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Long-Term Efficacy of Extended Dual Antiplatelet Therapy After Left Main Coronary Artery Bifurcation Stenting
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Long-Term Efficacy of Extended Dual Antiplatelet Therapy after Left Main Coronary Artery Bifurcation Stenting Sungsoo Cho MD, PhD , Jung-Sun Kim MD, PhD , Tae Soo Kang MD, PhD , Sung-Jin Hong MD , Dong-Ho Shin MD , Chul-Min Ahn MD, PhD , Byeong-Keuk Kim MD, PhD , Young-Guk Ko MD, PhD , Donghoon Choi MD, PhD , Young Bin Song MD, PhD , Joo-Yong Hahn MD, PhD , Seung-Hyuk Choi MD, PhD , Hyeon-Cheol Gwon MD, PhD , Myeong-Ki Hong MD, PhD , Yansoo Jang MD, PhD PII: DOI: Reference:
S0002-9149(19)31233-0 https://doi.org/10.1016/j.amjcard.2019.10.046 AJC 24276
To appear in:
The American Journal of Cardiology
Received date: Revised date: Accepted date:
17 August 2019 21 October 2019 28 October 2019
Please cite this article as: Sungsoo Cho MD, PhD , Jung-Sun Kim MD, PhD , Tae Soo Kang MD, PhD , Sung-Jin Hong MD , Dong-Ho Shin MD , Chul-Min Ahn MD, PhD , Byeong-Keuk Kim MD, PhD , Young-Guk Ko MD, PhD , Donghoon Choi MD, PhD , Young Bin Song MD, PhD , Joo-Yong Hahn MD, PhD , Seung-Hyuk Choi MD, PhD , Hyeon-Cheol Gwon MD, PhD , Myeong-Ki Hong MD, PhD , Yansoo Jang MD, PhD , Long-Term Efficacy of Extended Dual Antiplatelet Therapy after Left Main Coronary Artery Bifurcation Stenting, The American Journal of Cardiology (2019), doi: https://doi.org/10.1016/j.amjcard.2019.10.046
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Long-Term Efficacy of Extended Dual Antiplatelet Therapy after Left Main Coronary Artery Bifurcation Stenting Sungsoo Cho, MD, PhDa, Jung-Sun Kim MD, PhDb, *, Tae Soo Kang, MD, PhDa, *, Sung-Jin Hong, MDb, Dong-Ho Shin, MDb, Chul-Min Ahn, MD, PhDb, Byeong-Keuk Kim, MD, PhDb, Young-Guk Ko, MD, PhDb, Donghoon Choi, MD, PhDb, Young Bin Song, MD, PhDc, Joo-Yong Hahn, MD, PhDc, Seung-Hyuk Choi, MD, PhDc, Hyeon-Cheol Gwon, MD, PhDc, Myeong-Ki Hong, MD, PhDb, Yansoo Jang MD, PhDb a
Division of Cardiovascular Medicine, Department of Internal Medicine, Dankook University
Hospital, Dankook University College of Medicine, Cheonan-si, Choongcheongnam-do, Korea b
Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University College of
Medicine, Seoul, Korea c
Division of Cardiology, Samsung Medical Center, Sungkyunkwan University College of
Medicine, Seoul, Korea Funding This study was supported by grants from the National Research Foundation of Korea (NRF) funded by the Korean government (MSIT) (No. 2017R1A2B2003191), the Ministry of Science and ICT (2017M3A9E9073585), and the Cardiovascular Research Center (Seoul, Korea).
*ADDRESS FOR CORRESPONDENCE:
Jung-Sun Kim, MD, Ph.D. Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Yonsei-ro 50–1, Seodaemun-gu, Seoul, 03722, Korea. Telephone: (82-2)-2228-8457; FAX: (82-2)-393-2041; E-mail: [email protected] Tae Soo Kang, MD, Ph.D. Division of Cardiovascular Medicine, Department of Internal Medicine, Dankook University Hospital, Dankook University College of Medicine, 201 Manghyang-ro, Dongnam-gu, Cheonsi, Chunhcheongnam-do, 31116, Korea Telephone: (82-41)-550-6175, Fax: (82-41)-569-8122; Email: [email protected]
1
ABSTRACT Limited data exist on the long-term efficacy of extended dual antiplatelet therapy (DAPT) after left main coronary artery (LMCA) bifurcation stenting. This study investigated the longterm clinical outcomes associated with long-term DAPT after LMCA bifurcation stenting. Using data from the multicenter KOMATE and COBIS registries, we analyzed 1,142 patients who received a drug-eluting stent (DES) for a LMCA bifurcation lesion and who experienced no adverse events for 12 months after the index procedure. Patients were divided into two groups: DAPT >12 months (N=769) and DAPT ≤12 months (N=373). The primary endpoint was major adverse cardiovascular events (MACEs), as a composite of cardiac death, myocardial infarction, stroke, and stent thrombosis, over 5 years of follow-up. We further performed propensity score adjustment for clinical outcomes. DAPT >12 months afforded a lower MACE rate than DAPT ≤12 months (2.3% vs. 5.4%, adjusted hazard ratio [HR], 0.37; 95% confidence interval [CI], 0.19–0.71; p=0.003). The use of DAPT for >12 months was an independent predictor of a reduced likelihood of MACEs (HR, 0.34; 95% CI, 0.17–0.67; p=0.002). A DAPT score ≥2, chronic kidney disease, and age >75 years were significant independent predictors of MACEs. In subgroup analysis, the use of DAPT for >12 months consistently resulted in better clinical outcomes across all subgroups, especially among patients with ACS, compared with the use of DAPT for ≤12 months. In conclusion, an extended duration of DAPT reduces MACE rates after LMCA bifurcation stenting.
KEYWORDS: dual antiplatelet therapy, left main coronary artery, bifurcation lesion, percutaneous coronary intervention
2
Dual antiplatelet therapy (DAPT) is to be administered for a certain period of time in patients undergoing percutaneous coronary intervention (PCI) with a drug-eluting stent (DES).1 Although extended DAPT reduces ischemic events, such as myocardial infarction (MI), stent thrombosis (ST), and stroke, it also increases bleeding events.2 Therefore, studies have attempted to investigate the optimal duration of DAPT with which to minimize both ischemic events and bleeding risk in patients undergoing PCI with a DES.3-5 However, there are limited data on the optimal duration of DAPT in patients with advanced coronary artery disease who undergo complex revascularization procedures. Previous reports have indicated that an extended duration of DAPT leads to better clinical outcomes in complex coronary PCI patients6 and that prolonged DAPT beyond 12 months reduces the rate of ischemic events in patients with coronary bifurcation lesions.7 While bifurcation lesions in the left main coronary artery (LMCA) are a high-risk subset in PCI for which determining the optimal duration of DAPT would be important, few studies have tested DAPT durations among patients with LMCA bifurcation lesions, particularly a long-term duration. Therefore, we investigated the long-term outcomes of extended DAPT in patients with LMCA bifurcation lesions using large datasets from two multicenter registries.
METHODS The design and enrollment characteristics of the study from two multicenter registries, the Korean Multicenter Angioplasty Team (KOMATE) and the Coronary Bifurcation Stenting (COBIS) II registries, have been published previously.8 From February 2002 to September 2013, we identified a total of 1,352 LMCA bifurcation stenting patients. We excluded 121 patients who were not followed up for 12 months after the index procedure, 61 patients who underwent PCI for in-stent restenosis, 17 patients who had experienced an adverse event (i.e., death, MI, cerebrovascular accident, stent thrombosis, or revascularization) at 12-month 3
follow-up, and 11 patients who did not properly use DAPT. Finally, our analysis included 1,142 patients who were adverse event-free at 12 months after the index procedure. Next, patients were divided into two groups based on their duration of DAPT (aspirin + clopidogrel): >12 months or ≤12 months (Figure 1). As regulatory authorities require written informed consent for coronary intervention studies using the KOMATE registry, we obtained written informed consent from each patient. The institutional review boards of each hospital that contributes data to the COBIS II registry, which is funded by the Korean Society of Interventional Cardiology, approved the study protocol and waived the requirement for informed consent. All patients received loading doses of aspirin (300 mg/day) and clopidogrel (300 or 600 mg) before PCI. Aspects of access location, stent strategy, stent technique, and use of intravascular ultrasound were left to the operator’s discretion. The stent type according to stent generation was the same as that in a previous study.8 The duration of DAPT was left to the operator’s discretion. A 12-month duration of DAPT was defined as 2 months of DAPT before and 12 months of DAPT after the index procedure. New P2Y12 receptor inhibitors were not available during the study period in Korea. Clinical, angiographic, procedural, and outcome data were collected using a web-based reporting system. To identify the status of antiplatelet therapy, the dates and duration of prescribed antiplatelet agents were obtained from the electronic prescribing system of each hospital. Additional information was obtained by further inquiry into medical records or telephone contact, if necessary. An independent clinical event adjudicating committee reviewed all data on outcomes reported by participating centers. Patient in both registries received clinical follow up for up to 5 years (median, 1,526 days; interquartile range [IQR], 881 days).
4
Our primary endpoint was major adverse cardiovascular events (MACEs), defined as a composite of cardiac death, fatal or nonfatal acute MI, stroke, and ST, at 5 years after the index procedure. The secondary endpoint was all-cause death. Fatal or nonfatal acute MI was defined as an increase in the creatine kinase-myocardial band or troponin levels to the 99th percentile of the upper limit of normal with ischemic symptoms or electrocardiographic findings indicative of ischemia not related to the index procedure. ST was defined as definite ST according to the Academic Research Consortium definition. A major bleeding event was defined as severe or life-threatening bleeding by Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) bleeding criteria. Only the KOMATE registry was used to analyze bleeding events, because these events are not fully reported in the COBIS II registry. Continuous variables are reported as a mean ± standard deviation (SD) and were analyzed using Student’s t-tests. Categorical variables are reported as frequencies (percentages) and were analyzed using Chi-square tests. Survival curves were developed using Kaplan-Meier analysis and were analyzed using log-rank tests. Cox proportional hazards models were utilized to identify independent predictors of primary endpoints and to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for clinical outcomes. Propensity score matching was applied to reduce selection bias associated with stent strategy and potential confounding factors and to adjust for significant differences in baseline patient characteristics or procedural data. Propensity scores were estimated using multiple logistic regression analysis. Included covariates were age, sex, hypertension, diabetes mellitus, ACS, multi-vessel disease, stent strategy, chronic kidney disease, dyslipidemia, smoking, and previous PCI. Patients were matched based on the closest possible propensity score value (i.e., nearest neighbor matching). A matching caliper of 0.05 SDs from the logit of the estimated propensity score was enforced to ensure that matches of poor fit were excluded. We then performed 1:1 5
propensity score-matching iteration. The linearity assumption between DAPT duration and clinical outcomes was explored using penalized spline functions, allowing 2 df.9 In subgroup analyses, tests of interaction were used to confirm differential clinical outcomes among groups. SPSS (version 24.0, Chicago, IL, USA) and SAS (version 9.3, Cary, NC) software were used to conduct all statistical analyses.
RESULTS Of the 1,142 patients, 769 patients received DAPT for >12 months, and 373 received DAPT for ≤12 months. The median durations of DAPT were 731 days (IQR, 845 days) for the entire population, 269.5 days (IQR, 170 days) for the DAPT ≤ 12 months population, and 875 days (IQR, 846 days) for the DAPT > 12 months population, respectively. Patient clinical characteristics were similar between the two groups, except for dyslipidemia and history of previous PCI (Table 1). A two-stent strategy and final kissing balloon inflation patients were significantly more likely to receive DAPT for >12 months (Table 2). After 1:1 matching between groups using propensity scores, there were no significant differences between the two groups (Supplemental Table S1). Clinical outcomes are summarized in Table 3. Five years after the index procedure, the DAPT >12 months group had a lower rate of MACEs than the DAPT ≤12 months group. The rate of all-cause death was lower in the >12 months group than in the ≤12 months group. The rates of cardiac death and MI were lower in the >12 months group than in the ≤12 months group. Rates of stroke and ST were similar between the two groups (Figure 2 and Table 3). After 1:1 matching using propensity scores, the >12 months group still had significantly lower rates of MACEs, all-cause death, and cardiac death than the ≤12 months group (Table 3). In the KOMATE registry, major bleeding events tended to be more likely in the >12 months group than in the ≤12 months group, although this difference was not statistically 6
significant (Supplementary Figure S1). Among patients with a DAPT score <2, there was no significant difference in MACE rate between DAPT >12 months and ≤12 months groups. However, among patients with a DAPT score ≥2, the DAPT >12 months group had a lower rate of MACEs than the DAPT ≤12 months group (Supplemental Figure S2). Among patients treated with early generation DESs (E-DES), those treated with DAPT >12 months had a lower rate of MACEs than those treated with DAPT ≤12 months. Among patients treated with current generation DESs (C-DES), the DAPT >12 months group tended to have a lower rate of MACEs than the DAPT ≤12 months group, although this difference was not statistically significant (Supplemental Figure S3). Among patients treated with a one-stent strategy, DAPT >12 months afforded a lower rate of MACEs than DAPT ≤12 months. This was similar with a two-stent strategy, wherein the DAPT >12 months group tended to have a lower rate of MACEs than the DAPT ≤12 months group, although this difference was not statistically significant (Supplemental Figure S4). Analyzing the risk of MACE according to DAPT duration as a continuous variable, the risk of MACE progressively decreased with a longer DAPT duration (Figure 3). Subgroup analysis results for MACE are presented in Figure 4. The rate of MACEs was consistently lower in the DAPT >12 months group than in the DAPT ≤12 months group across several subgroups. In particular, there was a significant interaction between the presence or absence of ACS and DAPT duration (p = 0.04). Use of DAPT for >12 months was an independent predictor of reduced MACEs (Table 4). The strongest predictors of MACEs were chronic kidney disease, age >75 years, and DAPT score ≥2.
DISCUSSION Our main findings were as follows: 1) DAPT for >12 months after an index procedure was associated with a reduced MACE rate among patients with LMCA bifurcation 7
stenting, compared with DAPT for ≤12 months; 2) among patients with DAPT scores ≥2 or E-DESs, DAPT for >12 months reduced the MACE rate; and 3) DAPT for >12 months was an independent predictor of a reduced likelihood of MACEs. In recent studies, PCI with a DES for the treatment of LMCA bifurcation lesions has been shown to offer acceptable procedural and satisfactory long-term clinical outcomes.8,10,11 In real-world practice, patients receiving LMCA interventions frequently undergo multi-vessel complex PCI with a greater number of stents and longer stent lengths, compared with patients undergoing PCI for other coronary segments.12 However, there is a lack of evidence on the appropriate duration of DAPT for patients with LMCA bifurcation lesion stenting. In a post hoc patient-level pooled analysis of six randomized controlled trials including patients undergoing complex PCI, longer DAPT (≥1 year) was found to significantly reduce the risk of ischemic events, compared with shorter periods of DAPT (3 or 6 months). However, in this previous study, there were only 49 patients with LMCA among the 1,680 patients undergoing complex PCI.13 In the PROGIDY trial, which included 336 patients who underwent coronary stenting of the LMCA and/or proximal left anterior descending coronary artery, prolonged DAPT (≥24 months) provided consistent benefits over shorter DAPT (6 months).14 In the present study, 5 years after PCI, the DAPT >12 months group had lower rates of MACEs, all-cause death, cardiac death, and MI than the DAPT ≤12 months group. The MACE rate consistently decreased with prolongation of the DAPT duration. A previous study reported that patients with complex target-lesion anatomy, including a LMCA bifurcation lesion, had a higher rate of ischemic events than patients without complex target-lesion anatomy. Another study showed that a high DAPT score in patients with or without complex anatomy is suggestive of a likelihood of benefiting from extended DAPT.6 In the present study, DAPT >12 months afforded a lower MACE rate than DAPT ≤12 months among patients with a DAPT score ≥2 but not those with a DAPT score <2. Despite several 8
validation studies of DAPT score in various cohorts and clinical settings, its usefulness is still under debate. In a Japanese population including 407 LMCA stenting patients, the cumulative 3-year incidence of MI and ST at 13 months after PCI was significantly higher among patients with a high DAPT score (≥2) than among those with a low DAPT score (<2).15 However, a recent study using data from the SWEDEHEART registry reported that DAPT score was a poor discrimination factor for ischemic risk16. Further studies will be needed to determine the optimal DAPT duration using a scoring system that predicts ischemic risk, including DAPT score, in more patients with LMCA bifurcation stenting. Although E-DESs are no longer implanted, patients who have received E-DESs are still followed up in real-world practice. Moreover, components of DAPT score include whether PESs are deployed. In the present study, 58.3% of patients received E-DESs (e.g., SES or PES). Within the E-DES population, MACE rate was lower in the DAPT >12 months group than in the DAPT ≤12 months group. For contrast, in the EXCEL trial, continuation of DAPT beyond 1 year was not associated with improved event (death, MI or stroke)-free survival after PCI with everolimus-eluting stents in patients with LMCA disease. 17 In present study, within the C-DES population, the MACE rate was similar between two DAPT groups. Thus, our results suggest that longer use of DAPT should be considered in patients who present with a DAPT score ≥2 or have received an E-DES. Future studies are required to determine the optimal DAPT duration in LMCA bifurcation lesion patients with a C-DES. LMCA bifurcation lesions are complex and indicated high risk PCI lesion subsets due to very large diameter left main and large side branch left circumflex artery. Therefore, stent strategy, stent optimization technique (final kissing balloon inflation [FKBI], proximal optimization [POT]) and device (intravascular ultrasound [IVUS]) have a significant effect on clinical outcomes. However, there were few studies with DAPT duration and stent strategies and techniques in LMCA bifurcation stenting patients. In our study, extended use of 9
DAPT reduced MACE rate in both 1- and 2-stent strategies. Although our study mainly used the 1-stent strategy, the extended DAPT may have influenced the clinical outcomes because of relatively low implement of stent optimization such as use of IVUS or kissing ballooning as well as considerable amount of stent metal across the ostium of the side branch as a nidus of thrombus and flow barrier to left circumflex artery. Further studies will be needed to determine how different DAPT duration affect clinical outcomes with the optimal stent strategies and techniques. The present study has some limitations. First, as patients were not randomized into groups, selection bias might have affected the results. Second, bleeding events are not fully reported in the COBIS II registry. Also, we could not investigate bleeding risk score, such as PRECISE-DAPT score. Extended DAPT might increase the risk of fatal or major bleeding, which could offset benefits from reducing ischemic events. However, all-cause mortality was significantly lower in the DAPT >12 months group than in the DAPT ≤12 months group in our results. Therefore, a reduction of ischemic events due to extended DAPT could be beneficial despite an increase in bleeding events. Further studies should include more patients to adequately investigate bleeding events and bleeding risk score during long-term follow-up. Third, the small number of C-DES patients included in this study limits the determination of the optimal DAPT duration for this population. Fourth, we did not include data on oral anticoagulation agents or new P2Y12 inhibitors, such as ticagrelor and prasugrel. Fifth, our sample size was too small to evaluate low frequency events despite using two of the largest data registries available. In conclusion, using data from two large multicenter registries, KOMATE and COBIS II, we found that extended DAPT is associated with a reduced rate of MACEs among patients with LMCA bifurcation stenting. ACKNOWLEDGEMENTS: None Disclosures: The authors have no conflicts of interest to disclose.
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FIGURE LEGENDS Figure 1. Overview of study scheme. KOMATE = Korean Multicenter Angioplasty Team, COBIS = Coronary Bifurcation Stenting, DAPT = dual antiplatelet therapy, LMCA = left main coronary artery
Figure 2. Kaplan-Meier curves for MACE, all-cause death, cardiac death, and MI after DAPT >12 months versus DAPT ≤ 12 months. Cumulative incidence of MACEs (A), all-cause death (B), cardiac death (C), and MI (D). DAPT = dual antiplatelet therapy, MACE = major adverse cardiovascular event, MI = myocardial infarction; HR = hazard ratio, CI = confidence interval
Figure 3. Spline curves of HRs for MACE according to DAPT duration modeled as a continuous variable. HR = hazard ratio, DAPT = dual antiplatelet therapy, MACE = major adverse cardiovascular event
Figure 4. Subgroup analysis. DAPT = dual antiplatelet therapy, ACS = acute coronary syndrome, DM = diabetes mellitus, CKD = chronic kidney disease, C-DES = current generation drug-eluting stent, IVUS = intravascular ultrasound
15
Table 1. Patient Clinical, Angiographic, and Procedural Characteristics Variable
Entire
>12 DAPT
DAPT
population (N = months
(N = months
≤12 p-value (N =
1,142)
769)
373)
Age (years)
63.03 ± 10.25
62.63 ± 10.21
63.86 ± 10.28
0.06
Men
852 (74.6%)
571 (74.3%)
281 (75.3%)
0.69
DAPT duration
900 ± 662
1,102 ± 462
314 ± 138
<0.0001
DAPT score
0.62 ± 1.18
0.64 ± 1.17
0.58 ± 1.19
0.43
SYNTAX score
22.59 ± 8.47
22.39 ± 8.45
22.99 ± 8.51
0.26
ACS
567 (49.6%)
397 (51.6%)
170 (45.6%)
0.06
Multi-vessel
710 (62.2%)
471 (61.2%)
239 (64.1%)
0.36
Smoking
376 (32.9%)
253 (32.9%)
123 (33%)
0.98
DM
369 (32.3%)
246 (32%)
123 (33%)
0.74
Hypertension
685 (60%)
467 (60.7%)
218 (58.4%)
0.46
CKD
40 (3.5%)
28 (3.6%)
12 (3.2%)
0.72
Old CVA
110 (9.6%)
76 (9.9%)
34 (9.1%)
0.68
Dyslipidemia
507 (44.4%)
316 (41.1%)
191 (51.2%)
0.001
Previous PCI
234 (20.5%)
170 (22.1%)
64 (17.2%)
0.05
Previous
40 (3.5%)
25 (3.3%)
15 (4%)
0.51
55.9 ± 19.3
55.9 ± 19.2
56.1 ± 19.5
0.87
(days)
disease
CABG LVEF
Values are n (%) or mean ± SD. DAPT = dual antiplatelet therapy; ACS = acute coronary syndrome; DM = diabetes mellitus; CKD = chronic kidney disease; CVA = cerebrovascular accident; PCI = percutaneous coronary intervention; CABG = coronary bypass graft; LVEF = left ventricular ejection fraction
16
Table 2. Patient Angiographic and Procedural Characteristics Variable
True bifurcation
Entire population
DAPT > 12 months
DAPT ≤ 12 months
(N = 1,142)
(N = 769)
(N = 373)
454 (39.8%)
294 (38.2%)
160 (42.9%)
p-value
0.13 0.08
Medina 1,1,1
334 (29.2%)
218 (28.3%)
116 (31.1%)
1,0,1
63 (5.5%)
41 (5.3%)
22 (5.9%)
0,1,1
57 (5.0%)
35 (4.6%)
22 (5.9%)
1,0,0
124 (10.9%)
95 (12.4%)
29 (7.8%)
1,1,0
294 (25.7%)
187 (24.3%)
107 (28.7%)
0,1,0
222 (19.4%)
156 (20.3%)
66 (17.7%)
0,0,1
48 (4.2%)
37 (4.8%)
11 (2.9%) <0.0001
Stent type SES
486 (42.6%)
391 (50.8%)
95 (25.5%)
PES
179 (15.7%)
128 (16.6%)
51 (13.7%)
EES
246 (21.5%)
140 (18.2%)
106 (28.4%)
ZES
157 (13.7%)
85 (11.1%)
72 (19.3%)
BES
74 (6.5%)
25 (3.3%)
49 (13.1%) <0.0001
Stent technique 1-stent strategy
838 (73.4%)
535 (69.6%)
303 (81.2%)
2-stent strategy
304 (26.6%)
234 (30.4%)
70 (18.8%)
T-stenting
109 (9.5%)
86 (11.2%)
23 (6.2%)
Crush
129 (11.3%)
102 (13.3%)
27 (7.2%)
Kissing or V stent
11 (1%)
9 (1.2%)
2 (0.5%)
Culottes
48 (4.2%)
34 (4.4%)
14 (3.8%)
Others
7 (0.6%)
3 (0.3%)
4 (1.1%)
Kissing
495 (43.3%)
365 (47.5%)
130 (34.9%)
<0.0001
IVUS
659 (57.7%)
440 (57.2%)
219 (58.7%)
0.63
Values are n (%) or mean ± SD. True bifurcation = Medina classification type 1,1,1, 1,0,1, or 0,1,1; DAPT = dual antiplatelet therapy; SES = sirolimus-eluting stent; PES = paclitaxeleluting stent; ZES-S = zotarolimus-eluting stent-SPLINT; EES = everolimus-eluting stent; ZES-R = zotarolimus-eluting stent-RESOLUTE; BES = biolimus-eluting stent; IVUS = intravascular ultrasound 17
Table 3. Hazard Ratios for DAPT Duration and Clinical Outcomes Variable
DAPT >12
DAPT ≤12
Unadjusted
months (N =
months (N =
HR (95%
769)
373)
CI)
p-value
Adjusted HR p-value
Propensity
(95% CI)
score-
p-value
matched HR (95% CI)
MACE
18 (2.3%)
20 (5.4%)
All-cause
24 (3.1%)
23 (6.2%)
0.43 (0.23–
0.01
0.37 (0.19–
0.81)
0.71) 0.02
0.42 (0.24-
0.89)
death Cardiac
0.5 (0.28-
6 (0.8%)
11 (2.9%)
0.26 (0.1–
0.01
0.19 (0.07–
MI
9 (1.2%)
10 (2.7%)
Stroke
9 (1.2%)
5 (1.3%)
0.42 (0.17–
0.37 (0.15–
1.04) 0.87 (0.29–
1.38 (0.46–
2.59) ST
3 (0.4%)
3 (0.8%)
0.47 (0.1–
0.001
0.49 (0.24-
0.05
0.17 (0.04-
0.02
0.79) 0.03
0.92) 0.8
0.01
1.0)
0.51) 0.06
0.25 (0.10.68)
0.003
0.75)
0.7)
death
0.003
0.39 (0.12-
0.11
1.23) 0.57
0.5 (0.09-2.7)
0.42
4.19) 0.36
0.34 (0.06–
2.34)
0.21
1.84)
Values are n (%) or mean ± SD. HR = hazard ratio; CI = confidence interval; DAPT = dual antiplatelet therapy; MACE = major adverse cardiovascular event; MI = myocardial infarction; ST = stent thrombosis
1
Table 4. Independent Predictors of Clinical Outcomes Univariate analysis
Multivariate analysis
Variable
HR (95% CI)
p-value
HR (95% CI)
p-value
Age >75 years
3.5 (1.7–7.2)
0.001
3.58 (1.63–7.87)
0.002
DAPT >12 months
0.43 (0.23–0.81)
0.01
0.34 (0.17–0.67)
0.002
DAPT score ≥2
2.17 (1.08–4.35)
0.03
2.76 (1.33–5.7)
0.01
CKD
6.87 (3.03–15.61)
<0.0001
6.85 (2.83–16.61)
<0.0001
2-stent strategy
0.92 (0.43–1.94)
0.82
Male
1.13 (0.54–2.39)
0.74
ACS
2.32 (1.17–4.61)
0.02
Multi-vessel disease
1.43 (0.71–2.88)
0.32
DM
1.26 (0.65–2.43)
0.5
Hyptertension
1.29 (0.66–2.53)
0.45
Previous PCI
1.58 (0.78–3.19)
0.2
Previous CABG
1.51 (0.36–6.27)
0.57
IVUS
0.67 (0.36–1.27)
0.22
Table 4. Independent Predictors of Clinical Outcomes MACE = major adverse cardiovascular event; HR = hazard ratio; CI = confidence interval; DAPT = dual antiplatelet therapy; CKD = chronic kidney disease; ACS = acute coronary syndrome; DM = diabetes mellitus; PCI = percutaneous coronary intervention; CABG = coronary artery bypass graft; IVUS = intravascular ultrasound
1
Figure 1
2
Figure 2
3
Figure 3
4
Figure 4
5
Long-Term Efficacy of Extended Dual Antiplatelet Therapy after Left Main Coronary Artery Bifurcation Stenting Sungsoo Cho MD, PhD , Jung-Sun Kim MD, PhD , Tae Soo Kang MD, PhD , Sung-Jin Hong MD , Dong-Ho Shin MD , Chul-Min Ahn MD, PhD , Byeong-Keuk Kim MD, PhD , Young-Guk Ko MD, PhD , Donghoon Choi MD, PhD , Young Bin Song MD, PhD , Joo-Yong Hahn MD, PhD , Seung-Hyuk Choi MD, PhD , Hyeon-Cheol Gwon MD, PhD , Myeong-Ki Hong MD, PhD , Yansoo Jang MD, PhD PII: DOI: Reference:
S0002-9149(19)31233-0 https://doi.org/10.1016/j.amjcard.2019.10.046 AJC 24276
To appear in:
The American Journal of Cardiology
Received date: Revised date: Accepted date:
17 August 2019 21 October 2019 28 October 2019
Please cite this article as: Sungsoo Cho MD, PhD , Jung-Sun Kim MD, PhD , Tae Soo Kang MD, PhD , Sung-Jin Hong MD , Dong-Ho Shin MD , Chul-Min Ahn MD, PhD , Byeong-Keuk Kim MD, PhD , Young-Guk Ko MD, PhD , Donghoon Choi MD, PhD , Young Bin Song MD, PhD , Joo-Yong Hahn MD, PhD , Seung-Hyuk Choi MD, PhD , Hyeon-Cheol Gwon MD, PhD , Myeong-Ki Hong MD, PhD , Yansoo Jang MD, PhD , Long-Term Efficacy of Extended Dual Antiplatelet Therapy after Left Main Coronary Artery Bifurcation Stenting, The American Journal of Cardiology (2019), doi: https://doi.org/10.1016/j.amjcard.2019.10.046
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc.
Long-Term Efficacy of Extended Dual Antiplatelet Therapy after Left Main Coronary Artery Bifurcation Stenting Sungsoo Cho, MD, PhDa, Jung-Sun Kim MD, PhDb, *, Tae Soo Kang, MD, PhDa, *, Sung-Jin Hong, MDb, Dong-Ho Shin, MDb, Chul-Min Ahn, MD, PhDb, Byeong-Keuk Kim, MD, PhDb, Young-Guk Ko, MD, PhDb, Donghoon Choi, MD, PhDb, Young Bin Song, MD, PhDc, Joo-Yong Hahn, MD, PhDc, Seung-Hyuk Choi, MD, PhDc, Hyeon-Cheol Gwon, MD, PhDc, Myeong-Ki Hong, MD, PhDb, Yansoo Jang MD, PhDb a
Division of Cardiovascular Medicine, Department of Internal Medicine, Dankook University
Hospital, Dankook University College of Medicine, Cheonan-si, Choongcheongnam-do, Korea b
Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University College of
Medicine, Seoul, Korea c
Division of Cardiology, Samsung Medical Center, Sungkyunkwan University College of
Medicine, Seoul, Korea Funding This study was supported by grants from the National Research Foundation of Korea (NRF) funded by the Korean government (MSIT) (No. 2017R1A2B2003191), the Ministry of Science and ICT (2017M3A9E9073585), and the Cardiovascular Research Center (Seoul, Korea).
*ADDRESS FOR CORRESPONDENCE:
Jung-Sun Kim, MD, Ph.D. Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Yonsei-ro 50–1, Seodaemun-gu, Seoul, 03722, Korea. Telephone: (82-2)-2228-8457; FAX: (82-2)-393-2041; E-mail: [email protected] Tae Soo Kang, MD, Ph.D. Division of Cardiovascular Medicine, Department of Internal Medicine, Dankook University Hospital, Dankook University College of Medicine, 201 Manghyang-ro, Dongnam-gu, Cheonsi, Chunhcheongnam-do, 31116, Korea Telephone: (82-41)-550-6175, Fax: (82-41)-569-8122; Email: [email protected]
1
ABSTRACT Limited data exist on the long-term efficacy of extended dual antiplatelet therapy (DAPT) after left main coronary artery (LMCA) bifurcation stenting. This study investigated the longterm clinical outcomes associated with long-term DAPT after LMCA bifurcation stenting. Using data from the multicenter KOMATE and COBIS registries, we analyzed 1,142 patients who received a drug-eluting stent (DES) for a LMCA bifurcation lesion and who experienced no adverse events for 12 months after the index procedure. Patients were divided into two groups: DAPT >12 months (N=769) and DAPT ≤12 months (N=373). The primary endpoint was major adverse cardiovascular events (MACEs), as a composite of cardiac death, myocardial infarction, stroke, and stent thrombosis, over 5 years of follow-up. We further performed propensity score adjustment for clinical outcomes. DAPT >12 months afforded a lower MACE rate than DAPT ≤12 months (2.3% vs. 5.4%, adjusted hazard ratio [HR], 0.37; 95% confidence interval [CI], 0.19–0.71; p=0.003). The use of DAPT for >12 months was an independent predictor of a reduced likelihood of MACEs (HR, 0.34; 95% CI, 0.17–0.67; p=0.002). A DAPT score ≥2, chronic kidney disease, and age >75 years were significant independent predictors of MACEs. In subgroup analysis, the use of DAPT for >12 months consistently resulted in better clinical outcomes across all subgroups, especially among patients with ACS, compared with the use of DAPT for ≤12 months. In conclusion, an extended duration of DAPT reduces MACE rates after LMCA bifurcation stenting.
KEYWORDS: dual antiplatelet therapy, left main coronary artery, bifurcation lesion, percutaneous coronary intervention
2
Dual antiplatelet therapy (DAPT) is to be administered for a certain period of time in patients undergoing percutaneous coronary intervention (PCI) with a drug-eluting stent (DES).1 Although extended DAPT reduces ischemic events, such as myocardial infarction (MI), stent thrombosis (ST), and stroke, it also increases bleeding events.2 Therefore, studies have attempted to investigate the optimal duration of DAPT with which to minimize both ischemic events and bleeding risk in patients undergoing PCI with a DES.3-5 However, there are limited data on the optimal duration of DAPT in patients with advanced coronary artery disease who undergo complex revascularization procedures. Previous reports have indicated that an extended duration of DAPT leads to better clinical outcomes in complex coronary PCI patients6 and that prolonged DAPT beyond 12 months reduces the rate of ischemic events in patients with coronary bifurcation lesions.7 While bifurcation lesions in the left main coronary artery (LMCA) are a high-risk subset in PCI for which determining the optimal duration of DAPT would be important, few studies have tested DAPT durations among patients with LMCA bifurcation lesions, particularly a long-term duration. Therefore, we investigated the long-term outcomes of extended DAPT in patients with LMCA bifurcation lesions using large datasets from two multicenter registries.
METHODS The design and enrollment characteristics of the study from two multicenter registries, the Korean Multicenter Angioplasty Team (KOMATE) and the Coronary Bifurcation Stenting (COBIS) II registries, have been published previously.8 From February 2002 to September 2013, we identified a total of 1,352 LMCA bifurcation stenting patients. We excluded 121 patients who were not followed up for 12 months after the index procedure, 61 patients who underwent PCI for in-stent restenosis, 17 patients who had experienced an adverse event (i.e., death, MI, cerebrovascular accident, stent thrombosis, or revascularization) at 12-month 3
follow-up, and 11 patients who did not properly use DAPT. Finally, our analysis included 1,142 patients who were adverse event-free at 12 months after the index procedure. Next, patients were divided into two groups based on their duration of DAPT (aspirin + clopidogrel): >12 months or ≤12 months (Figure 1). As regulatory authorities require written informed consent for coronary intervention studies using the KOMATE registry, we obtained written informed consent from each patient. The institutional review boards of each hospital that contributes data to the COBIS II registry, which is funded by the Korean Society of Interventional Cardiology, approved the study protocol and waived the requirement for informed consent. All patients received loading doses of aspirin (300 mg/day) and clopidogrel (300 or 600 mg) before PCI. Aspects of access location, stent strategy, stent technique, and use of intravascular ultrasound were left to the operator’s discretion. The stent type according to stent generation was the same as that in a previous study.8 The duration of DAPT was left to the operator’s discretion. A 12-month duration of DAPT was defined as 2 months of DAPT before and 12 months of DAPT after the index procedure. New P2Y12 receptor inhibitors were not available during the study period in Korea. Clinical, angiographic, procedural, and outcome data were collected using a web-based reporting system. To identify the status of antiplatelet therapy, the dates and duration of prescribed antiplatelet agents were obtained from the electronic prescribing system of each hospital. Additional information was obtained by further inquiry into medical records or telephone contact, if necessary. An independent clinical event adjudicating committee reviewed all data on outcomes reported by participating centers. Patient in both registries received clinical follow up for up to 5 years (median, 1,526 days; interquartile range [IQR], 881 days).
4
Our primary endpoint was major adverse cardiovascular events (MACEs), defined as a composite of cardiac death, fatal or nonfatal acute MI, stroke, and ST, at 5 years after the index procedure. The secondary endpoint was all-cause death. Fatal or nonfatal acute MI was defined as an increase in the creatine kinase-myocardial band or troponin levels to the 99th percentile of the upper limit of normal with ischemic symptoms or electrocardiographic findings indicative of ischemia not related to the index procedure. ST was defined as definite ST according to the Academic Research Consortium definition. A major bleeding event was defined as severe or life-threatening bleeding by Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) bleeding criteria. Only the KOMATE registry was used to analyze bleeding events, because these events are not fully reported in the COBIS II registry. Continuous variables are reported as a mean ± standard deviation (SD) and were analyzed using Student’s t-tests. Categorical variables are reported as frequencies (percentages) and were analyzed using Chi-square tests. Survival curves were developed using Kaplan-Meier analysis and were analyzed using log-rank tests. Cox proportional hazards models were utilized to identify independent predictors of primary endpoints and to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for clinical outcomes. Propensity score matching was applied to reduce selection bias associated with stent strategy and potential confounding factors and to adjust for significant differences in baseline patient characteristics or procedural data. Propensity scores were estimated using multiple logistic regression analysis. Included covariates were age, sex, hypertension, diabetes mellitus, ACS, multi-vessel disease, stent strategy, chronic kidney disease, dyslipidemia, smoking, and previous PCI. Patients were matched based on the closest possible propensity score value (i.e., nearest neighbor matching). A matching caliper of 0.05 SDs from the logit of the estimated propensity score was enforced to ensure that matches of poor fit were excluded. We then performed 1:1 5
propensity score-matching iteration. The linearity assumption between DAPT duration and clinical outcomes was explored using penalized spline functions, allowing 2 df.9 In subgroup analyses, tests of interaction were used to confirm differential clinical outcomes among groups. SPSS (version 24.0, Chicago, IL, USA) and SAS (version 9.3, Cary, NC) software were used to conduct all statistical analyses.
RESULTS Of the 1,142 patients, 769 patients received DAPT for >12 months, and 373 received DAPT for ≤12 months. The median durations of DAPT were 731 days (IQR, 845 days) for the entire population, 269.5 days (IQR, 170 days) for the DAPT ≤ 12 months population, and 875 days (IQR, 846 days) for the DAPT > 12 months population, respectively. Patient clinical characteristics were similar between the two groups, except for dyslipidemia and history of previous PCI (Table 1). A two-stent strategy and final kissing balloon inflation patients were significantly more likely to receive DAPT for >12 months (Table 2). After 1:1 matching between groups using propensity scores, there were no significant differences between the two groups (Supplemental Table S1). Clinical outcomes are summarized in Table 3. Five years after the index procedure, the DAPT >12 months group had a lower rate of MACEs than the DAPT ≤12 months group. The rate of all-cause death was lower in the >12 months group than in the ≤12 months group. The rates of cardiac death and MI were lower in the >12 months group than in the ≤12 months group. Rates of stroke and ST were similar between the two groups (Figure 2 and Table 3). After 1:1 matching using propensity scores, the >12 months group still had significantly lower rates of MACEs, all-cause death, and cardiac death than the ≤12 months group (Table 3). In the KOMATE registry, major bleeding events tended to be more likely in the >12 months group than in the ≤12 months group, although this difference was not statistically 6
significant (Supplementary Figure S1). Among patients with a DAPT score <2, there was no significant difference in MACE rate between DAPT >12 months and ≤12 months groups. However, among patients with a DAPT score ≥2, the DAPT >12 months group had a lower rate of MACEs than the DAPT ≤12 months group (Supplemental Figure S2). Among patients treated with early generation DESs (E-DES), those treated with DAPT >12 months had a lower rate of MACEs than those treated with DAPT ≤12 months. Among patients treated with current generation DESs (C-DES), the DAPT >12 months group tended to have a lower rate of MACEs than the DAPT ≤12 months group, although this difference was not statistically significant (Supplemental Figure S3). Among patients treated with a one-stent strategy, DAPT >12 months afforded a lower rate of MACEs than DAPT ≤12 months. This was similar with a two-stent strategy, wherein the DAPT >12 months group tended to have a lower rate of MACEs than the DAPT ≤12 months group, although this difference was not statistically significant (Supplemental Figure S4). Analyzing the risk of MACE according to DAPT duration as a continuous variable, the risk of MACE progressively decreased with a longer DAPT duration (Figure 3). Subgroup analysis results for MACE are presented in Figure 4. The rate of MACEs was consistently lower in the DAPT >12 months group than in the DAPT ≤12 months group across several subgroups. In particular, there was a significant interaction between the presence or absence of ACS and DAPT duration (p = 0.04). Use of DAPT for >12 months was an independent predictor of reduced MACEs (Table 4). The strongest predictors of MACEs were chronic kidney disease, age >75 years, and DAPT score ≥2.
DISCUSSION Our main findings were as follows: 1) DAPT for >12 months after an index procedure was associated with a reduced MACE rate among patients with LMCA bifurcation 7
stenting, compared with DAPT for ≤12 months; 2) among patients with DAPT scores ≥2 or E-DESs, DAPT for >12 months reduced the MACE rate; and 3) DAPT for >12 months was an independent predictor of a reduced likelihood of MACEs. In recent studies, PCI with a DES for the treatment of LMCA bifurcation lesions has been shown to offer acceptable procedural and satisfactory long-term clinical outcomes.8,10,11 In real-world practice, patients receiving LMCA interventions frequently undergo multi-vessel complex PCI with a greater number of stents and longer stent lengths, compared with patients undergoing PCI for other coronary segments.12 However, there is a lack of evidence on the appropriate duration of DAPT for patients with LMCA bifurcation lesion stenting. In a post hoc patient-level pooled analysis of six randomized controlled trials including patients undergoing complex PCI, longer DAPT (≥1 year) was found to significantly reduce the risk of ischemic events, compared with shorter periods of DAPT (3 or 6 months). However, in this previous study, there were only 49 patients with LMCA among the 1,680 patients undergoing complex PCI.13 In the PROGIDY trial, which included 336 patients who underwent coronary stenting of the LMCA and/or proximal left anterior descending coronary artery, prolonged DAPT (≥24 months) provided consistent benefits over shorter DAPT (6 months).14 In the present study, 5 years after PCI, the DAPT >12 months group had lower rates of MACEs, all-cause death, cardiac death, and MI than the DAPT ≤12 months group. The MACE rate consistently decreased with prolongation of the DAPT duration. A previous study reported that patients with complex target-lesion anatomy, including a LMCA bifurcation lesion, had a higher rate of ischemic events than patients without complex target-lesion anatomy. Another study showed that a high DAPT score in patients with or without complex anatomy is suggestive of a likelihood of benefiting from extended DAPT.6 In the present study, DAPT >12 months afforded a lower MACE rate than DAPT ≤12 months among patients with a DAPT score ≥2 but not those with a DAPT score <2. Despite several 8
validation studies of DAPT score in various cohorts and clinical settings, its usefulness is still under debate. In a Japanese population including 407 LMCA stenting patients, the cumulative 3-year incidence of MI and ST at 13 months after PCI was significantly higher among patients with a high DAPT score (≥2) than among those with a low DAPT score (<2).15 However, a recent study using data from the SWEDEHEART registry reported that DAPT score was a poor discrimination factor for ischemic risk16. Further studies will be needed to determine the optimal DAPT duration using a scoring system that predicts ischemic risk, including DAPT score, in more patients with LMCA bifurcation stenting. Although E-DESs are no longer implanted, patients who have received E-DESs are still followed up in real-world practice. Moreover, components of DAPT score include whether PESs are deployed. In the present study, 58.3% of patients received E-DESs (e.g., SES or PES). Within the E-DES population, MACE rate was lower in the DAPT >12 months group than in the DAPT ≤12 months group. For contrast, in the EXCEL trial, continuation of DAPT beyond 1 year was not associated with improved event (death, MI or stroke)-free survival after PCI with everolimus-eluting stents in patients with LMCA disease. 17 In present study, within the C-DES population, the MACE rate was similar between two DAPT groups. Thus, our results suggest that longer use of DAPT should be considered in patients who present with a DAPT score ≥2 or have received an E-DES. Future studies are required to determine the optimal DAPT duration in LMCA bifurcation lesion patients with a C-DES. LMCA bifurcation lesions are complex and indicated high risk PCI lesion subsets due to very large diameter left main and large side branch left circumflex artery. Therefore, stent strategy, stent optimization technique (final kissing balloon inflation [FKBI], proximal optimization [POT]) and device (intravascular ultrasound [IVUS]) have a significant effect on clinical outcomes. However, there were few studies with DAPT duration and stent strategies and techniques in LMCA bifurcation stenting patients. In our study, extended use of 9
DAPT reduced MACE rate in both 1- and 2-stent strategies. Although our study mainly used the 1-stent strategy, the extended DAPT may have influenced the clinical outcomes because of relatively low implement of stent optimization such as use of IVUS or kissing ballooning as well as considerable amount of stent metal across the ostium of the side branch as a nidus of thrombus and flow barrier to left circumflex artery. Further studies will be needed to determine how different DAPT duration affect clinical outcomes with the optimal stent strategies and techniques. The present study has some limitations. First, as patients were not randomized into groups, selection bias might have affected the results. Second, bleeding events are not fully reported in the COBIS II registry. Also, we could not investigate bleeding risk score, such as PRECISE-DAPT score. Extended DAPT might increase the risk of fatal or major bleeding, which could offset benefits from reducing ischemic events. However, all-cause mortality was significantly lower in the DAPT >12 months group than in the DAPT ≤12 months group in our results. Therefore, a reduction of ischemic events due to extended DAPT could be beneficial despite an increase in bleeding events. Further studies should include more patients to adequately investigate bleeding events and bleeding risk score during long-term follow-up. Third, the small number of C-DES patients included in this study limits the determination of the optimal DAPT duration for this population. Fourth, we did not include data on oral anticoagulation agents or new P2Y12 inhibitors, such as ticagrelor and prasugrel. Fifth, our sample size was too small to evaluate low frequency events despite using two of the largest data registries available. In conclusion, using data from two large multicenter registries, KOMATE and COBIS II, we found that extended DAPT is associated with a reduced rate of MACEs among patients with LMCA bifurcation stenting. ACKNOWLEDGEMENTS: None Disclosures: The authors have no conflicts of interest to disclose.
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FIGURE LEGENDS Figure 1. Overview of study scheme. KOMATE = Korean Multicenter Angioplasty Team, COBIS = Coronary Bifurcation Stenting, DAPT = dual antiplatelet therapy, LMCA = left main coronary artery
Figure 2. Kaplan-Meier curves for MACE, all-cause death, cardiac death, and MI after DAPT >12 months versus DAPT ≤ 12 months. Cumulative incidence of MACEs (A), all-cause death (B), cardiac death (C), and MI (D). DAPT = dual antiplatelet therapy, MACE = major adverse cardiovascular event, MI = myocardial infarction; HR = hazard ratio, CI = confidence interval
Figure 3. Spline curves of HRs for MACE according to DAPT duration modeled as a continuous variable. HR = hazard ratio, DAPT = dual antiplatelet therapy, MACE = major adverse cardiovascular event
Figure 4. Subgroup analysis. DAPT = dual antiplatelet therapy, ACS = acute coronary syndrome, DM = diabetes mellitus, CKD = chronic kidney disease, C-DES = current generation drug-eluting stent, IVUS = intravascular ultrasound
15
Table 1. Patient Clinical, Angiographic, and Procedural Characteristics Variable
Entire
>12 DAPT
DAPT
population (N = months
(N = months
≤12 p-value (N =
1,142)
769)
373)
Age (years)
63.03 ± 10.25
62.63 ± 10.21
63.86 ± 10.28
0.06
Men
852 (74.6%)
571 (74.3%)
281 (75.3%)
0.69
DAPT duration
900 ± 662
1,102 ± 462
314 ± 138
<0.0001
DAPT score
0.62 ± 1.18
0.64 ± 1.17
0.58 ± 1.19
0.43
SYNTAX score
22.59 ± 8.47
22.39 ± 8.45
22.99 ± 8.51
0.26
ACS
567 (49.6%)
397 (51.6%)
170 (45.6%)
0.06
Multi-vessel
710 (62.2%)
471 (61.2%)
239 (64.1%)
0.36
Smoking
376 (32.9%)
253 (32.9%)
123 (33%)
0.98
DM
369 (32.3%)
246 (32%)
123 (33%)
0.74
Hypertension
685 (60%)
467 (60.7%)
218 (58.4%)
0.46
CKD
40 (3.5%)
28 (3.6%)
12 (3.2%)
0.72
Old CVA
110 (9.6%)
76 (9.9%)
34 (9.1%)
0.68
Dyslipidemia
507 (44.4%)
316 (41.1%)
191 (51.2%)
0.001
Previous PCI
234 (20.5%)
170 (22.1%)
64 (17.2%)
0.05
Previous
40 (3.5%)
25 (3.3%)
15 (4%)
0.51
55.9 ± 19.3
55.9 ± 19.2
56.1 ± 19.5
0.87
(days)
disease
CABG LVEF
Values are n (%) or mean ± SD. DAPT = dual antiplatelet therapy; ACS = acute coronary syndrome; DM = diabetes mellitus; CKD = chronic kidney disease; CVA = cerebrovascular accident; PCI = percutaneous coronary intervention; CABG = coronary bypass graft; LVEF = left ventricular ejection fraction
16
Table 2. Patient Angiographic and Procedural Characteristics Variable
True bifurcation
Entire population
DAPT > 12 months
DAPT ≤ 12 months
(N = 1,142)
(N = 769)
(N = 373)
454 (39.8%)
294 (38.2%)
160 (42.9%)
p-value
0.13 0.08
Medina 1,1,1
334 (29.2%)
218 (28.3%)
116 (31.1%)
1,0,1
63 (5.5%)
41 (5.3%)
22 (5.9%)
0,1,1
57 (5.0%)
35 (4.6%)
22 (5.9%)
1,0,0
124 (10.9%)
95 (12.4%)
29 (7.8%)
1,1,0
294 (25.7%)
187 (24.3%)
107 (28.7%)
0,1,0
222 (19.4%)
156 (20.3%)
66 (17.7%)
0,0,1
48 (4.2%)
37 (4.8%)
11 (2.9%) <0.0001
Stent type SES
486 (42.6%)
391 (50.8%)
95 (25.5%)
PES
179 (15.7%)
128 (16.6%)
51 (13.7%)
EES
246 (21.5%)
140 (18.2%)
106 (28.4%)
ZES
157 (13.7%)
85 (11.1%)
72 (19.3%)
BES
74 (6.5%)
25 (3.3%)
49 (13.1%) <0.0001
Stent technique 1-stent strategy
838 (73.4%)
535 (69.6%)
303 (81.2%)
2-stent strategy
304 (26.6%)
234 (30.4%)
70 (18.8%)
T-stenting
109 (9.5%)
86 (11.2%)
23 (6.2%)
Crush
129 (11.3%)
102 (13.3%)
27 (7.2%)
Kissing or V stent
11 (1%)
9 (1.2%)
2 (0.5%)
Culottes
48 (4.2%)
34 (4.4%)
14 (3.8%)
Others
7 (0.6%)
3 (0.3%)
4 (1.1%)
Kissing
495 (43.3%)
365 (47.5%)
130 (34.9%)
<0.0001
IVUS
659 (57.7%)
440 (57.2%)
219 (58.7%)
0.63
Values are n (%) or mean ± SD. True bifurcation = Medina classification type 1,1,1, 1,0,1, or 0,1,1; DAPT = dual antiplatelet therapy; SES = sirolimus-eluting stent; PES = paclitaxeleluting stent; ZES-S = zotarolimus-eluting stent-SPLINT; EES = everolimus-eluting stent; ZES-R = zotarolimus-eluting stent-RESOLUTE; BES = biolimus-eluting stent; IVUS = intravascular ultrasound 17
Table 3. Hazard Ratios for DAPT Duration and Clinical Outcomes Variable
DAPT >12
DAPT ≤12
Unadjusted
months (N =
months (N =
HR (95%
769)
373)
CI)
p-value
Adjusted HR p-value
Propensity
(95% CI)
score-
p-value
matched HR (95% CI)
MACE
18 (2.3%)
20 (5.4%)
All-cause
24 (3.1%)
23 (6.2%)
0.43 (0.23–
0.01
0.37 (0.19–
0.81)
0.71) 0.02
0.42 (0.24-
0.89)
death Cardiac
0.5 (0.28-
6 (0.8%)
11 (2.9%)
0.26 (0.1–
0.01
0.19 (0.07–
MI
9 (1.2%)
10 (2.7%)
Stroke
9 (1.2%)
5 (1.3%)
0.42 (0.17–
0.37 (0.15–
1.04) 0.87 (0.29–
1.38 (0.46–
2.59) ST
3 (0.4%)
3 (0.8%)
0.47 (0.1–
0.001
0.49 (0.24-
0.05
0.17 (0.04-
0.02
0.79) 0.03
0.92) 0.8
0.01
1.0)
0.51) 0.06
0.25 (0.10.68)
0.003
0.75)
0.7)
death
0.003
0.39 (0.12-
0.11
1.23) 0.57
0.5 (0.09-2.7)
0.42
4.19) 0.36
0.34 (0.06–
2.34)
0.21
1.84)
Values are n (%) or mean ± SD. HR = hazard ratio; CI = confidence interval; DAPT = dual antiplatelet therapy; MACE = major adverse cardiovascular event; MI = myocardial infarction; ST = stent thrombosis
1
Table 4. Independent Predictors of Clinical Outcomes Univariate analysis
Multivariate analysis
Variable
HR (95% CI)
p-value
HR (95% CI)
p-value
Age >75 years
3.5 (1.7–7.2)
0.001
3.58 (1.63–7.87)
0.002
DAPT >12 months
0.43 (0.23–0.81)
0.01
0.34 (0.17–0.67)
0.002
DAPT score ≥2
2.17 (1.08–4.35)
0.03
2.76 (1.33–5.7)
0.01
CKD
6.87 (3.03–15.61)
<0.0001
6.85 (2.83–16.61)
<0.0001
2-stent strategy
0.92 (0.43–1.94)
0.82
Male
1.13 (0.54–2.39)
0.74
ACS
2.32 (1.17–4.61)
0.02
Multi-vessel disease
1.43 (0.71–2.88)
0.32
DM
1.26 (0.65–2.43)
0.5
Hyptertension
1.29 (0.66–2.53)
0.45
Previous PCI
1.58 (0.78–3.19)
0.2
Previous CABG
1.51 (0.36–6.27)
0.57
IVUS
0.67 (0.36–1.27)
0.22
Table 4. Independent Predictors of Clinical Outcomes MACE = major adverse cardiovascular event; HR = hazard ratio; CI = confidence interval; DAPT = dual antiplatelet therapy; CKD = chronic kidney disease; ACS = acute coronary syndrome; DM = diabetes mellitus; PCI = percutaneous coronary intervention; CABG = coronary artery bypass graft; IVUS = intravascular ultrasound
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Figure 1
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Figure 2
3
Figure 3
4
Figure 4
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