Abstract
Background
It remains unclear whether P2Y12 monotherapy, especially clopidogrel, following short-duration dual antiplatelet therapy (DAPT) is associated with favorable outcomes in patients undergoing complex percutaneous coronary intervention (PCI). Therefore, this study analyzed the efficacy and safety of P2Y12 inhibitor monotherapy, mostly clopidogrel (78%), in complex PCI following short-term DAPT.
Methods
The post-hoc analysis of the SMART-CHOICE trial involving 2,993 patients included 498 cases of complex PCIs, defined by at least one of the following features: 3 vessels treated, ≥ 3 stents implanted, ≥ 3 lesions treated, bifurcation with ≥ 2 stents implanted, and a total stent length of ≥ 60 mm. The primary endpoint was major adverse cardiac and cerebrovascular event (MACCE), defined as the composite of all-cause death, myocardial infarction, and stroke. The primary safety endpoint included bleeding, defined as Bleeding Academic Research Consortium (BARC) types 2 to 5.
Results
Complex PCI group had a higher risk of MACCE (4.0% vs. 2.3%, hazard ratio [HR] = 1.74, 95% confidence interval [CI]: 1.05–2.89, p = 0.033) and a similar risk of BARC types 2–5 bleeding (2.6% vs. 2.6%, HR = 1.02, 95% CI: 0.56–1.86, p = 0.939) compared with those without complex PCIs. Patients undergoing complex PCIs, followed by P2Y12 inhibitor monotherapy and 12 months of DAPT exhibited similar rates of MACCE (3.8% vs. 4.2%, HR = 0.92, 95% CI: 0.38–2.21, p = 0.853).
Conclusions
P2Y12 inhibitor monotherapy, mostly clopidogrel, following 3 months of DAPT did not increase ischemic events in patients with complex PCIs.
Keywords: clopidogrel, high-risk, percutaneous coronary intervention
Introduction
With the development of new-generation drug-eluting stents (DES), several studies including GLOBAL-LEADERS, TWILIGHT, TICO, and the SMART-CHOICE trial have reported the safety and effectiveness of P2Y12 monotherapy following short-term dual antiplatelet therapy (DAPT) [1–4]. However, short-term DAPT therapy in complex percutaneous coronary intervention (PCI) remains a concern. The concept of complex PCI has been recently proposed [5]. However, there is currently no universal definition of a complex PCI. In general, complex PCI includes bifurcation with 2 stent implants, ≥ 3 stents implanted, ≥ 3 lesions treated, and total stent length ≥ 60 mm or stent with chronic total occlusion lesions [6]. Patients with complex PCIs carry a higher risk of ischemic adverse events that is proportional to their burden and severity of coronary artery disease [7], and require longer DAPT to prevent ischemic events [8]. Although prolonged DAPT is associated with a potential benefit in preventing ischemic events, it also increases bleeding risk, which is correlated with the morbidity and mortality of patients [9]. Sub-group analyses of complex PCI focusing on monotherapy with ticagrelor, but not clopidogrel which is used more in real-world practice showing favorable ischemic outcomes [6, 10].
The aim of this present sub-study of the SMART-CHOICE trial was to investigate the effectiveness and safety of P2Y12 inhibitor monotherapy, mostly clopidogrel (78%), following short-term DAPT in patients with complex PCI compared with 12 months of DAPT.
Methods
Study design
This study involved a post-hoc analysis of the SMART-CHOICE trial, a multicenter, prospective open-label randomized clinical trial (NCT02079194). The study design and protocol have been reported in detail elsewhere [2]. In brief, the trial randomly assigned patients to two groups before PCI: (i) 3 months of DAPT (acetylsalicylic acid [ASA] and a P2Y12 inhibitor), followed by 9 months of P2Y12 inhibitor monotherapy, and (ii) 12 months of DAPT. The trial was designed and coordinated by the Academic Clinical Research Organization of Samsung Medical Center (Seoul, Korea). The trial randomized a total of 2,993 patients at 33 hospitals. This trial was approved by the Institutional Review Board of each center. The study followed the ethical principles of the Declaration of Helsinki. All patients provided written informed consent before participating in the trial. Patients and the public were not involved in the design of conduct in this research.
Study proceedings
In the present analysis, complex PCI was defined by at least one of the following angiographic characteristics: 3 vessels treated, ≥ 3 stents implanted, ≥ 3 lesions treated, bifurcation PCI with ≥ 2 stents, and a total stent length of ≥ 60 mm. These five high-risk features of complex percutaneous procedures for ischemic events have been reported in previous studies [10].
Study endpoints
The primary efficacy endpoint included major adverse cardiac and cerebrovascular event (MACCE) defined as a composite of all-cause death, myocardial infarction (MI), and stroke at 1 year after the index procedure. The primary safety endpoint was bleeding defined as Bleeding Academic Research Consortium (BARC) types 2 to 5 at 12 months after the index procedure.
Definitions
Unless a definite noncardiac cause could be established, cardiac disease was assumed as the default cause of death. Myocardial infarction was defined as elevated cardiac enzyme levels (cardiac troponin or myocardial band fraction of creatine kinase) above the upper reference limits with ischemic symptoms or electrocardiographic findings indicative of ischemia. However, periprocedural enzyme elevations within 48 hours after the index procedure without concomitant ischemic symptoms or electrocardiographic findings indicative of ischemia were excluded from the endpoint assessment. Stroke was defined as any nonconvulsive focal or global neurologic deficit of abrupt onset lasting more than 24 hours or leading to death caused by cerebral ischemia or hemorrhage. Stent thrombosis was defined as definite or probable type according to the Academic Research Consortium classification [11]. Major bleeding was defined as BARC types 3, 4, and 5 [12].
Statistical analysis
Categoric variables are presented as numbers and percentages and were compared using the χ2 test or the Fisher exact test. Continuous variables are presented as the mean ± standard deviation and compared using the Student t-test. The cumulative incidence of clinical events up to 1 year was calculated using the Kaplan-Meier method and compared using the log-rank test. The hazard ratio (HR), with a 95% confidence interval (CI) was derived from a Cox regression model. Subgroup analyses of the outcomes were performed to evaluate the effects of P2Y12 inhibitor monotherapy compared with DAPT using Cox regression models with tests for interaction. All tests were two-sided and a p-value of < 0.05 was considered statistically significant. All analyses were performed using R version 3.5.0 (R Foundation for Statistical Computing, Vienna, Austria).
Results
The SMART-CHOICE trial randomized a total of 2,993 patients including 498 treated with complex PCIs and 2,495 undergoing non-complex PCIs. The prevalence of complex PCI components in the overall population is shown in Figure 1. The baseline clinical and procedural characteristics according to PCI complexity are summarized in Table 1. Of the patients, 76.3% (380/498) who underwent complex PCIs and 83.8% (1961/2495) of those who underwent non-complex PCIs were exposed to clopidogrel-based therapy. Patients undergoing complex PCIs manifested higher rates of hypertension, diabetes mellitus, and chronic renal failure, but lower rate of prior revascularization, and low ejection fraction. Angiographically, the complex PCI group had more diseased, treated lesions, and total stents implanted, with increased usage of intravascular ultrasound.
Figure 1.
Prevalence of complex percutaneous coronary intervention components.
Table 1.
Baseline and procedural characteristics in patients according to percutaneous coronary intervention (PCI) complexity
| Complex PCI (n = 498) | Non-complex PCI (n = 2495) | P value | |
|---|---|---|---|
| Age [years] | 64.4 ± 10.7 | 64.5 ± 10.7 | 0.755 |
| Male | 376 (75.5%) | 1822 (73.0%) | 0.220 |
| Body mass index | 24.7 ± 3.1 | 24.6 ± 3.1 | 0.340 |
| Hypertension | 340 (68.3%) | 1500 (60.1%) | 0.001 |
| Diabetes mellitus | 218 (43.8%) | 904 (36.3%) | 0.002 |
| Dyslipidemia | 222 (44.6%) | 1130 (45.5%) | 0.767 |
| Current smoking | 127 (25.5%) | 664 (26.7%) | 0.630 |
| Prior myocardial infarction | 18 (3.6%) | 109 (4.4%) | 0.520 |
| Prior revascularization | 44 (8.8%) | 305 (12.2%) | 0.037 |
| Prior stroke | 41 (8.2%) | 160 (6.4%) | 0.168 |
| Chronic renal failure | 28 (5.6%) | 69 (2.8%) | 0.002 |
| LVEF [%] | 58.1 ± 11.9 | 60.3 ± 10.5 | < 0.001 |
| Acute coronary syndrome | 288 (57.8%) | 1453 (58.3%) | 0.891 |
| Shorter DAPT | 260 (52.2%) | 1235 (49.5%) | 0.350 |
| Clopidogrel based therapy | 380 (76.3%) | 1961 (83.8%) | 0.258 |
| Procedural characteristics | |||
| No. of diseased lesion/patient | 2.39 ± 0.85 | 1.23 ± 0.47 | < 0.001 |
| No. of lesions stented/patient | 2.37 ± 0.78 | 1.18 ± 0.38 | < 0.001 |
| No. of stents implanted/patient | 2.75 ± 0.78 | 1.22 ± 0.43 | < 0.001 |
| Target vessels: | |||
| Left main | 9 (1.8%) | 49 (2.0%) | 0.957 |
| Left anterior descending | 382 (76.7%) | 1471 (59.0%) | < 0.001 |
| Left circumflex | 235 (47.2%) | 540 (21.6%) | < 0.001 |
| Right coronary | 313 (62.9%) | 735 (29.5%) | < 0.001 |
| Trans radial approach | 367 (73.7%) | 1815 (72.7%) | 0.704 |
| Use of IVUS | 156 (31.5%) | 622 (25.0%) | 0.004 |
DAPT — dual antiplatelet therapy; IVUS — intravascular ultrasound; LVEF — left ventricular ejection fraction
At 1 year, the patients who underwent complex PCIs carried higher rates of MACCE (4.0% vs. 2.3%, HR = 1.74, 95% CI: 1.05–2.89, p = 0.033), all-cause death (2.6% vs. 1.0%, HR = 2.52, 95% CI: 1.30–4.90, p = 0.007), cardiac death (1.6% vs. 0.6%, HR = 2.51, 95% CI: 1.08–5.88, p = 0.033), and stent thrombosis (0.6% vs. 0.1%, HR = 7.53, 95% CI: 1.26–45.06, p = 0.027). However, BARC bleeding types 2–5 showed similar rates (2.6% vs. 2.6%, HR = 1.02, 95% CI: 0.56–1.86, p = 0.939) in the complex and non-complex PCI groups (Table 2, Fig. 2).
Table 2.
Clinical outcomes in patients according to percutaneous coronary intervention (PCI) complexity.
| Complex PCI (n = 498) | Non-complex PCI (n = 2495) | Univariate hazard ratio | P value | |
|---|---|---|---|---|
| MACCE | 20 (4.0%) | 58 (2.3%) | 1.74 (1.05–2.89) | 0.033 |
| Bleeding BARC type 2–5 | 13 (2.6%) | 64 (2.6%) | 1.02 (0.56–1.86) | 0.939 |
| All death: | 13 (2.6%) | 26 (1.0%) | 2.52 (1.30–4.90) | 0.007 |
| Cardiac death | 8 (1.6%) | 16 (0.6%) | 2.51 (1.08–5.88) | 0.033 |
| Non-cardiac death | 5 (1.0%) | 10 (0.4%) | 2.52 (0.86–7.38) | 0.091 |
| Myocardial infarction | 6 (1.2%) | 22 (0.9%) | 1.38 (0.56–3.40) | 0.487 |
| Stroke | 3 (0.6%) | 13 (0.5%) | 1.16 (0.33–4.07) | 0.816 |
| Stent thrombosis | 3 (0.6%) | 2 (0.1%) | 7.53 (1.26–45.06) | 0.027 |
| Major bleeding* | 2 (0.4%) | 24 (1.0%) | 0.42 (0.10–1.77) | 0.236 |
BARC type 3 to 5 bleeding;
BARC — Bleeding Academic Research Consortium; MACCE — major adverse cardiac and cerebrovascular event
Figure 2.
Cumulative incidence of events at 1 year on crude analysis according to complex and non-complex percutaneous coronary interventions (PCI); A. Major adverse cardiovascular and cerebrovascular events (MACCE); B. Bleeding Academic Research Consortium (BARC) types 2–5; CI — confidence interval; HR — hazard ratio.
Baseline characteristics according to the antiplatelet regimen used in patients with complex and non-complex PCIs are presented in Table 3. No significant differences were found in any variables. The effects of DAPT and P2Y12 inhibitor monotherapy in the complex and non-complex PCI groups are presented in Table 4 and Figure 3. In non-complex PCI, P2Y12 monotherapy showed similar MACCE rates (2.6% vs. 2.1%; HR = 1.27; 95% CI: 0.76–2.14; p = 0.359) and significantly lower BARC 2–5 bleeding rates (1.9% vs. 3.3%; HR = 0.57; 95% CI: 0.34–0.96; p = 0.033) compared with the DAPT group. Similar MACCE rates were found among patients exposed to P2Y12 inhibitor monotherapy and DAPT (3.8% vs. 4.2%; HR = 0.92; 95% CI: 0.38–2.21; p = 0.853). P2Y12 monotherapy was associated with lower BARC 2–5 bleeding rates compared with the DAPT group without statistical significance (1.9% vs. 3.4%; HR = 0.58; 95% CI: 0.19–1.77; p = 0.340). The interaction was not statistically significant between complex and non-complex PCI groups with MACCE (interaction p = 0.483) and BARC bleeding types 2–5 (interaction p = 0.904).
Table 3.
Baseline and procedural characteristics stratified according to percutaneous coronary intervention (PCI) complexity and randomized regimen.
| Complex PCI (n = 498) | Non-complex PCI (n = 2495) | |||||
|---|---|---|---|---|---|---|
|
|
|
|||||
| P2Y12 monotherapy (n = 260) | DAPT (n = 238) | P | P2Y12 monotherapy (n = 1235) | DAPT (n = 1260) | P | |
| Age [years] | 64.7 ± 10.5 | 64.0 ± 10.9 | 0.458 | 64.6 ± 10.8 | 64.4 ± 10.6 | 0.695 |
| Male | 191 (73.5%) | 185 (77.7%) | 0.316 | 896 (72.6%) | 926 (73.5%) | 0.628 |
| Body mass index | 24.6 ± 3.3 | 24.8 ± 2.9 | 0.680 | 24.5 ± 3.1 | 24.7 ± 3.2 | 0.101 |
| Hypertension | 177 (68.1%) | 163 (68.5%) | 0.978 | 744 (60.3%) | 756 (60.0%) | 0.914 |
| Diabetes mellitus | 119 (45.8%) | 99 (41.6%) | 0.397 | 451 (36.6%) | 453 (36.0%) | 0.766 |
| Dyslipidemia | 115 (44.2%) | 107 (45.0%) | 0.942 | 558 (45.3%) | 572 (45.7%) | 0.904 |
| Current smoking | 67 (25.8%) | 60 (25.2%) | 0.968 | 357 (29.0%) | 307 (24.4%) | 0.072 |
| Prior myocardial infarction | 9 (3.5%) | 9 (3.8%) | 0.987 | 53 (4.3%) | 56 (4.4%) | 0.929 |
| Prior revascularization | 19 (7.3%) | 25 (10.5%) | 0.272 | 153 (12.4%) | 152 (12.1%) | 0.840 |
| Prior stroke | 22 (8.5%) | 19 (8.0%) | 0.975 | 77 (6.2%) | 83 (6.6%) | 0.789 |
| Chronic renal failure | 16 (6.2%) | 12 (5.0%) | 0.731 | 28 (2.3%) | 41 (3.3%) | 0.168 |
| LVEF [%] | 58.3 ± 10.9 | 57.9 ± 11.6 | 0.657 | 60.2 ± 10.1 | 60.2 ± 9.8 | 0.950 |
| Acute coronary syndrome | 142 (54.6%) | 146 (61.3%) | 0.153 | 728 (58.9%) | 725 (57.6%) | 0.163 |
| Clopidogrel based therapy | 198 (76.2%) | 182 (76.5%) | 0.934 | 967 (78.3%) | 994 (78.9%) | 0.720 |
| Procedural characteristics | ||||||
| No. of diseased lesion/patient | 2.39 ± 0.95 | 2.39 ± 0.79 | 0.336 | 1.23 ± 0.40 | 1.23 ± 0.51 | 0.307 |
| No. of lesions stented/patient | 2.37 ± 0.58 | 2.37 ± 0.91 | 0.144 | 1.18 ± 0.41 | 1.18 ± 0.36 | 0.381 |
| No. of stents implanted/patient | 2.75 ± 0.82 | 2.75 ± 0.71 | 0.347 | 1.22 ± 0.41 | 1.22 ± 0.45 | 0.662 |
| Target vessels: | ||||||
| Left main | 5 (1.9%) | 4 (1.7%) | 0.419 | 20 (1.6%) | 29 (2.3%) | 0.279 |
| Left anterior descending | 193 (74.2%) | 189 (79.4%) | 0.208 | 710 (57.5%) | 761 (60.4%) | 0.151 |
| Left circumflex | 123 (47.3%) | 112 (47.1%) | 0.853 | 276 (22.3%) | 264 (21.0%) | 0.425 |
| Right coronary | 156 (60.0%) | 157 (66.0%) | 0.199 | 368 (29.8%) | 367 (29.1%) | 0.746 |
| Trans radial approach | 191 (73.5%) | 176 (73.9%) | 0.983 | 900 (72.9%) | 915 (72.6%) | 0.922 |
| Use of IVUS | 82 (31.7%) | 74 (31.2%) | 0.954 | 290 (23.6%) | 332 (26.4%) | 0.110 |
DAPT — dual antiplatelet therapy; IVUS — intravascular ultrasound; LVEF — left ventricular ejection fraction
Table 4.
Comparison of clinical outcomes in patients stratified according to percutaneous coronary intervention (PCI) complexity and randomized regimen.
| Percent (number) | Hazard ratio | P value | Interaction p | ||
|---|---|---|---|---|---|
|
| |||||
| P2Y12 monotherapy | DAPT | ||||
| MACCE: | |||||
| Complex | 3.8% (10/260) | 4.2% (10/238) | 0.92 (0.38–2.21) | 0.853 | 0.483 |
| Non-complex | 2.6% (32/1235) | 2.1% (26/1260) | 1.27 (0.76–2.14) | 0.359 | |
| Bleeding BARC type 2–5: | |||||
| Complex | 1.9% (5/260) | 3.4% (8/238) | 0.58 (0.19–1.77) | 0.340 | 0.904 |
| Non-complex | 1.9% (23/1235) | 3.3% (41/1260) | 0.57 (0.34–0.96) | 0.033 | |
| All death: | |||||
| Complex | 3.1% (8/260) | 2.1% (5/238) | 1.48 (0.48–4.51) | 0.494 | 0.646 |
| Non-complex | 1.1% (13/1235) | 1.0% (13/1260) | 1.03 (0.48–2.22) | 0.942 | |
| Cardiac death: | |||||
| Complex | 1.9% (5/260) | 1.3% (3/238) | 1.54 (0.37–6.42) | 0.557 | 0.671 |
| Non-complex | 0.5% (6/1235) | 0.8% (10/1260) | 0.62 (0.23–1.70) | 0.351 | |
| Non-cardiac death: | |||||
| Complex | 1.2% (3/260) | 0.8% (2/238) | 1.39 (0.23–8.31) | 0.719 | 0.210 |
| Non-complex | 0.6% (7/1235) | 0.2% (3/1260) | 2.40 (0.62–9.27) | 0.205 | |
| Myocardial infarction: | |||||
| Complex | 0.8% (2/260) | 1.7% (4/238) | 0.46 (0.09–2.53) | 0.375 | 0.306 |
| Non-complex | 0.7% (9/1235) | 1.0% (13/1260) | 0.71 (0.31–1.67) | 0.438 | |
| Stroke: | |||||
| Complex | 0% (0/260) | 1.3% (3/238) | 0.01 (0.01–153.1) | 0.369 | 0.126 |
| Non-complex | 0.9% (11/1235) | 0.2% (2/1260) | 5.69 (1.26–25.67) | 0.024 | |
| Stent thrombosis: | |||||
| Complex | 0.8% (2/260) | 0.4% (1/238) | 1.82 (0.17–20.11) | 0.624 | 0.320 |
| Non-complex | 0.1% (1/1235) | 0.1% (1/1260) | 1.02 (0.06–16.36) | 0.987 | |
| Major bleeding: | |||||
| Complex | 0% (0/260) | 0.8% (2/238) | 0.01 (0.01–125.1) | 0.464 | 0.721 |
| Non-complex | 1.0% (12/1235) | 1.0% (12/1260) | 1.03 (0.46–2.30) | 0.939 | |
BARC — Bleeding Academic Research Consortium; DAPT — dual antiplatelet therapy; MACCE — major adverse cardiac and cerebrovascular event
Figure 3.
Cumulative incidence of events at 1 year after randomization according to randomization group (dual antiplatelet therapy [DAPT] vs. P2Y12 monotherapy) in subjects with and without complex percutaneous coronary interventions (PCI); A. Major adverse cardiovascular and cerebrovascular events (MACCE); B. Bleeding Academic Research Consortium (BARC) types 2–5; CI — confidence interval; HR — hazard ratio.
Discussion
The current study compared the clinical outcomes of patients treated with P2Y12 inhibitor monotherapy, mostly clopidogrel, following 3 months of DAPT and 12 months of standard DAPT according to the PCI complexity. The findings of this study were as follows. First, patients undergoing complex PCIs carried a higher risk of ischemic and similar risk of bleeding events than those with non-complex PCIs. Second, patients with complex PCIs treated with P2Y12 inhibitor monotherapy, mostly clopidogrel, following short-term DAPT showed favorable ischemic outcomes comparable to those 12 months of DAPT.
Regarding new-generation DESs, compared with standard DAPT, patients treated with PCI undergoing P2Y12 inhibitor monotherapy following short-term DAPT showed non-inferior ischemic outcomes [2]. P2Y12 inhibitor monotherapy reduced the risk of bleeding compared with DAPT [13]. These results suggest that P2Y12 inhibitor monotherapy after short-term DAPT might be comparable to long-term DAPT for preventing ischemic events, with a lower risk of bleeding in patients undergoing PCIs with new-generation DESs. However, the risk-benefit profile of antiplatelet therapy regimens and their duration in patients with complex PCI remains disputed.
The concept of complex PCI has recently been proposed along with improvement in PCI techniques, adjunct pharmacological therapy, and the development of new-generation DES. However, currently, there is no universal definition of complex PCI in terms of angiographic or lesion characteristics. In the present study, the definition proposed by Serruys et al. [10], was used.
The study pooled patient-level data from 6 randomized controlled trials and compared long-term (≥ 12 months) and short-term (3 or 6 months) DAPT following ASA monotherapy in patients undergoing complex PCIs. The results showed that long-term DAPT significantly reduced MACCEs compared with short-term DAPT in the complex PCI group. That study also found that the benefit of long-term DAPT was increased additively with each increase in procedural complexity. However, the ischemic benefit of extended DAPT was offset by an increased risk of bleeding [14].
P2Y12 inhibitor monotherapy has been suggested as a new alternative antiplatelet strategy to ASA because it reduced the cardiovascular events and gastrointestinal bleeding [15]. Recently, 4 large randomized clinical trials showed favorable results with P2Y12 inhibitor monotherapy after short-term DAPT. Among them, sub-analyses of the Global Leaders and TWILIGHT trials showed efficacy and safety of ticagrelor monotherapy in complex PCI. A post-hoc study of the Global Leaders trial revealed that 23 months of ticagrelor monotherapy following 1 month of DAPT provided a net clinical benefit for patients with complex PCIs [10]. The post-hoc study of the TWILIGHT trial showed that ticagrelor monotherapy was associated with a lower incidence of bleeding without an increased risk of ischemic events compared with continuing ticagrelor plus ASA for 12 months among patients undergoing complex PCIs [6]. In contrast to the previous 2 sub-studies, the present study used P2Y12 inhibitor monotherapy, mostly clopidogrel, in more than three-quarters of the total study population following 3 months of DAPT. Although clopidogrel is most often used after PCI in real-world clinical practice, clopidogrel monotherapy may be inadequate in preventing ischemic events associated with complex PCIs due to less potency and wide individual variability of the drug response.
Although the current study involved only East Asians who carry a lower ischemic risk than Westerners, P2Y12 inhibitor monotherapy, mostly clopidogrel, did not increase the ischemic risk compared with 12 months of DAPT. However, patients with P2Y12 monotherapy carrying non-complex lesions showed significantly lower bleeding rates (1.9% vs. 3.3%; HR = 0.57, 95% CI: 0.34–0.96; p = 0.033) than patients with 12 months of DAPT, although the patients with complex PCIs did not show significantly lower bleeding rates (1.9% vs. 3.3%; HR = 0.58, 95% CI: 0.19–0.77; p = 0.340). The p-value for the interaction between the two treatment arms was close to one, which is thought to be a type II statistical error due to the small sample size, and P2Y12 monotherapy also might have a favorable effect on bleeding events in complex PCIs.
An expert consensus suggested that the selection and duration of the antiplatelet agents should be individualized by balancing ischemic and bleeding risks. Accordingly, three scoring systems were developed, including the PRECISE-DAPT score to facilitate the selection and duration of antiplatelet agents for patients with high bleeding risk (PRECISE-DAPT score ≥ 25) [16]. In a study of patients who underwent complex PCI and using PRECISE-DAPT score, the long-term DAPT was associated with net adverse clinical events (NACE) only if the bleeding risk was low (PRECISE-DAPT score < 25) and no ischemic benefit and significantly higher bleeding events in patients with high bleeding risk (PRECISE-DAPT score ≥ 25) [17]. In the present study of complex PCI stratified according to PRECISE-DAPT score, the high bleeding risk group was associated with higher rates of MACCE and NACE. In particular, the high bleeding risk group, unlike the low bleeding risk group, manifested fewer BARC type 2–5 bleeding events and a HR 0.35 in the P2Y12 monotherapy group, without statistical significance due to the possibility of type 2 error associated with small sample size (Suppl. Table 1). Another significant feature in this study was that intravascular ultrasound was used more in the complex PCI group, which may have affected lower ischemic events in the P2Y12 monotherapy group. Recently, the European Bifurcation Club proposed an algorithm for DAPT duration after PCI for bifurcation with a higher risk of both procedural and long-term adverse events. They proposed that decisions of DAPT duration should be based on the clinical presentation, bleeding risk, stenting strategy, and the possible use of intracoronary imaging. When confirming coronary imaging during PCI, the duration of DAPT should be reduced [18].
Limitations of the study
The present study has notable strengths associated with a well-randomized study design involving mainly clopidogrel but also had several limitations. First, the present study on complex PCI was not pre-specified in the protocol. Therefore, the current findings must only be interpreted as hypothesis-generating. Confirmatory randomized trials for complex PCI with proper antiplatelet therapy are still needed in the future. Second, the complexity of coronary anatomy and lesions were site-reported, not reviewed by an angiographic core laboratory. Thus, they might not have included all angiographic markers of lesion complexity or risk. Third, in bleeding events of complex PCI, P2Y12 inhibitor monotherapy resulted in fewer bleeding events without statistical significance due to type II error associated with a small sample size. Unfortunately, the advantage of P2Y12 monotherapy with fewer bleeding events in complex PCIs could not be established. Fourth, the study findings cannot be generalized to Western patients because all patients were East Asians who were relatively resistant to ischemic events but more susceptible to bleeding events.
Conclusions
In conclusion, compared with patients treated with non-complex PCIs, patients with complex PCIs carried a higher risk of ischemic events at 1 year. P2Y12 inhibitor monotherapy, mostly with clopidogrel, following 3 months of DAPT resulted in favorable ischemic events comparable to the standard 12 months of DAPT regimen for complex PCIs. These findings need to be considered as hypothesis-generating. This study should be viewed as a dedicated prospective trial of proper antiplatelet regimen for complex PCI.
Supplementary Information
Acknowledgments
All authors listed met the authorship requirements in the latest guidelines of the International Committee of Medical Journal Editors. All authors agreed with the publication of the manuscript.
Footnotes
Conflict of interest: Dr. Hahn reports receiving grants from Abbott Vascular, Boston Scientific, Biotronik, the Korean Society of Interventional Cardiology, and Medtronic; and speaker fees from AstraZeneca, Daiichi Sankyo, and Sanofi-Aventis. Dr. Gwon reports receiving research grants from Abbott Vascular, Boston Scientific, and Medtronic; and speaker fees from Abbott Vascular Boston Scientific, and Medtronic. All other authors declare that they have no conflicts of interest.
This article is accompanied by the editorial on page 804
Funding
This study was supported by unrestricted grants from the Korean Society of Interventional Cardiology (grant 2013-3), Abbott Vascular, Biotronik, and Boston Scientific.
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