Prognostic Implication of Platelet Reactivity According to Procedural Complexity After PCI

Background Complex percutaneous coronary intervention (C-PCI) and high platelet reactivity (HPR) have been proposed as representative risk factors for the high ischemic phenotype. Uncertainty remains regarding the relative prognostic importance of these factors. Objectives This study aimed to investigate the prognostic implication of HPR according to procedural complexity. Methods Patients treated with drug-eluting stent implantation (PTRG-PFT cohort; N = 11,714) were classified according to procedural complexity. HPR criteria were determined using VerifyNow (≥252 P2Y12 reaction units). The major adverse cardiac and cerebrovascular events (MACCE) (the composite of all-cause death, myocardial infarction, definite stent thrombosis, or stroke) and major bleeding were assessed for up to 3 years. Results C-PCI was performed in 3,152 patients (26.9%). C-PCI significantly increased the risk of MACCE (HRadjusted: 1.21; 95% CI: 1.01-1.44; P = 0.035), driven by a higher rate of all-cause death (HRadjusted: 1.45; 95% CI: 1.15-1.83; P = 0.002), although it did not increase the risk of major bleeding. Irrespective of procedural complexity, the HPR phenotype was significantly associated with MACCE (Pinteraction = 0.731) and all-cause mortality (Pinteraction = 0.978), in which the prognostic implication appeared prominent within 1 year. The HPR phenotype did not show a significant interaction with any type of C-PCI. In addition, the number of complexity features per procedure did not proportionally increase the risk of MACCE. Conclusions C-PCI was significantly associated with 3-year risk of MACCE and all-cause death. The HPR phenotype appears to have a similar prognostic implication irrespective of the type and extent of procedural complexity. (Platelet Function and Genotype-Related Long-Term Prognosis in DES-Treated Patients [PTRG-DES]; NCT04734028)

2][3][4][5] The first broadly used P2Y 12 inhibitor clopidogrel has considerable interindividual variation and achieves inadequate platelet inhibition in the majority of cases. 68][9] Therefore, addressing this issue is critical for high-risk patients, including those presenting with acute coronary syndrome (ACS).
The concept of complex PCI (C-PCI) has recently been proposed as a representative factor for high-risk cohorts. 10Increasing the atherosclerotic burden and complicated implementations of stent struts in diseased vessels can lead to potential interactions with blood risk factors such as platelet activation.Although the clinical application of potent P2Y 12 inhibition and/or a prolonged DAPT strategy 11 has been suggested to prevent the risk of atherothrombotic complications in patients treated with C-PCI, 12 there have been few dedicated prospective clinical trials in the current era of drug-eluting stents (DES).
The present analysis was performed to evaluate the impact of platelet reactivity on long-term clinical outcomes according to procedural complexity using data from a largescale real-world DES-treated cohort.PLATELET FUNCTION TEST.Platelet reactivity was measured after an adequate period to ensure a full antiplatelet effect, using the VerifyNow P2Y 12 assay (Accriva Diagnostics). 15The protocol followed the manufacturer's recommendations, with details described previously. 16PFT for clopidogrel responsiveness was performed after either: 1) 600-mg loading for at least 6 hours; 2) 300-mg loading for at least 12 hours; or 3) 75-mg maintenance for at least 5 days before PCI.If eptifibatide or tirofiban was used during PCI, a 24-hour washout period was required before VerifyNow testing.No patients receiving abciximab were enrolled due to the long washout period.

METHODS
On-clopidogrel platelet reactivity was reported in P2Y 12 reaction units (PRUs).We assessed PRUs as continuous and categorical measures.Additionally, the cutoff of HPR to adenosine diphosphate was defined as $252 PRU according to the time-dependent receiver-operating characteristic curve analysis for East Asian patients. 13FINITION OF COMPLEX PCI.In the present analysis, C-PCI was defined according to a modified version of previously published criteria, 3 which included PCI with at least 1 of the following characteristics: 1) 3 vessels treated; 2) $3 lesions treated; 3) $3 stents implanted; 4) total stent length >60 mm; 5) bifurcation with 2 stents implanted; 6) left main PCI; and 7) chronic total occlusion PCI.
CLINICAL OUTCOMES.The primary endpoint was the occurrence of major adverse cardiac and cerebrovascular events (MACCE) including all-cause death, nonfatal myocardial infarction (MI), definite stent thrombosis (ST), or nonfatal stroke during the 3-year follow-up period.The key secondary endpoints were all-cause death and major bleeding (Bleeding Academic Research Consortium [BARC] type 3-5). 17l deaths were considered to be due to cardiovascular causes unless a definite noncardiovascular cause could be established.MI was defined as increased cardiac troponin values with ischemic symptoms, or ischemic changes on electrocardiogram, or imaging evidence of recent loss of viable myocardium, or new regional wall motion abnormalities that were not related to the interventional procedure (type 4a). 13,18 (definite) was defined according to Academic Research Consortium criteria. 19Stroke was defined as evidence of neurological deficit requiring hospitalization and clinically documented lesions on brain computed tomography or magnetic resonance imaging.An independent clinical event committee masked to VerifyNow results adjudicated all clinical events using the original source documents.
STATISTICAL ANALYSIS.The Kolmogorov-Smirnov test was performed to analyze the normal distribution of continuous variables.Continuous variables are expressed as mean AE SD or as median (Q1-Q3), whereas categorical variables are presented as absolute numbers and frequencies (%).Student's   2), but the other adverse events did not reach statistical significance between the groups (Table 2).
Using the landmark analysis (Supplemental Table 1, Supplemental Figure 1), we evaluated the association between PCI phenotype and clinical events over time.
CLINICAL OUTCOMES ACCORDING TO PLATELET REACTIVITY AND PROCEDURAL COMPLEXITY.The incidence rate of MACCE during the follow-up period according to the quartile distribution of PRU is presented in Figure 3.We categorized the enrolled patients into the groups based on the procedural complexity and HPR phenotype.The rates of MACCE and all-cause mortality increased proportionally according to C-PCI and HPR phenotype (Figure 4).Irrespective of procedural complexity, the impact of HPR criteria on clinical events appeared similar across each event (Table 3), in which ST appeared to be the most platelet-centric event (by an approximate 3-fold increase).In addition, the prognostic implications of HPR seemed to be more prominent within 1 year (Supplemental Table 2, Supplemental Figure 2).The rate of major bleeding did not differ between the groups (Supplemental Table 3, Supplemental Figure 3).
The adjusted impact of HPR on the occurrence of   tients) reported that procedural complexity was significantly associated with an increased incidence of ischemic events (HR adjusted : 1.44; 95% CI: 1.14-1.82;P ¼ 0.002) at 1 year after the procedure. 21Clinical evidence suggests that the prognostic implication of procedural complexity is similar regardless of the disease entity (ACS vs stable angina).
Several clinical studies in East Asian countries have shown conflicting results on this issue.Endo et al 22 reported that patients who underwent complex DES implantation did not show differences in the risk of all-cause death (log-rank P ¼ 0.12) and MACCE (logrank P ¼ 0.64) during 3-year follow-up (1,062 DEStreated patients).In addition, another Korean study also showed that the clinical outcomes did not differ according to lesion complexity for up to 2 years after the current DES implantation (N ¼ 926) 23 However, these studies enrolled relatively small numbers of participants.A largescale Korean registry study (N ¼ 13,172) has supported the close relationship between procedural complexity and clinical events, showing that clinical and procedural factors were both significant predictors of MACCE within the second year. 24In addition, the present PTRG-DES consortium (N ¼ 11,714) showed that procedural complexity was associated with long-term clinical events.
IMPACT OF HPR ACCORDING TO PROCEDURAL COMPLEXITY.In the setting of complex PCI cases, the use of a potent antiplatelet regimen and/or prolonged use of DAPT with moderate P2Y 12 inhibition would be worth considering to prevent the occurrence of thrombotic events, which may be related to the close interaction between anatomical/procedural Kaplan-Meier estimates were conducted among the 4 groups for (A) MACCE and (B) death according to complex PCI and HPR.Bonferroni's correction was applied for multiple comparisons among the 4 groups.Abbreviations as in Figure 1.
complexity and thrombogenic components. 25However, recent evidence has suggested conflicting findings for an optimal strategy to overcome this accompanying risk following C-PCI.
The prognostic implication of HPR or type of P2Y 12 inhibitor according to procedural complexity has not been extensively investigated in patients treated with the current-generation DES.In a subanalysis of the

ADAPT-DES (Assessment of Dual Antiplatelet Therapy
With DES) trial (N ¼ 8,582), there was no statistical interaction between HPR and bifurcation PCI regarding the risk of target vessel failure (adjusted P interaction ¼ 0.87).In addition, bifurcation PCI was associated with a higher risk of 2-year adverse ischemic events than nonbifurcation PCI, a risk that is particularly high when both bifurcation branches are stented, and with HPR conferring similar risk for bifurcation and nonbifurcation PCI. 26 On the contrary, there are some reports that pro- 95% CI: 0.38-0.79;P ¼ 0.001) and without (HR adjusted : 0.52; 95% CI: 0.39-0.69;P < 0.001) anatomical complexity (P interaction ¼ 0.81). 27Another recent pooled patient-level study showed that P2Y 12 inhibitor monotherapy after 1-to 3-month DAPT vs standard DAPT (approximately 70% of the cohort: treated with potent P2Y 12 inhibitor) was associated with similar rate of ischemic events and lower risk of major bleeding, irrespective of PCI complexity. 28ken together, the clinical evidence supports the notion that potent P2Y 12 inhibition is required to overcome ischemic risk related to the thrombogenic milieu, and early aspirin discontinuation combined with potent P2Y 12 inhibition could be applicable even for these cases.Therefore, an optimized and individualized DAPT strategy could be required to prevent atherothrombotic events in patients with C-PCI features.inhibition is an important topic to be explored.
Finally, the number of patients might be insufficient to observe the effect of HPR on clinical events in each component in complex PCI.Therefore, the possibility of insufficient power in the statistical analysis should be considered.

CONCLUSIONS
In this largescale East Asian cohort, complex PCI was significantly associated with 3-year rates of MACCE and all-cause death.The HPR phenotype increased the risk of atherothrombotic events, but its prognostic implication appears similar irrespective of the type and extent of procedural complexity.This finding may support the clinical benefit of potent P2Y 12 inhibition being primarily related to the presence of the HPR phenotype, and having a lower association with procedural complexity.

FUNDING SUPPORT AND AUTHOR DISCLOSURES
The study was designed by the principal investigator and executive  TRANSLATIONAL OUTLOOK: Large randomized trials are necessary to prove the benefit of dose escalation for antiplatelet therapy to reduce ischemic risk in complex coronary artery disease patients undergoing PCI.
Figure 1.PROCEDURE.All PCI procedures were performed according to standard techniques. 13Following procedures, patients were administered with 100 mg of aspirin and 75 mg of clopidogrel daily.Patients were recommended to stay on aspirin treatment indefinitely and clopidogrel for at least 1 year, with all other treatments as per standard of care.Clinical outcomes were evaluated until the last outpatient visit.

FIGURE 1 B
FIGURE 1 Study Flow Diagram

FIGURE 2
FIGURE 2 Kaplan-Meier Curves for MACCE and Death According to Complex PCI

J
A C C : A S I A , V O L . 4 , N O . 3 , 2 0 2 4 implications in terms of the extent of procedural complexity.DISCUSSION This subanalysis using a PTRG-PFT set investigated the long-term prognostic implication of HPR according to procedural complexity in DES-treated East Asian patients.The principal findings are as follows: 1) C-PCI phenotype increased the risk of MACCE and all-cause death during the 3-year clinical follow-up; 2) HPR criteria were significantly associated with MACCE occurrence, irrespective of procedural complexity; 3) the prognostic implication of HPR was prominently related to ST; and 4) the relative contribution of HPR toward clinical events did not significantly change according to the type or extent of procedural complexity.THE PROGNOSTIC IMPLICATIONS OF COMPLEX PCI.Procedural complexity has been hypothesized to increase ischemic risk, especially when multiple complexity features are present. 3However, the prognostic implications can vary according to the time interval after PCI and the characteristics of the patients studied.Giustino et al 3 reported that patients who underwent C-PCI had a higher incidence of coronary thrombotic events, but this feature was not associated with an increased risk of major bleeding during 1-year follow-up.The e-Ultimaster registry (Prospective, Single-arm, Multi Centre Observations Ultimaster DES Registry) also showed that C-PCI phenotype increased the risk of 1-year cardiac death and complications compared with simple PCI. 20A subanalysis from the ISAR-REACT (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment) trial (3,377 ACS pa-

FIGURE 3
FIGURE 3 Incidence Rate of MACCE According to Quartile Distribution of PRU complexity itself would increase the clinical benefit with the use of a potent P2Y 12 inhibitor.A subanalysis from the multicenter observational study comparing clopidogrel vs prasugrel in acute coronary syndrome patients undergoing PCI (PROMETHEUS) compared clinical outcomes during clopidogrel vs prasugrel treatment in ACS patients undergoing PCI (N ¼ 19,914). 11Compared with clopidogrel, prasugrel significantly decreased the risk of 1-year MACE for C-PCI (HR adjusted : 0.79; 95% CI: 0.68-0.92),but not for non-C-PCI (HR adjusted : 0.91; 95% CI: 0.77-1.08),albeit there was no evidence of interaction (P interaction ¼ 0.281).Prolonged DAPT administration may be applicable to overcome long-term atherothrombotic events following procedural complexity.In the patient-level analysis of 6 randomized controlled trials investigating post-PCI DAPT duration (N ¼ 9,577), 3 long-term DAPT ($12 months) yielded significant reductions in MACCE in C-PCI (HR adjusted : 0.56; 95% CI: 0.35-0.89)vs non-C-PCI (HR adjusted : 1.01; 95% CI: 0.75-1.35)(P interaction ¼ 0.01) compared with short-term DAPT (3-6 months).However, the post hoc analysis of the DAPT study suggested a contrary result showing similar benefit against MI and ST during 30-vs 12-month DAPT for patients with (HR adjusted : 0.55;

17.
Mehran R, Rao SV, Bhatt DL, et al.Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding PERSPECTIVES COMPETENCY IN MEDICAL KNOWLEDGE: Complex PCI increased 3-year rates of MACCE and all-cause death compared with non-complex PCI after stenting.Although HPR phenotype increased the risk of atherothrombotic events, the prognostic implications appear similar irrespective of the type and extent of procedural complexity.COMPETENCY IN PATIENT CARE: Potent P2Y 12 inhibition may be necessary to overcome ischemic risk related to factors in the thrombogenic milieu such as HPR phenotype in complex PCI patients.

TABLE 1
Baseline Characteristics of Study Population Continued on the next pageproportional hazards assumption was tested on the basis of Schoenfeld residuals test and proportional hazards assumptions being met.Statistical significance was set at P value <0.05.All statistical analyses were performed using IBM/SPSS v23.0 (IBM/SPSS) and RStudio (Integrated Development Environment for R. RStudio, PBC).hypertension, diabetes, and chronic kidney disease.Various features of the procedure were higher in the C-PCI group.Cilostazol was more frequently used for the C-PCI group, whereas statins and proton pump inhibitors were more commonly prescribed in the non-C-PCI group (Table1).There were no differences in PRU value (218 AE 79 PRU vs 218 AE 78 PRU; P ¼ 0.972) and HPR rate (33.1% vs 34.6%; P ¼ 0.129) between the groups.

TABLE 2
Incidence of Clinical Outcomes According to Procedural Complexity Values are n (%) unless otherwise indicated.MACCE ¼ major adverse cardiac and cerebrovascular event(s); PCI ¼ percutaneous coronary intervention.

Up Duration (Months) All-Cause Death (%)
FIGURE 4 Kaplan-Meier Curves for MACCE and Death by PCI and HPR

TABLE 3
Incidence of Clinical Outcomes According to Complex PCI and HPR (A and C) subtype of complex PCI and (B and D) the extent of procedural complexity.Abbreviations as in Figures1 and 2.
committee, and was sponsored by the Korean Society of Interventional Cardiology.Dr Jeong has received honoraria for lectures for AstraZeneca, Daiichi-Sankyo, Sanofi, Hanmi Pharmaceuticals, and 7. Gurbel PA, Bliden KP, Samara W, et al.Clopidogrel effect on platelet reactivity in patients with stent thrombosis: results of the CREST Study.J Am Coll Cardiol.2005;46:1827-1832.8. sociations between complex PCI and prasugrel or clopidogrel use in patients with acute coronary syndrome who undergo PCI: from the PROME-THEUS study.Can J Cardiol.2018;34:319-329.12. Giustino G, Baber U, Aquino M, et al.Safety and efficacy of new-generation drug-eluting stents in women undergoing complex percutaneous coronary artery revascularization: from the WIN-DES collaborative patient-level pooled analysis.J Am Coll Cardiol Intv.2016;9:674-684.13. 16.Jeong YH, Bliden KP, Antonino MJ, et al.Usefulness of the VerifyNow P2Y12 assay to evaluate the antiplatelet effects of ticagrelor and clopidogrel therapies.Am Heart J. 2012;164: 35-42.