoint was major adverse cardiac events (MACE) defined as cardiac death, non-fatal MI, target vessel revascularization, or ischemic stroke during 2 years of clinical follow-up. Secondary endpoints were thrombolysis in myocardial infarction (TIMI) major or minor bleeding, net clinical event composed of MACE and TIMI major bleeding, any repeated percutaneous coronary intervention, heart failure requiring rehospitalization, and stent thrombosis. After propensity score matching analysis, the primary endpoint was lower in ticagrelor group compared to the clopidogrel group (8.6 % vs. 11.9 %; HR: 0.68; 95 % CI: 0.500.94; p = 0.018). The risk of TIMI major or minor bleeding was higher in the ticagrelor group (10.8 % vs. 4.8 %; HR: 2.51; 95 % CI: 1.68–3.76; p < 0.001). The net clinical event was similar between ticagrelor and clopidogrel group (11.3 % vs. 13.6 %; HR 0.82; 95 % CI: 0.60–1.11; p = 0.195). Conclusion: Ticagrelor significantly reduced the risk of MACE than clopidogrel for AMI patients with MVD in Korea. However, the risk of TIMI major or minor bleeding was higher and the net clinical benefit was similar. Further large-scale multi-center randomized clinical trials are needed to clarify the proper use dual antiplatelet therapy in East Asian populations. © 2019 Published by Elsevier Ltd on behalf of Japanese College of Cardiology.
Keywords: Multivessel disease Acute myocardial infarction East Asian populations Ticagrelor
Introduction * Corresponding author: Department of Cardiology, Cardiovascular Center, Chonnam National University Hospital, Institute of Molecular Medicine, BK21 Plus, Chonnam National University Medical School, 42Jebong-ro, Dong-gu, Gwangju 61469, South Korea. E-mail address: [email protected] (Y. Ahn).
Over the past few decades, dual antiplatelet therapy (DAPT) has become one of the major issues in the pharmacologic treatment modalities in acute myocardial infarction (AMI) [1]. DAPT remarkably reduced the rate of thrombotic and ischemic complications including
https://doi.org/10.1016/j.jjcc.2019.11.003 0914-5087/© 2019 Published by Elsevier Ltd on behalf of Japanese College of Cardiology.
Please cite this article in press as: Ahn JH, et al. Ticagrelor versus clopidogrel in acute myocardial infarction patients with multivessel disease; From Korea Acute Myocardial Infarction Registry-National Institute of Health. J Cardiol (2019), https://doi.org/10.1016/j. jjcc.2019.11.003
17
18 19 20
G Model
JJCC 1958 1–7 J.H. Ahn et al. / Journal of Cardiology xxx (2019) xxx–xxx
2 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61
stent thrombosis and MI after percutaneous coronary intervention (PCI) [2]. Shortcomings of second-generation P2Y12 inhibitor, clopidogrel, have emerged during the past 10 years and the major randomized clinical trial, Platelet Inhibition and Patient Outcomes (PLATO) demonstrated the superiority of new generation P2Y12 inhibitor, ticagrelor in MI patients compared to clopidogrel [3–5]. According to this major trial, the 2016 American College of Cardiology Foundation/American Heart Association (ACCF/AHA) and 2017 European Society of Cardiology (ESC) guidelines for DAPT recommend ticagrelor over clopidogrel in acute coronary syndrome (ACS) patients after PCI (Class IIa, level of evidence B), (Class I, level of evidence B) [6,7]. The efficacy and safety of new generation P2Y12 inhibitor ticagrelor in East Asian populations however is questionable [8]. In these circumstance, we considered that further study was necessary to select certain high-risk group of patients in East Asian population that might have clear clinical benefit of ticagrelor use. Multivessel coronary artery disease (MVD) presents in more serious clinical manifestations and shows poor clinical outcomes than single vessel coronary artery disease [9,10]. We assumed that AMI patients with MVD were those high-risk group patients that might benefit from ticagrelor. The main purpose of our study is to compare the clinical impact of ticagrelor and clopidogrel in AMI patients with MVD in Korea. Methods Among the 13,650 patients enrolled in Korea AMI Registry National Institutes of Health (KAMIR-NIH) from November 2011 to June 2015, 5390 AMI patients with MVD were selected. Either primary PCI or elective PCI was done for the entire selected patients. The KAMIR-NIH is a prospective, open, multi-center, webbased cohort study to investigate the prognosis of real world outcome of Korean patients with AMI from 15 centers in Korea and has been performed with support by a grant of Korea Centers for Disease Control and Prevention since November 2011. Data were retrospectively collected by a trained study coordinator based on the standardized protocol. The study was conducted according to the Declaration of Helsinki. The institutional review board of all individual participating centers approved the study protocol. The approval number was CNUH-2011-172 of Chonnam National University Hospital. Written informed consent was obtained from all participating patients. From these 5390 individuals, the
following patients were sequentially excluded: left main disease; patients treated with prasugrel as the new generation P2Y12 inhibitor and those receiving either cilostazol or ticlopidine; patients with no P2Y12 inhibitor treatment; patients with different drug loading or maintenance dose of ticagrelor or clopidogrel; patients switched from ticagrelor to clopidogrel during the inhospital period; patients lost by in-hospital death or outpatient clinical follow-up data loss. A total of 2275 patients were included in the present study. The patients were finally divided into ticagrelor (n = 837) and clopidogrel group (n = 1438) (Fig. 1). All patients received 300 mg loading dose of aspirin 180 mg of ticagrelor or 600 mg of clopidogrel before the diagnostic coronary angiography. Coronary angiography was performed through either the radial or the femoral artery. Unfractionated heparin 50–100 U/ kg was administered and activated clotting time at >250 s were maintained. PCIs were performed by using standard techniques. After PCI, both treatment groups maintained 100 mg of aspirin and ticagrelor 90 mg twice daily or clopidogrel 75 mg daily. Patients were recommended to maintain at least one year of DAPT. Other medications including ß-blocker, statin, renin angiotensin system (RAS) blocker were prescribed to each patient as clinically indicated. Two-dimensional echocardiography was performed in all patients during the initial hospitalization period and left ventricular ejection fraction (LVEF) was estimated. The primary endpoint of this study was the cumulative incidence of major adverse cardiac events (MACE) during 2 years of clinical follow up. MACE were composed of cardiac death, nonfatal MI, target vessel revascularization (TVR), and ischemic stroke. The secondary endpoints were thrombolysis in myocardial infarction (TIMI) major or minor bleeding during in-hospital and follow up period, net clinical event composed of MACE and TIMI major bleeding, any repeated PCI, heart failure (HF) requiring rehospitalization, and stent thrombosis. MVD was defined as critical stenosis (>70 % of diameter) by quantitative coronary angiography in at least 2 major epicardial coronary arteries. All deaths were considered cardiac deaths if non-cardiac death could be excluded. Non-fatal MI was defined as recurrent symptoms with new ST-segment elevation in the electrocardiogram or re-elevation of cardiac markers to at least twice the upper limit of normal. TVR was defined as repeated PCI of any segment within the target vessel. Bleeding events were classified as major or minor according to the TIMI scales [11]. Stent thrombosis was defined according to the Academic Research Consortium definitions [12].
Fig. 1. Study flow chart. AMI, acute myocardial infarction.
Please cite this article in press as: Ahn JH, et al. Ticagrelor versus clopidogrel in acute myocardial infarction patients with multivessel disease; From Korea Acute Myocardial Infarction Registry-National Institute of Health. J Cardiol (2019), https://doi.org/10.1016/j. jjcc.2019.11.003
62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104
G Model
JJCC 1958 1–7 J.H. Ahn et al. / Journal of Cardiology xxx (2019) xxx–xxx 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127
The baseline clinical characteristics of both treatment groups were analyzed. Continuous variables are presented as means standard deviations and were compared by using unpaired Student’s t-tests and Mann-Whitney U test. Discrete variables are expressed as percentages and frequencies and were compared by using chi-square statistics or Fisher's exact test. The propensity score matching analysis was done by using a multiple logistic regression model to minimize the selection bias in comparing the effect of ticagrelor and clopidogrel. The relevant variables included were age, sex, Killip class on admission, diagnosis of ST elevation MI (STEMI), cardiovascular risk factors (hypertension, diabetes mellitus, dyslipidemia, smoking status), previous MI, previous cerebrovascular accident, estimated glomerular filtration rate (eGFR), LVEF, prescribed medications (ß-blocker, statin, RAS blockade, oral anticoagulant), transradial approach, infarct-related artery (IRA), preprocedural and postprocedural IRA TIMI flow grade, ACCF/AHA lesion classification type B2 or C, three vessel disease, PCI modalities (balloon angioplasty, bare metal stent, firstgeneration and second-generation drug-eluting stent), IRA stent size and length, total implanted stent number, use of glycoprotein (GP) IIb/IIIa inhibitor, thrombus aspiration. The model was well calibrated with good discrimination and the clopidogrel group patients were 1-on-1 matched to the ticagrelor group patients on
3
their propensity scores using the nearest available pair matching method [13]. The clinical characteristics and angiographic characteristics were also compared in the propensity matched populations. In the propensity matched population, the hazard ratio (HR) and their 95 % confidence interval (CI) were calculated for each clinical endpoint by using a Cox proportional hazard regression analysis and multiple logistic regression analysis. The HRs were adjusted according to the variables that had statistical significance (p < 0.1) in the univariable analysis or the variables considered to be clinically important in the multivariate model. Cumulative event rates in ticagrelor and clopidogrel groups were estimated and displayed by Kaplan-Meier analysis using long-rank. SPSS for Windows, version 25.0 (Armonk, NY, USA) was used. All statistical tests were 2-tailed with statistical significance defined as a p-value 0.05.
128
Results
143
The baseline clinical and angiographic characteristics of both treatment groups in crude populations are shown in Table 1. Ticagrelor group patients were younger and had a higher portion of male patients compare to the clopidogrel group. Admission period Killip class III-IV presentation rate was higher
144
Table 1 Baseline clinical and angiographic characteristics.
Age, years Age < 65 years, n (%) Male, n(%) Killip class III-IV, n (%) STEMI diagnosis, n (%) Risk factors, n (%) Hypertension Diabetes mellitus Dyslipidemia Previous MI Previous CVA Smoking eGFR, (ml/min/1.73 m2) eGFR <60 ml/min/1.73 m2, n (%). LVEF, (%) LVEF < 40 %, n (%). Medications, n (%) ß-blocker Statin RAS blockade Oral anticoagulant Infarct-related artery, n (%) Left anterior descending artery Right coronary artery Left circumflex artery Transradial approach, n (%) IRA TIMI flow grade 0,1, n (%) IRA B2/C lesion, n (%) Three-vessel disease, n (%) PCI modality, n (%) Balloon angioplasty BMS First-generation DES Second-generation DES IRA post TIMI flow grade 3, n (%) IRA stent diameter, (mm) IRA stent length, (mm) Total implanted stent number GP IIb/IIIa inhibitor use, n (%) Thrombus aspiration, n (%)
Ticagrelor group (n = 837)
Clopidogrel group (n = 1438)
p-value
62.9 11.1 373 (44.6) 660 (78.9) 69 (8.2) 457 (54.6)
66.1 12.6 818 (56.9) 1026 (71.3) 215 (15.0) 742 (51.6)
<0.001 <0.001 <0.001 <0.001 0.167
428 (51.1) 245 (29.3) 91 (10.9) 40 (4.8) 40 (4.8) 536 (64.0) 86.7 44.8 119 (14.2) 52.5 10.0 84 (10.0)
808 (56.2) 459 (31.9) 146 (10.2) 88 (6.1) 108 (7.5) 793 (55.1) 78.7 33.5 390 (27.1) 51.6 10.8 182 (12.7)
0.020 0.188 0.588 0.181 0.011 <0.001 <0.001 <0.001 0.101 0.061
717 (85.7) 817 (97.6) 674 (80.5) 8 (1.0)
1236 (86.0) 1349 (93.8) 1213 (84.4) 39 (2.7)
0.848 <0.001 0.019 0.005
347 (41.5) 323 (38.6) 167 (20.0) 408 (48.7) 470 (56.2) 774 (92.5) 336 (40.1)
607 (42.2) 543 (37.8) 288 (20.0) 391 (27.2) 846 (58.8) 1213 (84.4) 523 (36.4)
0.725 0.694 0.965 <0.001 0.212 <0.001 0.073
25 (3.0) 11 (1.3) 18 (2.2) 787 (94.0) 819 (97.8) 3.14 0.43 26.4 7.19 2.16 0.93 142 (17.0) 230 (27.5)
59 (4.1) 28 (1.9) 27 (1.9) 1331 (92.6) 1396 (97.1) 3.09 0.44 26.0 7.46 2.14 0.90 181 (12.6) 368 (25.6)
0.173 0.262 0.652 0.183 0.965 0.002 0.537 0.149 0.004 0.324
Values are presented as the n (%) of patients or mean SD. BMS, bare metal stent; CVA, cerebrovascular accident; DES, drug-eluting stent; eGFR, estimated glomerular filtration rate; GP, glycoprotein; IRA, infarct-related artery; LVEF, left ventricular ejection fraction; MI, myocardial infarction; PCI, percutaneous coronary intervention; RAS, renin angiotensin system; STEMI, ST elevation myocardial infarction; TIMI, Thrombolysis in Myocardial Infarction.
Please cite this article in press as: Ahn JH, et al. Ticagrelor versus clopidogrel in acute myocardial infarction patients with multivessel disease; From Korea Acute Myocardial Infarction Registry-National Institute of Health. J Cardiol (2019), https://doi.org/10.1016/j. jjcc.2019.11.003
129 130 131 132 133 134 135 136 137 138 139 140 141 142
145 146 147 148
G Model
JJCC 1958 1–7 J.H. Ahn et al. / Journal of Cardiology xxx (2019) xxx–xxx
4
Table 2 Propensity matched populations clinical and angiographic characteristics.
Age, years Age < 65 years, n (%) Male, n (%) Killip class III-IV, n (%) STEMI diagnosis, n (%) Risk factors, n (%) Hypertension Diabetes mellitus Dyslipidemia Previous MI Previous CVA Smoking eGFR, (ml/min/1.73 m2) eGFR < 60 ml/min/1.73 m2, n (%). LVEF, (%) LVEF < 40 %, n (%). Medications, n (%) ß-blocker Statin RAS blockade Oral anticoagulant Infarct-related artery, n (%) Left anterior descending artery Right coronary artery Left circumflex artery Transradial approach, n (%) IRA TIMI flow grade 0,1, n (%) IRA B2/C lesion, n (%) Three vessel disease, n (%) PCI modality, n (%) Balloon angioplasty BMS First-generation DES Second-generation DES IRA post TIMI flow grade 3, n (%) IRA stent diameter, (mm) IRA stent length, (mm) Total implanted stent number GP IIb/IIIa inhibitor use, n (%) Thrombus aspiration, n (%)
Ticagrelor group (n = 787)
Clopidogrel group (n = 787)
p-value
63.1 11.1 355 (45.1) 617 (78.4) 67 (8.5) 433 (55.0)
63.6 12.5 372 (47.3) 605 (76.9) 68 (8.6) 432 (54.9)
0.379 0.390 0.468 0.928 0.960
405 (51.5) 230 (29.2) 86 (10.9) 38 (4.8) 37 (4.7) 499 (63.4) 86.3 45.6 117 (14.9) 52.5 10.0 80 (10.2)
404 (51.3) 228 (29.0) 86 (10.9) 38 (4.8) 42 (5.3) 481 (61.1) 86.4 33.4 124 (15.8) 52.6 9.9 79 (10.0)
0.960 0.912 1.000 1.000 0.564 0.349 0.651 0.624 0.859 0.933
675 (85.8) 767 (97.5) 634 (80.6) 8 (1.0)
674 (85.6) 774 (98.3) 652 (82.8) 5 (0.6)
0.943 0.218 0.241 0.403
326 (41.4) 305 (38.8) 156 (19.8) 366 (46.5) 448 (56.9) 726 (92.2) 315 (40.0)
326 (41.4) 299 (38.0) 162 (20.6) 331 (42.1) 443 (56.3) 727 (92.4) 299 (38.0)
1.000 0.756 0.706 0.076 0.799 0.925 0.408
23 (2.9) 11 (1.4) 17 (2.2) 740 (94.0) 770 (97.8) 3.13 0.44 26.4 7.21 2.16 0.93 133 (16.9) 216 (27.4)
24 (3.0) 14 (1.8) 16 (2.0) 740 (94.0) 768 (97.6) 3.11 0.45 26.0 7.23 2.15 0.90 129 (16.4) 211 (26.8)
0.882 0.545 0.860 1.000 0.736 0.216 0.394 0.601 0.787 0.777
Values are presented as the n (%) of patients or mean SD. BMS, bare metal stent; CVA, cerebrovascular accident; DES, drug-eluting stent; eGFR, estimated glomerular filtration rate; GP, glycoprotein; IRA, infarct-related artery; LVEF, left ventricular ejection fraction; MI, myocardial infarction; PCI, percutaneous coronary intervention; RAS, renin angiotensin system; STEMI, ST elevation myocardial infarction; TIMI, Thrombolysis in Myocardial Infarction.
149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171
in the clopidogrel group. Among the conventional cardiovascular risk factors, clopidogrel group patients were more hypertensive and had more previous cerebrovascular events. However, smoking rate was dominant in the ticagrelor group. Patients with decreased renal function was dominant in the clopidogrel group. In other medications, statin prescription rate was higher in the ticagrelor group, while the RAS blockade prescription and the use of oral anticoagulants were higher in the clopdiogrel group. Angiographic characteristics showed that transradial approach rate was dominant in the ticagrelor group patients with higher rate of IRA B2/C lesion and larger IRA stent diameter. GP IIb/IIIa inhibitors were more used in the ticagrelor group. After the propensity score matching analysis, baseline clinical characteristics and angiographic characteristics were similar between two groups (Table 2). The clinical outcomes before and after propensity score matching are presented in Table 3 and Fig. 2. During the 2 years clinical follow-up period, the total incidence of the primary end point in the crude population was lower in the ticagrelor group compared to the clopidogrel group patients (9.0 % vs. 14.3 %; p < 0.001). Cardiac death was lower in the ticagrelor group (2.3 % vs. 5.6 %; p < 0.001). In the secondary endpoints, TIMI major or minor bleeding was higher in the ticagrelor group (10.4 % vs. 5.5 %; p < 0.001). Net clinical events were significantly lower in the
ticagrelor group (11.5 % vs. 15.8 %; p = 0.004). After propensity score matching analysis, the 2-year cumulative incidence and risk of MACE in AMI patients with MVD was lower (8.6 % vs. 11.9 %; HR: 0.68; 95 % CI: 0.50-0.94; p = 0.018) and the incidence and risk of TIMI major or minor bleeding was higher (10.8 % vs. 4.8 %; HR: 2.51; 95 % CI: 1.68–3.76; p < 0.001) in the ticagrelor group. However, TIMI major bleeding was similar in both groups (3.3 % vs. 2.0 %; HR: 1.69; 95 % CI: 0.89–3.20; p = 0.106). Also the net clinical event was similar in both treatment groups (11.3 % vs. 13.6 %; HR: 0.82; 95 % CI: 0.60–1.11; p = 0.195). The multivariate analysis resulted that eGFR <60 mL/min/1.73㎡ (HR: 1.76; 95 % CI: 1.21–2.57; p = 0.003), LVEF <40 % (HR: 1.58; 95 % CI: 1.03–2.43; p = 0.038) were other independent factors in MACE and diabetes (HR: 1.81; 95 % CI: 1.222.67; p = 0.003), transradial approach (HR: 0.43; 95 % CI: 0.28-0.59; p < 0.001) were other independent factors in TIMI major or minor bleeding (Table 4).
172
Discussion
188
The present study results showed that ticagrelor reduced the risk of MACE in AMI patients with MVD. Risk of TIMI major or minor bleeding was increased with ticagrelor treatment. However, the risk of TIMI major bleeding compared to clopidogrel treatment
189
Please cite this article in press as: Ahn JH, et al. Ticagrelor versus clopidogrel in acute myocardial infarction patients with multivessel disease; From Korea Acute Myocardial Infarction Registry-National Institute of Health. J Cardiol (2019), https://doi.org/10.1016/j. jjcc.2019.11.003
173 174 175 176 177 178 179 180 181 182 183 184 185 186 187
190 191 192
G Model
JJCC 1958 1–7 J.H. Ahn et al. / Journal of Cardiology xxx (2019) xxx–xxx
5
Table 3 Clinical outcomes in crude and propensity matched populations.
MACEa, n (%) Cardiac death Non-fatal MI TVR Stroke TIMI major and minor bleeding, n (%) TIMI major bleeding, n (%) Net clinical eventb, n (%) Any repeated PCI, n (%) Stent thrombosis, n (%) HF requiring re-hospitalization, n(%)
Ticagrelor group (n = 837)
Clopidogrel group (n = 1438)
p-value
Ticagrelor group (n = 787)
Clopidogrel group (n = 787)
Adjusted HR (95 % CI)
p-value
75 (9.0) 19 (2.3) 20 (2.4) 37 (4.4) 12 (1.4) 87 (10.4) 26 (3.1) 96 (11.5) 78 (9.3) 12 (1.4) 24 (2.9)
205 (14.3) 81 (5.6) 46 (3.2) 80 (5.6) 33 (2.3) 79 (5.5) 28 (1.9) 227 (15.8) 169 (11.8) 11 (0.8) 63 (4.4)
<0.001 <0.001 0.267 0.234 0.155 <0.001 0.080 0.004 0.072 0.124 0.069
68 (8.6) 17 (2.2) 20 (2.5) 33 (4.2) 11 (1.4) 85 (10.8) 26 (3.3) 89 (11.3) 74 (9.4) 10 (1.3) 23 (2.9)
94 (11.9) 22 (2.8) 23 (2.9) 47 (6.0) 18 (2.3) 38 (4.8) 16 (2.0) 107 (13.6) 94 (11.9) 10 (1.3) 22 (2.8)
0.68 (0.50–0.94) 0.84 (0.44–1.62) 0.86 (0.47–1.58) 0.67 (0.43–1.04) 0.52 (0.24–1.13) 2.51 (1.68–3.76) 1.69 (0.89–3.20) 0.82 (0.60–1.11) 0.75 (0.55–1.02) 0.97 (0.40–2.34) 1.21 (0.66–2.21)
0.018 0.605 0.617 0.077 0.097 <0.001 0.106 0.195 0.065 0.946 0.541
Values are presented as the n (%) of patients or mean SD. CI, confidence interval; HF, heart failure; HR, hazard ratio; MACE, major adverse cardiac event; TVR, target vessel revascularization; MI, myocardial infarction; PCI, percutaneous coronary intervention; TIMI, Thrombolysis in Myocardial Infarction. a Composite of cardiac death, non-fatal MI, TVR, stroke. b Composite of MACE and TIMI major bleeding.
Fig. 2. Kaplan-Meier curve for 2-year MACE in ticagrelor and clopidogrel group. MACE, major adverse cardiac event.
193 194 195 196 197 198 199 200
group was similar and net clinical event was comparable between two treatment groups. Current ACCF/AHA and ESC guidelines for DAPT recommend ticagrelor or prasugrel as first-line treatment in ACS patients after PCI [6,7]. However, the majority of the patients included in the previous randomized clinical trials comparing the effect of newgeneration P2Y12 inhibitors and clopidogrel were Caucasian and studies mainly targeted on East Asian populations had controverTable 4 Independent predictors of MACE and TIMI major or minor bleeding in multivariate analysis.
MACE eGFR < 60 mL/min/1.73㎡ Ticagrelor LVEF < 40 % TIMI major or minor bleeding Diabetes Ticagrelor Transradial approach
Adjusted HR(95 % CI)
p-value
1.76 (1.21–2.57) 0.68 (0.50–0.94) 1.58 (1.03–2.43)
0.003 0.018 0.038
1.81 (1.22–2.67) 2.51 (1.68–3.76) 0.43 (0.28–0.59)
0.003 <0.001 <0.001
CI, confidence interval; HR, hazard ratio; MACE, major adverse cardiac event; eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction; TIMI, Thrombolysis in Myocardial Infarction.
sial results. The substudy based on the PLATO trial showed there were no interactions between Asian and non-Asians patients. The study concluded that there was consistent clinical benefit of ticagrelor in Asian patients [14]. However, in the randomized clinical trial based on Japanese, Taiwanese, and South Korean patients with ACS after PCI (PHILO trial), both clopidogrel and ticagrelor had no significant difference in safety or efficacy endpoints [15]. Other retrospective registry studies in Korean AMI patients resulted that ischemic events were similar between clopidogrel and new-generation P2Y12 inhibitors while the bleeding events were higher in ticagrelor or prasugrel treatment group [16,17]. The concept of 'East Asian paradox' is a critical part in DAPT for the East Asian population and many experts are claiming that independent DAPT guideline should be developed [18,19]. The recent key issue in the DAPT field was 'De-escalation' of newgeneration P2Y12 inhibitors to clopidogrel in the Western society [20]. However, if the clear treatment benefit of new-generation P2Y12 inhibitor is still doubtful in general AMI patients in East Asian population, we thought that selecting certain patient group with high risk of ischemic cardiovascular events that might have benefit in new-generation P2Y12 inhibitors should be the crucial point. Numerous coronary artery angiographic findings have shown that nearly 50%–70% of AMI patients have MVD. As well known, the clinical outcomes of MVD are unfavorable compared to single vessel coronary artery disease because MVD tends to have more extensive atherosclerosis and relatively high ischemic burden [9,10]. Recently, a substudy of the Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis In Myocardial Infarction 54 (PEGASUS-TIMI 54) trial demonstrated that adverse events including coronary death and MI and definite stent thrombosis were higher in patients with MVD. The study result additionally showed that long-term add-on treatment with ticagrelor 60 mg or 90 mg twice daily on a background of low-dose aspirin reduced the risk of MACE compared to placebo (clopidogrel if indicated) in patients with prior MI with or without MVD. Another unique finding of this study was that risk reduction of MACE was greater in patients with MVD compared to patients without MVD [21]. Based on this study, we considered that AMI patients with MVD are the high-risk group of patients which would have a beneficial effect with the new-generation P2Y12 inhibitor ticagrelor among the East Asian population. To the best of our knowledge, the present study is the first study in Korea that directly compared the clinical efficacy of ticagrelor and clopidogrel
Please cite this article in press as: Ahn JH, et al. Ticagrelor versus clopidogrel in acute myocardial infarction patients with multivessel disease; From Korea Acute Myocardial Infarction Registry-National Institute of Health. J Cardiol (2019), https://doi.org/10.1016/j. jjcc.2019.11.003
201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245
G Model
JJCC 1958 1–7 6 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309
J.H. Ahn et al. / Journal of Cardiology xxx (2019) xxx–xxx
purely in AMI patients with MVD. The risk of MACE during a 2-year clinical follow-up period was lower in the ticagrelor patient group compared to the clopidogrel group and this finding was consistent with the substudy of PEGASUS-TIMI 54. Unfortunately, the risk of TIMI major or minor bleeding was higher with ticagrelor treatment in the present study which was consistent with other previous retrospective registry studies in Korea [16,22]. Experts had already argued that the lower dosage of new-generation P2Y12 inhibitors would be suitable for the East Asian patients compared to the Western patients based on the East Asian Paradox [18,23]. There was a single-center randomized trial in Korea comparing the clinical effect of low-dose (60 mg twice daily) versus standard-dose ticagrelor in ACS patients. The result of the study showed that there was no statistical difference in platelet inhibition between low-dose and standard-dose ticagrelor [24]. However, the present study only included patients with 90 mg twice daily maintenance dosage of ticagrelor. We insisted that excluding the drug dosage heterogeneity was a reasonable approach to directly compare the effect of ticagrelor and clopidogrel. Therefore, the incidence and risk of bleeding events were expected to be higher in the ticagrelor group than the clopidogrel group which was similar with the previous studies. An interesting finding was that the risk of TIMI major bleeding was comparable between both treatment groups and this finding was corresponding with the subgroup study based on PLATO trial and PHILO trial [14,15]. The important contributing factor for the similar incidence of TIMI major bleeding between the two treatment groups in the present study would be the proportion of patients with impaired renal function. Many clinical trials proved that MI patients with decreased renal function are vulnerable to bleeding complications [25,26]. A real world national cohort study based on Swedish Web-system concluded that bleeding events were abundant with ticagrelor compared to clopidogrel in patients with severe renal function (eGFR <30 formula) [27]. Compared with the other retrospective registry studies, the proportion of patients with renal dysfunction was relatively low in the present study [16,22,28]. The present study has several limitations. First, the study was not a randomized clinical trial but a retrospective analysis. The study was based on the registry data and selection bias might have existed. Although the propensity score matching analysis was done and most of potential confounders were adjusted and analyzed, other variables that have influence on the clinical outcomes might have not been included. Second, for the TIMI major and minor bleeding events after the hospitalization period, only the event of intracranial hemorrhage and 2-year outpatient follow-up laboratory findings were available in the registry data. Other additional bleeding events and detailed information including exact bleeding event time were not fully described. This might have underestimated the real world bleeding events and visualizing the accurate bleeding event by the time-event curve was unavailable. Third, the present study did not divide the specific patient groups into STEMI patients with or without cardiogenic shock or patients with non-STEMI. Various revascularization strategies according to each clinical situation would be different such as staged multivessel PCI or culprit only PCI and these different revascularization strategies could have impact in clinical outcomes [29–31]. Fourth, the present study did not focus on the long-term treatment effect of ticagrelor. The substudy of PEGASUS-TIMI 54 emphasized that long-term treatment with ticagrelor would be more beneficial in MVD patients. But, prolonged DAPT duration had only resulted in increased bleeding risk in East Asian population [21,23,28]. Therefore, detailed risk stratification for the DAPT duration based on East Asian population would also be important and further studies should be needed to evaluate the clinical efficacy and safety of long-term
use of especially low-dose ticagrelor in patients with high risk of ischemic events. In conclusion, ticagrelor reduced the risk of ischemic event MACE but increased the risk of TIMI major or minor bleeding compared to clopidogrel in Korean AMI patients with MVD. Further large-scale multi-center randomized clinical trials are warranted for the proper use of ticagrelor in East Asian patients.
310
Conflicts of interest
317
The authors have no conflicts of interest to declare
311 312 313 314 315 316
318
Acknowledgement
319
This work was supported by a fund from Korea Centers for Disease Control and Prevention (2016-ER6304-02), National Research Foundation of Korea (NRF-2019R1A2C3003547), and Chonnam National University Hospital Biomedical Research Institute (BCRI18017).
320
References
325
[1] Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, et al. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 2018;39:119–77. [2] Schomig A, Neumann FJ, Kastrati A, Schuhlen H, Blasini R, Hadamitzky M, et al. A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. N Engl J Med 1996;334:1084–9. [3] Price MJ, Endemann S, Gollapudi RR, Valencia R, Stinis CT, Levisay JP, et al. Prognostic significance of post-clopidogrel platelet reactivity assessed by a point-of-care assay on thrombotic events after drug-eluting stent implantation. Eur Heart J 2008;29:992–1000. [4] Price MJ, Berger PB, Teirstein PS, Tanguay JF, Angiolillo DJ, Spriggs D, et al. Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. JAMA 2011;305:1097–105. [5] Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045–57. [6] Levine GN, Bates ER, Bittl JA, Brindis RG, Fihn SD, Fleisher LA, et al. 2016 ACC/ AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the american college of Cardiology/American heart association task force on clinical practice guidelines: an update of the 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention, 2011 ACCF/AHA guideline for coronary artery bypass graft surgery, 2012 ACC/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease, 2013 ACCF/AHA guideline for the management of ST-Elevation myocardial infarction, 2014 AHA/ACC guideline for the management of patients with NonST-Elevation acute coronary syndromes, and 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery. Circulation 2016;134:e123–55. [7] Valgimigli M, Bueno H, Byrne RA, Collet JP, Costa F, Jeppsson A, et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: The Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2018;39:213–60. [8] Misumida N, Aoi S, Kim SM, Ziada KM, Abdel-Latif A. Ticagrelor versus clopidogrel in East Asian patients with acute coronary syndrome: systematic review and meta-analysis. Cardiovasc Revasc Med 2018;19:689–94. [9] van der Schaaf RJ, Timmer JR, Ottervanger JP, Hoorntje JC, de Boer MJ, Suryapranata H, et al. Long-term impact of multivessel disease on causespecific mortality after ST elevation myocardial infarction treated with reperfusion therapy. Heart 2006;92:1760–3. [10] Sorajja P, Gersh BJ, Cox DA, McLaughlin MG, Zimetbaum P, Costantini C, et al. Impact of multivessel disease on reperfusion success and clinical outcomes in patients undergoing primary percutaneous coronary intervention for acute myocardial infarction. Eur Heart J 2007;28:1709–16. [11] Cutlip DE, Windecker S, Mehran R, Boam A, Cohen DJ, van Es GA, et al. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007;115:2344–51. [12] Mauri L, Hsieh WH, Massaro JM, Ho KK, D’Agostino R, Cutlip DE. Stent thrombosis in randomized clinical trials of drug-eluting stents. N Engl J Med 2007;356:1020–9.
Please cite this article in press as: Ahn JH, et al. Ticagrelor versus clopidogrel in acute myocardial infarction patients with multivessel disease; From Korea Acute Myocardial Infarction Registry-National Institute of Health. J Cardiol (2019), https://doi.org/10.1016/j. jjcc.2019.11.003
321 322 323 324
326 327 328 329 330 331 332 333 334 335 336 337 338 339
340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358
359 360 361 362 363 364 365 366 367 368
G Model
JJCC 1958 1–7 J.H. Ahn et al. / Journal of Cardiology xxx (2019) xxx–xxx 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399 400
[13] Austin PC. An introduction to propensity score methods for reducing the effects of confounding in observational studies. Multivariate Behav Res 2011;46:399–424. [14] Kang HJ, Clare RM, Gao R, Held C, Himmelmann A, James SK, et al. Ticagrelor versus clopidogrel in Asian patients with acute coronary syndrome: A retrospective analysis from the Platelet Inhibition and Patient Outcomes (PLATO) Trial. Am Heart J 2015;169:899–905. e891. [15] Goto S, Huang CH, Park SJ, Emanuelsson H, Kimura T. Ticagrelor vs. Clopidogrel in Japanese, Korean and Taiwanese patients with acute coronary syndrome randomized, double-blind, phase III PHILO study. Circ J 2015;79:2452–60. [16] Park KH, Jeong MH, Ahn Y, Ahn TH, Seung KB, Oh DJ, et al. Comparison of shortterm 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. Int J Cardiol 2016;215:193–200. [17] Park KH, Jeong MH, Kim HK, Ahn TH, Seung KB, Oh DJ, et al. Comparison of prasugrel versus clopidogrel in Korean patients with acute myocardial infarction undergoing successful revascularization. J Cardiol 2018;71:36–43. [18] Jeong YH. "East asian paradox": challenge for the current antiplatelet strategy of "one-guideline-fits-all races" in acute coronary syndrome. Curr Cardiol Rep 2014;16:485. [19] Levine GN, Jeong YH, Goto S, Anderson JL, Huo Y, Mega JL, et al. Expert consensus document: world Heart Federation expert consensus statement on antiplatelet therapy in East Asian patients with ACS or undergoing PCI. Nat Rev Cardiol 2014;11:597–606. [20] Sibbing D, Aradi D, Jacobshagen C, Gross L, Trenk D, Geisler T, et al. Guided deescalation of antiplatelet treatment in patients with acute coronary syndrome undergoing percutaneous coronary intervention (TROPICAL-ACS): a randomised, open-label, multicentre trial. Lancet 2017;390:1747–57. [21] Bansilal S, Bonaca MP, Cornel JH, Storey RF, Bhatt DL, Steg PG, et al. Ticagrelor for secondary prevention of atherothrombotic events in patients with multivessel coronary disease. J Am Coll Cardiol 2018;71:489–96. [22] Sim DS, Jeong MH, Kim HS, Gwon HC, Seung KB, Rha SW, et al. Utility of GRACE and ACUITY-HORIZONS risk scores to guide dual antiplatelet therapy in Korean
[23]
[24]
[25]
[26]
[27]
[28]
[29]
[30]
[31]
7
patients with acute myocardial infarction undergoing drug-eluting stenting. J Cardiol 2018;72:411–9. Kang J, Kim HS. The evolving concept of dual antiplatelet therapy after percutaneous coronary intervention: focus on unique feature of East Asian and “Asian paradox”. Korean Circ J 2018;48:537–51. Park DW, Lee PH, Jang S, Lim HS, Kang DY, Lee CH, et al. Effect of low-dose versus standard-dose ticagrelor and clopidogrel on platelet inhibition in acute coronary syndromes. J Am Coll Cardiol 2018;71:1594–5. Flores-Blanco PJ, Lopez-Cuenca A, Januzzi JL, Marin F, Sanchez-Martinez M, Quintana-Giner M, et al. Major bleeding risk prediction using Chronic Kidney Disease Epidemiology Collaboration and Modification of Diet in Renal Disease equations in acute coronary syndrome. Eur J Clin Invest 2015;45:385–93. Burlacu A, Genovesi S, Ortiz A, Kanbay M, Rossignol P, Banach M, et al. The quest for equilibrium: exploring the thin red line between bleeding and ischaemic risks in the management of acute coronary syndromes in chronic kidney disease patients. Nephrol Dial Transplant 2017;32:1967–76. Edfors R, Sahlen A, Szummer K, Renlund H, Evans M, Carrero JJ, et al. Outcomes in patients treated with ticagrelor versus clopidogrel after acute myocardial infarction stratified by renal function. Heart 2018;104:1575–82. Kang J, Han JK, Ahn Y, Chae SC, Kim YJ, Chae IH, et al. Third-generation P2Y12 inhibitors in East Asian acute myocardial infarction patients: a nationwide prospective multicentre study. Thromb Haemost 2018;118:591–600. Sardella G, Lucisano L, Garbo R, Pennacchi M, Cavallo E, Stio RE, et al. Singlestaged compared with multi-staged PCI in multivessel NSTEMI patients: the SMILE trial. J Am Coll Cardiol 2016;67:264–72. Engstrøm T, Kelbæk H, Helqvist S, Høfsten DE, Kløvgaard L, Holmvang L, et al. Complete revascularisation versus treatment of the culprit lesion only in patients with ST-segment elevation myocardial infarction and multivessel disease (DANAMI-3—PRIMULTI): an open-label, randomised controlled trial. Lancet 2015;386:665–71. Khan MS, Siddiqi TJ, Usman MS, Riaz H, Khan AR, Murad MH, et al. Metaanalysis comparing culprit vessel only versus multivessel percutaneous coronary intervention in patients with acute myocardial infarction and cardiogenic shock. Am J Cardiol 2019;123:218–26.
Please cite this article in press as: Ahn JH, et al. Ticagrelor versus clopidogrel in acute myocardial infarction patients with multivessel disease; From Korea Acute Myocardial Infarction Registry-National Institute of Health. J Cardiol (2019), https://doi.org/10.1016/j. jjcc.2019.11.003
401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431
JJCC 1958 1–7 Journal of Cardiology xxx (2019) xxx–xxx
Contents lists available at ScienceDirect
Journal of Cardiology journal homepage: www.elsevier.com/locate/jjcc 1 2 3 4 5
6 7 8 9 10 11 12 13 14 15 16
Original article
Ticagrelor versus clopidogrel in acute myocardial infarction patients with multivessel disease; From Korea Acute Myocardial Infarction Registry-National Institute of Health Joon Ho Ahn (MD)a, Youngkeun Ahn (MD, PhD, FACC, FSCAI)a,*, Myung Ho Jeong (MD, PhD, FACC, FAHA, FESC, FASCAI)a, Ju Han Kim (MD, PhD)a, Young Joon Hong (MD, PhD)a, Doo Sun Sim (MD, PhD)a, Min Chul Kim (MD, PhD)a, Jin Yong Hwang (MD, PhD)b, Jung Han Yoon (MD, PhD)c, In Whan Seong (MD, PhD)d, Seung-Ho Hur (MD, PhD)e, Seok Kyu Oh (MD, PhD)f, other KAMIR-NIH Registry Investigators a
Chonnam National University Hospital, Gwangju, South Korea Gyeongsang National University Hospital, Jinju, South Korea Yonsei University Wonju College of Medicine, Wonju Severance Christian Hospital, Wonju, South Korea d Chungnam National University Hospital, Daejeon, South Korea e Keimyung University Dongsan Medical Center, Daegu, South Korea f Wonkwang University Hospital, Iksan, South Korea b c
A R T I C L E I N F O
A B S T R A C T
Article history: Received 17 June 2019 Received in revised form 24 October 2019 Accepted 17 November 2019 Available online xxx
Background: The clinical efficacy of ticagrelor is questionable in East Asian populations. Patients with acute myocardial infarction (AMI) with multivessel disease (MVD) are considered as high risk patients who might benefit from ticagrelor treatment. The purpose of this study is to compare the clinical effect of ticagrelor and clopidogrel in AMI patients with MVD in Korea. Methods and results: A total of 2275 patients between November 2011 and June 2015, diagnosed with AMI with MVD after successful percutaneous coronary intervention who were registered in the Korea Acute Myocardial Infarction Registry – National Institute of Health (KAMIR-NIH) were enrolled. Patients were divided into ticagrelor (n = 837) and clopidogrel group (n = 1438). The primary endpoint was major adverse cardiac events (MACE) defined as cardiac death, non-fatal MI, target vessel revascularization, or ischemic stroke during 2 years of clinical follow-up. Secondary endpoints were thrombolysis in myocardial infarction (TIMI) major or minor bleeding, net clinical event composed of MACE and TIMI major bleeding, any repeated percutaneous coronary intervention, heart failure requiring rehospitalization, and stent thrombosis. After propensity score matching analysis, the primary endpoint was lower in ticagrelor group compared to the clopidogrel group (8.6 % vs. 11.9 %; HR: 0.68; 95 % CI: 0.500.94; p = 0.018). The risk of TIMI major or minor bleeding was higher in the ticagrelor group (10.8 % vs. 4.8 %; HR: 2.51; 95 % CI: 1.68–3.76; p < 0.001). The net clinical event was similar between ticagrelor and clopidogrel group (11.3 % vs. 13.6 %; HR 0.82; 95 % CI: 0.60–1.11; p = 0.195). Conclusion: Ticagrelor significantly reduced the risk of MACE than clopidogrel for AMI patients with MVD in Korea. However, the risk of TIMI major or minor bleeding was higher and the net clinical benefit was similar. Further large-scale multi-center randomized clinical trials are needed to clarify the proper use dual antiplatelet therapy in East Asian populations. © 2019 Published by Elsevier Ltd on behalf of Japanese College of Cardiology.
Keywords: Multivessel disease Acute myocardial infarction East Asian populations Ticagrelor
Introduction * Corresponding author: Department of Cardiology, Cardiovascular Center, Chonnam National University Hospital, Institute of Molecular Medicine, BK21 Plus, Chonnam National University Medical School, 42Jebong-ro, Dong-gu, Gwangju 61469, South Korea. E-mail address: [email protected] (Y. Ahn).
Over the past few decades, dual antiplatelet therapy (DAPT) has become one of the major issues in the pharmacologic treatment modalities in acute myocardial infarction (AMI) [1]. DAPT remarkably reduced the rate of thrombotic and ischemic complications including
https://doi.org/10.1016/j.jjcc.2019.11.003 0914-5087/© 2019 Published by Elsevier Ltd on behalf of Japanese College of Cardiology.
Please cite this article in press as: Ahn JH, et al. Ticagrelor versus clopidogrel in acute myocardial infarction patients with multivessel disease; From Korea Acute Myocardial Infarction Registry-National Institute of Health. J Cardiol (2019), https://doi.org/10.1016/j. jjcc.2019.11.003
17
18 19 20
G Model
JJCC 1958 1–7 J.H. Ahn et al. / Journal of Cardiology xxx (2019) xxx–xxx
2 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61
stent thrombosis and MI after percutaneous coronary intervention (PCI) [2]. Shortcomings of second-generation P2Y12 inhibitor, clopidogrel, have emerged during the past 10 years and the major randomized clinical trial, Platelet Inhibition and Patient Outcomes (PLATO) demonstrated the superiority of new generation P2Y12 inhibitor, ticagrelor in MI patients compared to clopidogrel [3–5]. According to this major trial, the 2016 American College of Cardiology Foundation/American Heart Association (ACCF/AHA) and 2017 European Society of Cardiology (ESC) guidelines for DAPT recommend ticagrelor over clopidogrel in acute coronary syndrome (ACS) patients after PCI (Class IIa, level of evidence B), (Class I, level of evidence B) [6,7]. The efficacy and safety of new generation P2Y12 inhibitor ticagrelor in East Asian populations however is questionable [8]. In these circumstance, we considered that further study was necessary to select certain high-risk group of patients in East Asian population that might have clear clinical benefit of ticagrelor use. Multivessel coronary artery disease (MVD) presents in more serious clinical manifestations and shows poor clinical outcomes than single vessel coronary artery disease [9,10]. We assumed that AMI patients with MVD were those high-risk group patients that might benefit from ticagrelor. The main purpose of our study is to compare the clinical impact of ticagrelor and clopidogrel in AMI patients with MVD in Korea. Methods Among the 13,650 patients enrolled in Korea AMI Registry National Institutes of Health (KAMIR-NIH) from November 2011 to June 2015, 5390 AMI patients with MVD were selected. Either primary PCI or elective PCI was done for the entire selected patients. The KAMIR-NIH is a prospective, open, multi-center, webbased cohort study to investigate the prognosis of real world outcome of Korean patients with AMI from 15 centers in Korea and has been performed with support by a grant of Korea Centers for Disease Control and Prevention since November 2011. Data were retrospectively collected by a trained study coordinator based on the standardized protocol. The study was conducted according to the Declaration of Helsinki. The institutional review board of all individual participating centers approved the study protocol. The approval number was CNUH-2011-172 of Chonnam National University Hospital. Written informed consent was obtained from all participating patients. From these 5390 individuals, the
following patients were sequentially excluded: left main disease; patients treated with prasugrel as the new generation P2Y12 inhibitor and those receiving either cilostazol or ticlopidine; patients with no P2Y12 inhibitor treatment; patients with different drug loading or maintenance dose of ticagrelor or clopidogrel; patients switched from ticagrelor to clopidogrel during the inhospital period; patients lost by in-hospital death or outpatient clinical follow-up data loss. A total of 2275 patients were included in the present study. The patients were finally divided into ticagrelor (n = 837) and clopidogrel group (n = 1438) (Fig. 1). All patients received 300 mg loading dose of aspirin 180 mg of ticagrelor or 600 mg of clopidogrel before the diagnostic coronary angiography. Coronary angiography was performed through either the radial or the femoral artery. Unfractionated heparin 50–100 U/ kg was administered and activated clotting time at >250 s were maintained. PCIs were performed by using standard techniques. After PCI, both treatment groups maintained 100 mg of aspirin and ticagrelor 90 mg twice daily or clopidogrel 75 mg daily. Patients were recommended to maintain at least one year of DAPT. Other medications including ß-blocker, statin, renin angiotensin system (RAS) blocker were prescribed to each patient as clinically indicated. Two-dimensional echocardiography was performed in all patients during the initial hospitalization period and left ventricular ejection fraction (LVEF) was estimated. The primary endpoint of this study was the cumulative incidence of major adverse cardiac events (MACE) during 2 years of clinical follow up. MACE were composed of cardiac death, nonfatal MI, target vessel revascularization (TVR), and ischemic stroke. The secondary endpoints were thrombolysis in myocardial infarction (TIMI) major or minor bleeding during in-hospital and follow up period, net clinical event composed of MACE and TIMI major bleeding, any repeated PCI, heart failure (HF) requiring rehospitalization, and stent thrombosis. MVD was defined as critical stenosis (>70 % of diameter) by quantitative coronary angiography in at least 2 major epicardial coronary arteries. All deaths were considered cardiac deaths if non-cardiac death could be excluded. Non-fatal MI was defined as recurrent symptoms with new ST-segment elevation in the electrocardiogram or re-elevation of cardiac markers to at least twice the upper limit of normal. TVR was defined as repeated PCI of any segment within the target vessel. Bleeding events were classified as major or minor according to the TIMI scales [11]. Stent thrombosis was defined according to the Academic Research Consortium definitions [12].
Fig. 1. Study flow chart. AMI, acute myocardial infarction.
Please cite this article in press as: Ahn JH, et al. Ticagrelor versus clopidogrel in acute myocardial infarction patients with multivessel disease; From Korea Acute Myocardial Infarction Registry-National Institute of Health. J Cardiol (2019), https://doi.org/10.1016/j. jjcc.2019.11.003
62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104
G Model
JJCC 1958 1–7 J.H. Ahn et al. / Journal of Cardiology xxx (2019) xxx–xxx 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127
The baseline clinical characteristics of both treatment groups were analyzed. Continuous variables are presented as means standard deviations and were compared by using unpaired Student’s t-tests and Mann-Whitney U test. Discrete variables are expressed as percentages and frequencies and were compared by using chi-square statistics or Fisher's exact test. The propensity score matching analysis was done by using a multiple logistic regression model to minimize the selection bias in comparing the effect of ticagrelor and clopidogrel. The relevant variables included were age, sex, Killip class on admission, diagnosis of ST elevation MI (STEMI), cardiovascular risk factors (hypertension, diabetes mellitus, dyslipidemia, smoking status), previous MI, previous cerebrovascular accident, estimated glomerular filtration rate (eGFR), LVEF, prescribed medications (ß-blocker, statin, RAS blockade, oral anticoagulant), transradial approach, infarct-related artery (IRA), preprocedural and postprocedural IRA TIMI flow grade, ACCF/AHA lesion classification type B2 or C, three vessel disease, PCI modalities (balloon angioplasty, bare metal stent, firstgeneration and second-generation drug-eluting stent), IRA stent size and length, total implanted stent number, use of glycoprotein (GP) IIb/IIIa inhibitor, thrombus aspiration. The model was well calibrated with good discrimination and the clopidogrel group patients were 1-on-1 matched to the ticagrelor group patients on
3
their propensity scores using the nearest available pair matching method [13]. The clinical characteristics and angiographic characteristics were also compared in the propensity matched populations. In the propensity matched population, the hazard ratio (HR) and their 95 % confidence interval (CI) were calculated for each clinical endpoint by using a Cox proportional hazard regression analysis and multiple logistic regression analysis. The HRs were adjusted according to the variables that had statistical significance (p < 0.1) in the univariable analysis or the variables considered to be clinically important in the multivariate model. Cumulative event rates in ticagrelor and clopidogrel groups were estimated and displayed by Kaplan-Meier analysis using long-rank. SPSS for Windows, version 25.0 (Armonk, NY, USA) was used. All statistical tests were 2-tailed with statistical significance defined as a p-value 0.05.
128
Results
143
The baseline clinical and angiographic characteristics of both treatment groups in crude populations are shown in Table 1. Ticagrelor group patients were younger and had a higher portion of male patients compare to the clopidogrel group. Admission period Killip class III-IV presentation rate was higher
144
Table 1 Baseline clinical and angiographic characteristics.
Age, years Age < 65 years, n (%) Male, n(%) Killip class III-IV, n (%) STEMI diagnosis, n (%) Risk factors, n (%) Hypertension Diabetes mellitus Dyslipidemia Previous MI Previous CVA Smoking eGFR, (ml/min/1.73 m2) eGFR <60 ml/min/1.73 m2, n (%). LVEF, (%) LVEF < 40 %, n (%). Medications, n (%) ß-blocker Statin RAS blockade Oral anticoagulant Infarct-related artery, n (%) Left anterior descending artery Right coronary artery Left circumflex artery Transradial approach, n (%) IRA TIMI flow grade 0,1, n (%) IRA B2/C lesion, n (%) Three-vessel disease, n (%) PCI modality, n (%) Balloon angioplasty BMS First-generation DES Second-generation DES IRA post TIMI flow grade 3, n (%) IRA stent diameter, (mm) IRA stent length, (mm) Total implanted stent number GP IIb/IIIa inhibitor use, n (%) Thrombus aspiration, n (%)
Ticagrelor group (n = 837)
Clopidogrel group (n = 1438)
p-value
62.9 11.1 373 (44.6) 660 (78.9) 69 (8.2) 457 (54.6)
66.1 12.6 818 (56.9) 1026 (71.3) 215 (15.0) 742 (51.6)
<0.001 <0.001 <0.001 <0.001 0.167
428 (51.1) 245 (29.3) 91 (10.9) 40 (4.8) 40 (4.8) 536 (64.0) 86.7 44.8 119 (14.2) 52.5 10.0 84 (10.0)
808 (56.2) 459 (31.9) 146 (10.2) 88 (6.1) 108 (7.5) 793 (55.1) 78.7 33.5 390 (27.1) 51.6 10.8 182 (12.7)
0.020 0.188 0.588 0.181 0.011 <0.001 <0.001 <0.001 0.101 0.061
717 (85.7) 817 (97.6) 674 (80.5) 8 (1.0)
1236 (86.0) 1349 (93.8) 1213 (84.4) 39 (2.7)
0.848 <0.001 0.019 0.005
347 (41.5) 323 (38.6) 167 (20.0) 408 (48.7) 470 (56.2) 774 (92.5) 336 (40.1)
607 (42.2) 543 (37.8) 288 (20.0) 391 (27.2) 846 (58.8) 1213 (84.4) 523 (36.4)
0.725 0.694 0.965 <0.001 0.212 <0.001 0.073
25 (3.0) 11 (1.3) 18 (2.2) 787 (94.0) 819 (97.8) 3.14 0.43 26.4 7.19 2.16 0.93 142 (17.0) 230 (27.5)
59 (4.1) 28 (1.9) 27 (1.9) 1331 (92.6) 1396 (97.1) 3.09 0.44 26.0 7.46 2.14 0.90 181 (12.6) 368 (25.6)
0.173 0.262 0.652 0.183 0.965 0.002 0.537 0.149 0.004 0.324
Values are presented as the n (%) of patients or mean SD. BMS, bare metal stent; CVA, cerebrovascular accident; DES, drug-eluting stent; eGFR, estimated glomerular filtration rate; GP, glycoprotein; IRA, infarct-related artery; LVEF, left ventricular ejection fraction; MI, myocardial infarction; PCI, percutaneous coronary intervention; RAS, renin angiotensin system; STEMI, ST elevation myocardial infarction; TIMI, Thrombolysis in Myocardial Infarction.
Please cite this article in press as: Ahn JH, et al. Ticagrelor versus clopidogrel in acute myocardial infarction patients with multivessel disease; From Korea Acute Myocardial Infarction Registry-National Institute of Health. J Cardiol (2019), https://doi.org/10.1016/j. jjcc.2019.11.003
129 130 131 132 133 134 135 136 137 138 139 140 141 142
145 146 147 148
G Model
JJCC 1958 1–7 J.H. Ahn et al. / Journal of Cardiology xxx (2019) xxx–xxx
4
Table 2 Propensity matched populations clinical and angiographic characteristics.
Age, years Age < 65 years, n (%) Male, n (%) Killip class III-IV, n (%) STEMI diagnosis, n (%) Risk factors, n (%) Hypertension Diabetes mellitus Dyslipidemia Previous MI Previous CVA Smoking eGFR, (ml/min/1.73 m2) eGFR < 60 ml/min/1.73 m2, n (%). LVEF, (%) LVEF < 40 %, n (%). Medications, n (%) ß-blocker Statin RAS blockade Oral anticoagulant Infarct-related artery, n (%) Left anterior descending artery Right coronary artery Left circumflex artery Transradial approach, n (%) IRA TIMI flow grade 0,1, n (%) IRA B2/C lesion, n (%) Three vessel disease, n (%) PCI modality, n (%) Balloon angioplasty BMS First-generation DES Second-generation DES IRA post TIMI flow grade 3, n (%) IRA stent diameter, (mm) IRA stent length, (mm) Total implanted stent number GP IIb/IIIa inhibitor use, n (%) Thrombus aspiration, n (%)
Ticagrelor group (n = 787)
Clopidogrel group (n = 787)
p-value
63.1 11.1 355 (45.1) 617 (78.4) 67 (8.5) 433 (55.0)
63.6 12.5 372 (47.3) 605 (76.9) 68 (8.6) 432 (54.9)
0.379 0.390 0.468 0.928 0.960
405 (51.5) 230 (29.2) 86 (10.9) 38 (4.8) 37 (4.7) 499 (63.4) 86.3 45.6 117 (14.9) 52.5 10.0 80 (10.2)
404 (51.3) 228 (29.0) 86 (10.9) 38 (4.8) 42 (5.3) 481 (61.1) 86.4 33.4 124 (15.8) 52.6 9.9 79 (10.0)
0.960 0.912 1.000 1.000 0.564 0.349 0.651 0.624 0.859 0.933
675 (85.8) 767 (97.5) 634 (80.6) 8 (1.0)
674 (85.6) 774 (98.3) 652 (82.8) 5 (0.6)
0.943 0.218 0.241 0.403
326 (41.4) 305 (38.8) 156 (19.8) 366 (46.5) 448 (56.9) 726 (92.2) 315 (40.0)
326 (41.4) 299 (38.0) 162 (20.6) 331 (42.1) 443 (56.3) 727 (92.4) 299 (38.0)
1.000 0.756 0.706 0.076 0.799 0.925 0.408
23 (2.9) 11 (1.4) 17 (2.2) 740 (94.0) 770 (97.8) 3.13 0.44 26.4 7.21 2.16 0.93 133 (16.9) 216 (27.4)
24 (3.0) 14 (1.8) 16 (2.0) 740 (94.0) 768 (97.6) 3.11 0.45 26.0 7.23 2.15 0.90 129 (16.4) 211 (26.8)
0.882 0.545 0.860 1.000 0.736 0.216 0.394 0.601 0.787 0.777
Values are presented as the n (%) of patients or mean SD. BMS, bare metal stent; CVA, cerebrovascular accident; DES, drug-eluting stent; eGFR, estimated glomerular filtration rate; GP, glycoprotein; IRA, infarct-related artery; LVEF, left ventricular ejection fraction; MI, myocardial infarction; PCI, percutaneous coronary intervention; RAS, renin angiotensin system; STEMI, ST elevation myocardial infarction; TIMI, Thrombolysis in Myocardial Infarction.
149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171
in the clopidogrel group. Among the conventional cardiovascular risk factors, clopidogrel group patients were more hypertensive and had more previous cerebrovascular events. However, smoking rate was dominant in the ticagrelor group. Patients with decreased renal function was dominant in the clopidogrel group. In other medications, statin prescription rate was higher in the ticagrelor group, while the RAS blockade prescription and the use of oral anticoagulants were higher in the clopdiogrel group. Angiographic characteristics showed that transradial approach rate was dominant in the ticagrelor group patients with higher rate of IRA B2/C lesion and larger IRA stent diameter. GP IIb/IIIa inhibitors were more used in the ticagrelor group. After the propensity score matching analysis, baseline clinical characteristics and angiographic characteristics were similar between two groups (Table 2). The clinical outcomes before and after propensity score matching are presented in Table 3 and Fig. 2. During the 2 years clinical follow-up period, the total incidence of the primary end point in the crude population was lower in the ticagrelor group compared to the clopidogrel group patients (9.0 % vs. 14.3 %; p < 0.001). Cardiac death was lower in the ticagrelor group (2.3 % vs. 5.6 %; p < 0.001). In the secondary endpoints, TIMI major or minor bleeding was higher in the ticagrelor group (10.4 % vs. 5.5 %; p < 0.001). Net clinical events were significantly lower in the
ticagrelor group (11.5 % vs. 15.8 %; p = 0.004). After propensity score matching analysis, the 2-year cumulative incidence and risk of MACE in AMI patients with MVD was lower (8.6 % vs. 11.9 %; HR: 0.68; 95 % CI: 0.50-0.94; p = 0.018) and the incidence and risk of TIMI major or minor bleeding was higher (10.8 % vs. 4.8 %; HR: 2.51; 95 % CI: 1.68–3.76; p < 0.001) in the ticagrelor group. However, TIMI major bleeding was similar in both groups (3.3 % vs. 2.0 %; HR: 1.69; 95 % CI: 0.89–3.20; p = 0.106). Also the net clinical event was similar in both treatment groups (11.3 % vs. 13.6 %; HR: 0.82; 95 % CI: 0.60–1.11; p = 0.195). The multivariate analysis resulted that eGFR <60 mL/min/1.73㎡ (HR: 1.76; 95 % CI: 1.21–2.57; p = 0.003), LVEF <40 % (HR: 1.58; 95 % CI: 1.03–2.43; p = 0.038) were other independent factors in MACE and diabetes (HR: 1.81; 95 % CI: 1.222.67; p = 0.003), transradial approach (HR: 0.43; 95 % CI: 0.28-0.59; p < 0.001) were other independent factors in TIMI major or minor bleeding (Table 4).
172
Discussion
188
The present study results showed that ticagrelor reduced the risk of MACE in AMI patients with MVD. Risk of TIMI major or minor bleeding was increased with ticagrelor treatment. However, the risk of TIMI major bleeding compared to clopidogrel treatment
189
Please cite this article in press as: Ahn JH, et al. Ticagrelor versus clopidogrel in acute myocardial infarction patients with multivessel disease; From Korea Acute Myocardial Infarction Registry-National Institute of Health. J Cardiol (2019), https://doi.org/10.1016/j. jjcc.2019.11.003
173 174 175 176 177 178 179 180 181 182 183 184 185 186 187
190 191 192
G Model
JJCC 1958 1–7 J.H. Ahn et al. / Journal of Cardiology xxx (2019) xxx–xxx
5
Table 3 Clinical outcomes in crude and propensity matched populations.
MACEa, n (%) Cardiac death Non-fatal MI TVR Stroke TIMI major and minor bleeding, n (%) TIMI major bleeding, n (%) Net clinical eventb, n (%) Any repeated PCI, n (%) Stent thrombosis, n (%) HF requiring re-hospitalization, n(%)
Ticagrelor group (n = 837)
Clopidogrel group (n = 1438)
p-value
Ticagrelor group (n = 787)
Clopidogrel group (n = 787)
Adjusted HR (95 % CI)
p-value
75 (9.0) 19 (2.3) 20 (2.4) 37 (4.4) 12 (1.4) 87 (10.4) 26 (3.1) 96 (11.5) 78 (9.3) 12 (1.4) 24 (2.9)
205 (14.3) 81 (5.6) 46 (3.2) 80 (5.6) 33 (2.3) 79 (5.5) 28 (1.9) 227 (15.8) 169 (11.8) 11 (0.8) 63 (4.4)
<0.001 <0.001 0.267 0.234 0.155 <0.001 0.080 0.004 0.072 0.124 0.069
68 (8.6) 17 (2.2) 20 (2.5) 33 (4.2) 11 (1.4) 85 (10.8) 26 (3.3) 89 (11.3) 74 (9.4) 10 (1.3) 23 (2.9)
94 (11.9) 22 (2.8) 23 (2.9) 47 (6.0) 18 (2.3) 38 (4.8) 16 (2.0) 107 (13.6) 94 (11.9) 10 (1.3) 22 (2.8)
0.68 (0.50–0.94) 0.84 (0.44–1.62) 0.86 (0.47–1.58) 0.67 (0.43–1.04) 0.52 (0.24–1.13) 2.51 (1.68–3.76) 1.69 (0.89–3.20) 0.82 (0.60–1.11) 0.75 (0.55–1.02) 0.97 (0.40–2.34) 1.21 (0.66–2.21)
0.018 0.605 0.617 0.077 0.097 <0.001 0.106 0.195 0.065 0.946 0.541
Values are presented as the n (%) of patients or mean SD. CI, confidence interval; HF, heart failure; HR, hazard ratio; MACE, major adverse cardiac event; TVR, target vessel revascularization; MI, myocardial infarction; PCI, percutaneous coronary intervention; TIMI, Thrombolysis in Myocardial Infarction. a Composite of cardiac death, non-fatal MI, TVR, stroke. b Composite of MACE and TIMI major bleeding.
Fig. 2. Kaplan-Meier curve for 2-year MACE in ticagrelor and clopidogrel group. MACE, major adverse cardiac event.
193 194 195 196 197 198 199 200
group was similar and net clinical event was comparable between two treatment groups. Current ACCF/AHA and ESC guidelines for DAPT recommend ticagrelor or prasugrel as first-line treatment in ACS patients after PCI [6,7]. However, the majority of the patients included in the previous randomized clinical trials comparing the effect of newgeneration P2Y12 inhibitors and clopidogrel were Caucasian and studies mainly targeted on East Asian populations had controverTable 4 Independent predictors of MACE and TIMI major or minor bleeding in multivariate analysis.
MACE eGFR < 60 mL/min/1.73㎡ Ticagrelor LVEF < 40 % TIMI major or minor bleeding Diabetes Ticagrelor Transradial approach
Adjusted HR(95 % CI)
p-value
1.76 (1.21–2.57) 0.68 (0.50–0.94) 1.58 (1.03–2.43)
0.003 0.018 0.038
1.81 (1.22–2.67) 2.51 (1.68–3.76) 0.43 (0.28–0.59)
0.003 <0.001 <0.001
CI, confidence interval; HR, hazard ratio; MACE, major adverse cardiac event; eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction; TIMI, Thrombolysis in Myocardial Infarction.
sial results. The substudy based on the PLATO trial showed there were no interactions between Asian and non-Asians patients. The study concluded that there was consistent clinical benefit of ticagrelor in Asian patients [14]. However, in the randomized clinical trial based on Japanese, Taiwanese, and South Korean patients with ACS after PCI (PHILO trial), both clopidogrel and ticagrelor had no significant difference in safety or efficacy endpoints [15]. Other retrospective registry studies in Korean AMI patients resulted that ischemic events were similar between clopidogrel and new-generation P2Y12 inhibitors while the bleeding events were higher in ticagrelor or prasugrel treatment group [16,17]. The concept of 'East Asian paradox' is a critical part in DAPT for the East Asian population and many experts are claiming that independent DAPT guideline should be developed [18,19]. The recent key issue in the DAPT field was 'De-escalation' of newgeneration P2Y12 inhibitors to clopidogrel in the Western society [20]. However, if the clear treatment benefit of new-generation P2Y12 inhibitor is still doubtful in general AMI patients in East Asian population, we thought that selecting certain patient group with high risk of ischemic cardiovascular events that might have benefit in new-generation P2Y12 inhibitors should be the crucial point. Numerous coronary artery angiographic findings have shown that nearly 50%–70% of AMI patients have MVD. As well known, the clinical outcomes of MVD are unfavorable compared to single vessel coronary artery disease because MVD tends to have more extensive atherosclerosis and relatively high ischemic burden [9,10]. Recently, a substudy of the Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis In Myocardial Infarction 54 (PEGASUS-TIMI 54) trial demonstrated that adverse events including coronary death and MI and definite stent thrombosis were higher in patients with MVD. The study result additionally showed that long-term add-on treatment with ticagrelor 60 mg or 90 mg twice daily on a background of low-dose aspirin reduced the risk of MACE compared to placebo (clopidogrel if indicated) in patients with prior MI with or without MVD. Another unique finding of this study was that risk reduction of MACE was greater in patients with MVD compared to patients without MVD [21]. Based on this study, we considered that AMI patients with MVD are the high-risk group of patients which would have a beneficial effect with the new-generation P2Y12 inhibitor ticagrelor among the East Asian population. To the best of our knowledge, the present study is the first study in Korea that directly compared the clinical efficacy of ticagrelor and clopidogrel
Please cite this article in press as: Ahn JH, et al. Ticagrelor versus clopidogrel in acute myocardial infarction patients with multivessel disease; From Korea Acute Myocardial Infarction Registry-National Institute of Health. J Cardiol (2019), https://doi.org/10.1016/j. jjcc.2019.11.003
201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245
G Model
JJCC 1958 1–7 6 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309
J.H. Ahn et al. / Journal of Cardiology xxx (2019) xxx–xxx
purely in AMI patients with MVD. The risk of MACE during a 2-year clinical follow-up period was lower in the ticagrelor patient group compared to the clopidogrel group and this finding was consistent with the substudy of PEGASUS-TIMI 54. Unfortunately, the risk of TIMI major or minor bleeding was higher with ticagrelor treatment in the present study which was consistent with other previous retrospective registry studies in Korea [16,22]. Experts had already argued that the lower dosage of new-generation P2Y12 inhibitors would be suitable for the East Asian patients compared to the Western patients based on the East Asian Paradox [18,23]. There was a single-center randomized trial in Korea comparing the clinical effect of low-dose (60 mg twice daily) versus standard-dose ticagrelor in ACS patients. The result of the study showed that there was no statistical difference in platelet inhibition between low-dose and standard-dose ticagrelor [24]. However, the present study only included patients with 90 mg twice daily maintenance dosage of ticagrelor. We insisted that excluding the drug dosage heterogeneity was a reasonable approach to directly compare the effect of ticagrelor and clopidogrel. Therefore, the incidence and risk of bleeding events were expected to be higher in the ticagrelor group than the clopidogrel group which was similar with the previous studies. An interesting finding was that the risk of TIMI major bleeding was comparable between both treatment groups and this finding was corresponding with the subgroup study based on PLATO trial and PHILO trial [14,15]. The important contributing factor for the similar incidence of TIMI major bleeding between the two treatment groups in the present study would be the proportion of patients with impaired renal function. Many clinical trials proved that MI patients with decreased renal function are vulnerable to bleeding complications [25,26]. A real world national cohort study based on Swedish Web-system concluded that bleeding events were abundant with ticagrelor compared to clopidogrel in patients with severe renal function (eGFR <30 formula) [27]. Compared with the other retrospective registry studies, the proportion of patients with renal dysfunction was relatively low in the present study [16,22,28]. The present study has several limitations. First, the study was not a randomized clinical trial but a retrospective analysis. The study was based on the registry data and selection bias might have existed. Although the propensity score matching analysis was done and most of potential confounders were adjusted and analyzed, other variables that have influence on the clinical outcomes might have not been included. Second, for the TIMI major and minor bleeding events after the hospitalization period, only the event of intracranial hemorrhage and 2-year outpatient follow-up laboratory findings were available in the registry data. Other additional bleeding events and detailed information including exact bleeding event time were not fully described. This might have underestimated the real world bleeding events and visualizing the accurate bleeding event by the time-event curve was unavailable. Third, the present study did not divide the specific patient groups into STEMI patients with or without cardiogenic shock or patients with non-STEMI. Various revascularization strategies according to each clinical situation would be different such as staged multivessel PCI or culprit only PCI and these different revascularization strategies could have impact in clinical outcomes [29–31]. Fourth, the present study did not focus on the long-term treatment effect of ticagrelor. The substudy of PEGASUS-TIMI 54 emphasized that long-term treatment with ticagrelor would be more beneficial in MVD patients. But, prolonged DAPT duration had only resulted in increased bleeding risk in East Asian population [21,23,28]. Therefore, detailed risk stratification for the DAPT duration based on East Asian population would also be important and further studies should be needed to evaluate the clinical efficacy and safety of long-term
use of especially low-dose ticagrelor in patients with high risk of ischemic events. In conclusion, ticagrelor reduced the risk of ischemic event MACE but increased the risk of TIMI major or minor bleeding compared to clopidogrel in Korean AMI patients with MVD. Further large-scale multi-center randomized clinical trials are warranted for the proper use of ticagrelor in East Asian patients.
310
Conflicts of interest
317
The authors have no conflicts of interest to declare
311 312 313 314 315 316
318
Acknowledgement
319
This work was supported by a fund from Korea Centers for Disease Control and Prevention (2016-ER6304-02), National Research Foundation of Korea (NRF-2019R1A2C3003547), and Chonnam National University Hospital Biomedical Research Institute (BCRI18017).
320
References
325
[1] Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, et al. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 2018;39:119–77. [2] Schomig A, Neumann FJ, Kastrati A, Schuhlen H, Blasini R, Hadamitzky M, et al. A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. N Engl J Med 1996;334:1084–9. [3] Price MJ, Endemann S, Gollapudi RR, Valencia R, Stinis CT, Levisay JP, et al. Prognostic significance of post-clopidogrel platelet reactivity assessed by a point-of-care assay on thrombotic events after drug-eluting stent implantation. Eur Heart J 2008;29:992–1000. [4] Price MJ, Berger PB, Teirstein PS, Tanguay JF, Angiolillo DJ, Spriggs D, et al. Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. JAMA 2011;305:1097–105. [5] Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045–57. [6] Levine GN, Bates ER, Bittl JA, Brindis RG, Fihn SD, Fleisher LA, et al. 2016 ACC/ AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the american college of Cardiology/American heart association task force on clinical practice guidelines: an update of the 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention, 2011 ACCF/AHA guideline for coronary artery bypass graft surgery, 2012 ACC/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease, 2013 ACCF/AHA guideline for the management of ST-Elevation myocardial infarction, 2014 AHA/ACC guideline for the management of patients with NonST-Elevation acute coronary syndromes, and 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery. Circulation 2016;134:e123–55. [7] Valgimigli M, Bueno H, Byrne RA, Collet JP, Costa F, Jeppsson A, et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: The Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2018;39:213–60. [8] Misumida N, Aoi S, Kim SM, Ziada KM, Abdel-Latif A. Ticagrelor versus clopidogrel in East Asian patients with acute coronary syndrome: systematic review and meta-analysis. Cardiovasc Revasc Med 2018;19:689–94. [9] van der Schaaf RJ, Timmer JR, Ottervanger JP, Hoorntje JC, de Boer MJ, Suryapranata H, et al. Long-term impact of multivessel disease on causespecific mortality after ST elevation myocardial infarction treated with reperfusion therapy. Heart 2006;92:1760–3. [10] Sorajja P, Gersh BJ, Cox DA, McLaughlin MG, Zimetbaum P, Costantini C, et al. Impact of multivessel disease on reperfusion success and clinical outcomes in patients undergoing primary percutaneous coronary intervention for acute myocardial infarction. Eur Heart J 2007;28:1709–16. [11] Cutlip DE, Windecker S, Mehran R, Boam A, Cohen DJ, van Es GA, et al. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007;115:2344–51. [12] Mauri L, Hsieh WH, Massaro JM, Ho KK, D’Agostino R, Cutlip DE. Stent thrombosis in randomized clinical trials of drug-eluting stents. N Engl J Med 2007;356:1020–9.
Please cite this article in press as: Ahn JH, et al. Ticagrelor versus clopidogrel in acute myocardial infarction patients with multivessel disease; From Korea Acute Myocardial Infarction Registry-National Institute of Health. J Cardiol (2019), https://doi.org/10.1016/j. jjcc.2019.11.003
321 322 323 324
326 327 328 329 330 331 332 333 334 335 336 337 338 339
340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358
359 360 361 362 363 364 365 366 367 368
G Model
JJCC 1958 1–7 J.H. Ahn et al. / Journal of Cardiology xxx (2019) xxx–xxx 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399 400
[13] Austin PC. An introduction to propensity score methods for reducing the effects of confounding in observational studies. Multivariate Behav Res 2011;46:399–424. [14] Kang HJ, Clare RM, Gao R, Held C, Himmelmann A, James SK, et al. Ticagrelor versus clopidogrel in Asian patients with acute coronary syndrome: A retrospective analysis from the Platelet Inhibition and Patient Outcomes (PLATO) Trial. Am Heart J 2015;169:899–905. e891. [15] Goto S, Huang CH, Park SJ, Emanuelsson H, Kimura T. Ticagrelor vs. Clopidogrel in Japanese, Korean and Taiwanese patients with acute coronary syndrome randomized, double-blind, phase III PHILO study. Circ J 2015;79:2452–60. [16] Park KH, Jeong MH, Ahn Y, Ahn TH, Seung KB, Oh DJ, et al. Comparison of shortterm 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. Int J Cardiol 2016;215:193–200. [17] Park KH, Jeong MH, Kim HK, Ahn TH, Seung KB, Oh DJ, et al. Comparison of prasugrel versus clopidogrel in Korean patients with acute myocardial infarction undergoing successful revascularization. J Cardiol 2018;71:36–43. [18] Jeong YH. "East asian paradox": challenge for the current antiplatelet strategy of "one-guideline-fits-all races" in acute coronary syndrome. Curr Cardiol Rep 2014;16:485. [19] Levine GN, Jeong YH, Goto S, Anderson JL, Huo Y, Mega JL, et al. Expert consensus document: world Heart Federation expert consensus statement on antiplatelet therapy in East Asian patients with ACS or undergoing PCI. Nat Rev Cardiol 2014;11:597–606. [20] Sibbing D, Aradi D, Jacobshagen C, Gross L, Trenk D, Geisler T, et al. Guided deescalation of antiplatelet treatment in patients with acute coronary syndrome undergoing percutaneous coronary intervention (TROPICAL-ACS): a randomised, open-label, multicentre trial. Lancet 2017;390:1747–57. [21] Bansilal S, Bonaca MP, Cornel JH, Storey RF, Bhatt DL, Steg PG, et al. Ticagrelor for secondary prevention of atherothrombotic events in patients with multivessel coronary disease. J Am Coll Cardiol 2018;71:489–96. [22] Sim DS, Jeong MH, Kim HS, Gwon HC, Seung KB, Rha SW, et al. Utility of GRACE and ACUITY-HORIZONS risk scores to guide dual antiplatelet therapy in Korean
[23]
[24]
[25]
[26]
[27]
[28]
[29]
[30]
[31]
7
patients with acute myocardial infarction undergoing drug-eluting stenting. J Cardiol 2018;72:411–9. Kang J, Kim HS. The evolving concept of dual antiplatelet therapy after percutaneous coronary intervention: focus on unique feature of East Asian and “Asian paradox”. Korean Circ J 2018;48:537–51. Park DW, Lee PH, Jang S, Lim HS, Kang DY, Lee CH, et al. Effect of low-dose versus standard-dose ticagrelor and clopidogrel on platelet inhibition in acute coronary syndromes. J Am Coll Cardiol 2018;71:1594–5. Flores-Blanco PJ, Lopez-Cuenca A, Januzzi JL, Marin F, Sanchez-Martinez M, Quintana-Giner M, et al. Major bleeding risk prediction using Chronic Kidney Disease Epidemiology Collaboration and Modification of Diet in Renal Disease equations in acute coronary syndrome. Eur J Clin Invest 2015;45:385–93. Burlacu A, Genovesi S, Ortiz A, Kanbay M, Rossignol P, Banach M, et al. The quest for equilibrium: exploring the thin red line between bleeding and ischaemic risks in the management of acute coronary syndromes in chronic kidney disease patients. Nephrol Dial Transplant 2017;32:1967–76. Edfors R, Sahlen A, Szummer K, Renlund H, Evans M, Carrero JJ, et al. Outcomes in patients treated with ticagrelor versus clopidogrel after acute myocardial infarction stratified by renal function. Heart 2018;104:1575–82. Kang J, Han JK, Ahn Y, Chae SC, Kim YJ, Chae IH, et al. Third-generation P2Y12 inhibitors in East Asian acute myocardial infarction patients: a nationwide prospective multicentre study. Thromb Haemost 2018;118:591–600. Sardella G, Lucisano L, Garbo R, Pennacchi M, Cavallo E, Stio RE, et al. Singlestaged compared with multi-staged PCI in multivessel NSTEMI patients: the SMILE trial. J Am Coll Cardiol 2016;67:264–72. Engstrøm T, Kelbæk H, Helqvist S, Høfsten DE, Kløvgaard L, Holmvang L, et al. Complete revascularisation versus treatment of the culprit lesion only in patients with ST-segment elevation myocardial infarction and multivessel disease (DANAMI-3—PRIMULTI): an open-label, randomised controlled trial. Lancet 2015;386:665–71. Khan MS, Siddiqi TJ, Usman MS, Riaz H, Khan AR, Murad MH, et al. Metaanalysis comparing culprit vessel only versus multivessel percutaneous coronary intervention in patients with acute myocardial infarction and cardiogenic shock. Am J Cardiol 2019;123:218–26.
Please cite this article in press as: Ahn JH, et al. Ticagrelor versus clopidogrel in acute myocardial infarction patients with multivessel disease; From Korea Acute Myocardial Infarction Registry-National Institute of Health. J Cardiol (2019), https://doi.org/10.1016/j. jjcc.2019.11.003
401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431