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Background: The optimal duration of dual antiplatelet therapy (DAPT) in patients with chronic kidney disease undergoing percutaneous coronary intervention (PCI), especially with third-generation drug-eluting stents (DES), remains unknown., Methods and Results: We conducted a prespecified post hoc analysis of the HOST-IDEA trial, randomizing patients undergoing PCI with third-generation DES to 3- to 6-month or 12-month DAPT. In all, 1,997 patients were grouped by their estimated glomerular filtration rate (eGFR): high (>90 mL/min/1.73 m 2 ), intermediate (60-90 mL/min/1.73 m 2 ), and low (<60 mL/min/1.73 m 2 ). The primary outcome was net adverse clinical events (NACE), a composite of cardiac death, target vessel myocardial infarction, clinically driven target lesion revascularization, stent thrombosis, or major bleeding (Bleeding Academic Research Consortium Type 3 or 5) at 12 months. Secondary outcomes were target lesion failure (TLF) and major bleeding. The low eGFR group had the highest rates of NACE, TLF, and major bleeding compared with the other 2 groups (P<0.001). Rates of NACE were similar in the 3- to 6-month and 12-month DAPT in the high (2.9% vs. 3.2%; P=0.84), intermediate (2.1% vs. 2.8%, P=0.51), and low (8.9% vs. 9.1%; hazard ratio 0.99; P=0.97; P interaction =0.88) eGFR groups. TLF and major bleeding events showed similar trends., Conclusions: In patients undergoing PCI with third-generation DES, 3- to 6-month DAPT was comparable to 12-month DAPT for clinical outcomes regardless of renal function.

Background: Clopidogrel monotherapy improved clinical outcomes compared with aspirin monotherapy during a chronic maintenance period in patients who underwent coronary stenting in the HOST-EXAM (Harmonizing Optimal Strategy for Treatment of Coronary Artery Stenosis-Extended Antiplatelet Monotherapy) trial. However, it is uncertain whether the beneficial effect of clopidogrel over aspirin is different according to the renal function., Methods and Results: We conducted a post hoc analysis of the HOST-EXAM trial. Chronic kidney disease (CKD) was defined as baseline estimated glomerular filtration rate <60 mL/min per 1.73 m 2 . The primary end point was a composite of all-cause death, nonfatal myocardial infarction, stroke, readmission due to acute coronary syndrome, and Bleeding Academic Research Consortium bleeding type ≥3, during the 2-year follow up. Among the 5438 patients enrolled in the HOST-EXAM trial, 4844 patients (mean age, 63.3±10.6 years; 74.9% men) with a baseline creatinine value were analyzed in this study. A total of 508 (10.5%) patients had CKD, who were at higher risk of the primary end point compared with those without CKD (hazard ratio [HR], 2.01 [95% CI, 1.51-2.67]). Clopidogrel monotherapy was associated with a lower rate of the primary end point in both patients with CKD (HR, 0.74 [95% CI, 0.44-1.25]) and patients without CKD (HR, 0.71 [95% CI, 0.56-0.91]). No significant interaction was observed between the treatment effect and CKD status ( P for interaction=0.889)., Conclusions: During the chronic maintenance period after coronary stenting, the risk of thrombotic and bleeding events was significantly higher in patients with CKD compared with those without CKD. There was no statistical difference in the treatment effect of clopidogrel monotherapy in those with versus without CKD.

Background: The efficacy and safety of each third-generation drug-eluting stent with ultrathin struts and advanced polymer technology remain unclear. We investigated the clinical outcomes of percutaneous coronary intervention using the Coroflex ISAR polymer-free sirolimus-eluting stent (SES) or Orsiro biodegradable polymer SES., Methods: The HOST-IDEA trial (Harmonizing Optimal Strategy for Treatment of Coronary Artery Stenosis-Coronary Intervention With Next-Generation Drug-Eluting Stent Platforms and Abbreviated Dual Antiplatelet Therapy), initially designed with a 2×2 factorial approach, sought to randomize patients undergoing percutaneous coronary intervention based on dual antiplatelet therapy duration (3 versus 12 months) and stent type (Coroflex ISAR versus Orsiro). Despite randomizing 2013 patients for dual antiplatelet therapy duration, the stent arm transitioned to a registry format during the trial. Among these, 328 individuals (16.3%) were randomized for Coroflex ISAR or Orsiro SES, while 1685 (83.7%) underwent percutaneous coronary intervention without stent-type randomization. In this study, the Coroflex ISAR (n=559) and Orsiro groups (n=1449) were matched using a propensity score. The prespecified primary end point was target lesion failure, a composite of cardiac death, target vessel myocardial infarction, and clinically driven target lesion revascularization at 12 months., Results: The baseline patient and procedural characteristics were well balanced between the Coroflex ISAR and Orsiro groups after propensity score matching (n=559, each group). The Coroflex ISAR group was significantly associated with a higher rate of target lesion failure, mainly driven by clinically driven target lesion revascularization, compared with the Orsiro group (3.4% versus 1.1%; hazard ratio, 3.21 [95% CI, 1.28-8.05]; P =0.01). A higher risk of target lesion failure in the Coroflex ISAR group was consistently observed across various subgroups. The rates of any bleeding (hazard ratio, 0.85 [95% CI, 0.51-1.40]; P =0.52) and major bleeding (hazard ratio, 1.58 [95% CI, 0.61-4.08]; P =0.34) were comparable between the 2 groups., Conclusions: In this propensity score-matched analysis of the stent arm registry from the HOST-IDEA trial, the Orsiro SES was associated with significantly better outcomes in terms of 1-year target lesion failure, mainly driven by clinically driven target lesion revascularization, than the Coroflex ISAR SES., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02601157., Competing Interests: Dr Han reports grants from ChongKunDang and HanMi outside the submitted work. Dr K.W. Park reports speaker fees from Daiichi Sankyo, AstraZeneca, Sanofi, Bristol-Myers Squibb, Bayer, and Pfizer outside the submitted work. Dr H.-S. Kim reports grants or speaker fees from Daiichi Sankyo, Boston Scientific, Terumo, Biotronik, Dio, Medtronic, Abbott Vascular, Edwards Life Science, Amgen, and Behringer Ingelheim outside of the submitted work. The other authors report no conflicts.

Optimal dual antiplatelet therapy (DAPT) duration for patients undergoing percutaneous coronary intervention (PCI) for coronary bifurcations is an unmet issue. The BIFURCAT registry was obtained by merging two registries on coronary bifurcations. Three groups were compared in a two-by-two fashion: short-term DAPT (≤ 6 months), intermediate-term DAPT (6-12 months) and extended DAPT (>12 months). Major adverse cardiac events (MACE) (a composite of all-cause death, myocardial infarction (MI), target-lesion revascularization and stent thrombosis) were the primary endpoint. Single components of MACE were the secondary endpoints. Events were appraised according to the clinical presentation: chronic coronary syndrome (CCS) versus acute coronary syndrome (ACS). 5537 patients (3231 ACS, 2306 CCS) were included. After a median follow-up of 2.1 years (IQR 0.9-2.2), extended DAPT was associated with a lower incidence of MACE compared with intermediate-term DAPT (2.8% versus 3.4%, adjusted HR 0.23 [0.1-0.54], p <0.001), driven by a reduction of all-cause death in the ACS cohort. In the CCS cohort, an extended DAPT strategy was not associated with a reduced risk of MACE. In conclusion, among real-world patients receiving PCI for coronary bifurcation, an extended DAPT strategy was associated with a reduction of MACE in ACS but not in CCS patients., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: A potent P2Y12 inhibitor-based dual antiplatelet therapy is recommended for up to 1 year in patients with acute coronary syndrome receiving percutaneous coronary intervention (PCI). The greatest benefit of the potent agent is during the early phase, whereas the risk of excess bleeding continues in the chronic maintenance phase. Therefore, de-escalation of antiplatelet therapy might achieve an optimal balance between ischaemia and bleeding. We aimed to investigate the safety and efficacy of a prasugrel-based dose de-escalation therapy., Methods: HOST-REDUCE-POLYTECH-ACS is a randomised, open-label, multicentre, non-inferiority trial done at 35 hospitals in South Korea. We enrolled patients with acute coronary syndrome receiving PCI. Patients meeting the core indication for prasugrel were randomly assigned (1:1) to the de-escalation group or conventional group using a web-based randomisation system. The assessors were masked to the treatment allocation. After 1 month of treatment with 10 mg prasugrel plus 100 mg aspirin daily, the de-escalation group received 5 mg prasugrel, while the conventional group continued to receive 10 mg. The primary endpoint was net adverse clinical events (all-cause death, non-fatal myocardial infarction, stent thrombosis, repeat revascularisation, stroke, and bleeding events of grade 2 or higher according to Bleeding Academic Research Consortium [BARC] criteria) at 1 year. The absolute non-inferiority margin for the primary endpoint was 2·5%. The key secondary endpoints were efficacy outcomes (cardiovascular death, myocardial infarction, stent thrombosis, and ischaemic stroke) and safety outcomes (bleeding events of BARC grade ≥2). The primary analysis was in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02193971., Results: From Sept 30, 2014, to Dec 18, 2018, 3429 patients were screened, of whom 1075 patients did not meet the core indication for prasugrel and 16 were excluded due to randomisation error. 2338 patients were randomly assigned to the de-escalation group (n=1170) or the conventional group (n=1168). The primary endpoint occurred in 82 patients (Kaplan-Meier estimate 7·2%) in the de-escalation group and 116 patients (10·1%) in the conventional group (absolute risk difference -2·9%, p non-inferiority <0·0001; hazard ratio 0·70 [95% CI 0·52-0·92], p equivalence =0·012). There was no increase in ischaemic risk in the de-escalation group compared with the conventional group (0·76 [0·40-1·45]; p=0·40), and the risk of bleeding events was significantly decreased (0·48 [0·32-0·73]; p=0·0007)., Interpretation: In east Asian patients with acute coronary syndrome patients receiving PCI, a prasugrel-based dose de-escalation strategy from 1 month after PCI reduced the risk of net clinical outcomes up to 1 year, mainly driven by a reduction in bleeding without an increase in ischaemia., Funding: Daiichi Sankyo, Boston Scientific, Terumo, Biotronik, Qualitech Korea, and Dio., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background:  The ischemic/bleeding risk of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) is still uncertain. We sought to develop a tool to predict ischemic and bleeding events in East Asians receiving 2nd generation drug-eluting stents (DESs) PCI., Methods:  A pooled cohort of 13,172 East Asian patients receiving PCI with 2nd generation DES (the Grand DES cohort) was analyzed to develop a scoring system. A net score was calculated by subtracting the bleeding score from the ischemic score. External validation was performed in the HOST-ASSURE and NIPPON trials., Results:  Among the total population, ischemic and bleeding events occurred in 195 patients (1.5%) and 166 patients (1.3%), respectively. The score to predict ischemic events included previous myocardial infarction (MI) or PCI, presentation as acute MI, anemia, stent diameter < 3 mm, and total stent length of ≥30 mm, while that for bleeding events included older age, low creatinine clearance, and anemia. C-statistics of the ischemic and bleeding model was 0.708 and 0.665, respectively. Patients with a net score of ≥1 had a higher ischemic risk compared with bleeding risk, and patients with a net score of ≤-1 had a higher bleeding risk compared with ischemic risk. The validation cohort showed a C-statistic of 0.647 for ischemic events and 0.633 for bleeding events., Conclusion:  We developed a tool to predict ischemic and bleeding events in East Asian patients received PCI with 2nd generation DES. This system can be used to assess clinical event risks, and to determine the adequate duration of DAPT in East Asians., Competing Interests: Dr. Nakamura reports grants and other from Terumo Corporation, Sanofi, and Daiichi Sankyo, outside the submitted work., (Georg Thieme Verlag KG Stuttgart · New York.)

Objectives: The aim of this study was to investigate clinical outcomes after left main coronary artery (LM) bifurcation percutaneous coronary intervention (PCI) and the impact of the duration of dual antiplatelet therapy (DAPT) according to treatment strategy., Background: There are limited data regarding the optimal PCI strategy for LM bifurcation lesions with new-generation drug-eluting stents., Methods: A patient-level pooled analysis of 5 nationwide multicenter registries was performed. Rates of target lesion failure, thrombotic adverse cardiovascular events, and their individual components at 3-year were analyzed. Subgroup analysis according to DAPT duration was performed., Results: From 13,172 patients undergoing PCI with new-generation drug-eluting stents, a total of 700 patients were treated for LM bifurcation lesions, 567 with a 1-stent strategy and 133 with a 2-stent strategy. Rates of target lesion failure and target lesion revascularization were higher in the 2-stent group, driven mainly by complex lesion profiles. Risks for thrombotic adverse cardiovascular events and its components were comparable between the 2 strategies. Subgroup analysis showed that risks for target lesion failure and thrombotic adverse cardiovascular events in the 2-stent group were significantly higher than in the 1-stent group in those with DAPT interruption <1 year, while they were similar in those receiving DAPT maintenance ≥1 year., Conclusions: Up to 20% of patients who underwent LM bifurcation PCI eventually required a 2-stent strategy, which was as safe as a 1-stent strategy with the use of new-generation drug-eluting stents. Careful pre-emptive case selection as well as prolonged DAPT may be necessary when considering a 2-stent strategy in LM PCI given its higher rate of repeat revascularization and lesion failure than the 1-stent approach., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Introduction: We have recently seen the introduction of newer generation drug-eluting stents with ultrathin struts that use advanced polymer technologies. However, the efficacy and safety of these newest stents have not yet been fully explored. In addition, there are still controversies over the optimal duration of dual antiplatelet therapy (DAPT) after stent implantation, particularly for ultrathin stents with the newest polymer technologies., Methods and Analysis: The HOST-IDEA trial is a randomised, open-label, multicentre, non-inferiority trial and the first study to directly compare two of these ultrathin sirolimus-eluting stents: Orsiro stent with biodegradable polymer, and polymer-free Coroflex ISAR (CX-ISAR) stent. This study has a scheme of 2×2 factorial design according to the stent type and DAPT duration (3 vs 12 months). A total of 2152 patients will be randomised and stratified to demonstrate the non-inferiority of CX-ISAR to Orsiro, or of the abbreviated DAPT duration to the conventional 12 months (both in 1:1 ratio). For the comparison of stent type, the primary endpoint is target lesion failure (TLF), which is a composite of cardiac death, target vessel-related myocardial infarction and clinically driven target lesion revascularisation. For the comparison of DAPT duration, the net adverse clinical event is the coprimary endpoint, which is defined as a composite of TLF, definite/probable stent thrombosis and major bleeding., Ethic Approval and Dissemination: All the institutions involved in this study are required to have ethical approval prior to patient enrolment. This multicentre study will recruit patients through competitive registration, but institutions that have not yet obtained ethical approvals have made it impossible to enrol patients in a centralised web database. The final results will be presented at relevant international conferences and will be materialised in the form of papers., Trial Registration Number: NCT02601157; Pre-results., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Current 2nd-generation drug-eluting stents (DES) have dramatically improved clinical outcomes after percutaneous coronary intervention for coronary artery disease. However, DES implantation has major long-term limitations related to the permanent presence of foreign material in the coronary artery. Bioresorbable vascular scaffolds (BVS) were designed to overcome this limitation of permanent metal-based DES. However, because of immature manufacturing technology, BVS have several drawbacks, such as the thicker strut, poor deliverability, poor radio-opacity, poor radial strength, and cumbersome procedure to meet the principle of PSP (Preparation, Sizing, and Post-dilatation). Initial studies indicated that BVS outcomes were non-inferior to those of current DES and recent follow-up data of trials have revealed an additional critical drawback, higher rate of scaffold thrombosis, on the top of the existing limitations of BVS. Thus attention must be paid to the appropriate BVS-specific implantation protocols (i.e., PSP), as well as adequate intensity and duration of dual antiplatelet therapy. In any case, current BVS need further technical evolution to replace current metallic DES in routine clinical use.

Background: Antiplatelet treatment is an important component in optimizing the clinical outcomes after percutaneous coronary intervention (PCI) especially in patients with acute coronary syndrome (ACS). Prasugrel, which is a new P2Y12 inhibitor, has been confirmed as efficacious in a large trial in Western countries, and a similar trial is also to be launched in Asian countries. Although a 60-mg loading dose of prasugrel followed by 10 mg per day should be acceptable, there have been no data regarding the optimal dose in Asian patients. Furthermore, serum levels of prasugrel and the rates of platelet inhibition are known to be higher in Asians than Caucasians with the same dose of the drug. Polymer, a key component of drug-eluting stents (DES), has been suggested as the cause of inflammation leading to late complications, and has driven many companies to develop biodegradable-polymer DES. Currently, there are limited data regarding the head-to-head comparison between BP-BES and the biostable polymer CoCr-EES or the newest platinum-chromium everolimus-eluting stent (PtCr-EES). Furthermore, the polymer issue may be more important in ACS where there is ruptured thrombotic plaque where polymer-induced inflammation may affect the local milieu of the stented artery. Therefore, the present study dedicated only to ACS patients, will offer important information on the optimal prasugrel dose in the Asian population by comparing a 10-mg versus a 5-mg maintenance dose beyond 1 month after PCI, as well as giving important insight into the polymer issue by comparing BP-BES versus biostable-polymer PtCr-EES., Method/design: Harmonizing Optimal Strategy for Treatment of coronary artery diseases--comparison of REDUCtion of prasugrEl dose or POLYmer TECHnology in ACS patients (HOST-REDUCE-POLYTECH-ACS) trial is a multicenter, randomized and open-label clinical study with a 2 × 2 factorial design, according to the type of stent (PtCr-EES versus BP-BES) and prasugrel maintenance dose (5 mg versus 10 mg), to demonstrate non-inferiority of PtCr-EES relative to BP-BES or the reduced prasugrel dose relative to conventional dose in an Asian all-comers PCI population presenting with ACS. Approximately 3400 patients will undergo prospective, random assignment separately to either stent or prasugrel arm (1:1 ratio, respectively). When the patients have contraindications to prasugrel, they are categorized into an antiplatelet observation group after stent-randomization. The primary endpoint is the patient-oriented composite outcome, which is a composite of all-cause mortality, any myocardial infarction (MI), any repeat revascularization in the stent arm at 12 months after index PCI. In the prasugrel arm, primary endpoint is any major adverse cardiovascular event, which is a composite of all-cause mortality, any MI, any stent thrombosis (Academic Research Consortium (ARC)-defined), any repeat revascularization, stroke, or bleeding (BARC class ≥ 2)., Discussion: The HOST-REDUCE-POLYTECH-ACS RCT is the first study exploring the optimal maintenance dose of prasugrel beyond 1 month after PCI for ACS in Asian all-comers. In addition, this is the largest study dedicated only to ACS patients to evaluate the polymer issue in the situation of ACS by directly comparing biostable-polymer PtCr-EES versus BP-BES., Trial Registration: ClinicalTrials.gov (ID: NCT02193971, 13 July 2014).

Objectives: This study sought to test the noninferiority of triple antiplatelet therapy (TAT) versus double-dose clopidogrel dual antiplatelet therapy (DDAT) in patients undergoing percutaneous coronary intervention (PCI)., Background: Antiplatelet regimen is an integral component of medical therapy after PCI. A 1-week duration of doubling the dose of clopidogrel was shown to improve outcome at 1 month compared with the conventional dose in patients with acute coronary syndrome undergoing PCI. Yet in Asia, the addition of cilostazol is used more commonly than DDAT in high-risk patients., Methods: We randomly assigned 3,755 all-comers undergoing PCI to either TAT or DDAT, which was continued for 1 month, to test the noninferiority of TAT versus DDAT. The primary outcome was the cumulative incidence of net clinical outcome at 1 month post-PCI defined as the composite of cardiac death, nonfatal myocardial infarction, stent thrombosis, stroke, and PLATO (Platelet Inhibition and Patient Outcomes) major bleeding., Results: TAT was noninferior to DDAT with respect to the primary outcome, which occurred in 1.2% and 1.4% of patients, respectively (-0.22% absolute difference, 0.34% 1-sided 97.5% confidence interval, p = 0.0007 for noninferiority; hazard ratio: 0.85; 95% confidence interval: 0.49 to 1.48; p = 0.558 for superiority). The individual risks of cardiac death, nonfatal myocardial infarction, stent thrombosis, stroke, and PLATO major bleeding did not differ significantly between the 2 groups. There were no significant between-group differences in the treatment effect with regard to the rate of the primary outcome., Conclusions: The adjunctive use of cilostazol was noninferior to doubling the dose of clopidogrel for 1 month in all-comers undergoing PCI with exclusively drug-eluting stents. (Harmonizing Optimal Strategy for Treatment of Coronary Artery Stenosis-SAfety & EffectiveneSS of Drug-ElUting Stents & Anti-platelet REgimen [HOST-ASSURE]; NCT01267734)., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Calcium-channel blockers (CCBs) inhibit the CYP3A4 enzyme, which is involved in clopidogrel activation. Studies have shown conflicting results regarding the effect of concomitant CCB administration on clopidogrel response. We investigated the relationship between CYP3A4 genotype and the inhibitory effect of CCBs on clopidogrel response., Methods and Results: Clopidogrel on-treatment platelet reactivity (OPR) was measured and CYP3A4 (IVS10+12G>A) genotyped in 1,247 consecutive patients with drug-eluting stent implantation. The mean OPR was 231±83 (P2Y12 reaction units: PRU). In total, 332 (26.6%) CCB users had higher OPR compared with 915 (73.4%) non-CCB users (245±84 vs. 227±83 PRU, P=0.001). The distribution of CYP3A4 (IVS10+12G>A) genotype was 63.6%, 32.6% and 3.8% for GG, GA and AA genotypes, respectively. After adjustment for possible confounding factors, the number of A-alleles was associated with increased vulnerability to CCB use (effect of CCB use ΔPRU: +8 PRU, P=0.210, +24 PRU, P=0.012, +50 PRU, P=0.025, for patients with 0, 1, and 2 A-alleles, respectively, +24 PRU, P=0.005 for GA/AA genotypes). Furthermore, only in the GA/AA-genotype did CCB use result in a significantly increased risk for high-OPR (odds ratio 1.84, 95% confidence interval 1.15-2.92, P=0.010)., Conclusions: CCB use is associated with increased OPR. The number of CYP3A4 (IVS10+12G>A) A-alleles may be associated with an increased vulnerability to the effects of CCBs on clopidogrel response variation.

Background: Paraoxonase (PON) is a high-density-lipoprotein (HDL) associated enzyme with antioxidative and anti-atherogenic property. Its function is associated with coronary artery disease and its activity genetically controlled. We evaluated whether genetic variation of PON-1 is associated with clinical outcome in a large cohort of Korean patients with drug-eluting stents implantation., Methods: A total of 1676 patients with drug-eluting stent implantation were enrolled in the prospective CROSS-VERIFY cohort from June 2006 to June 2010. We genotyped the PON1-Q192R gene, measured clopidogrel on-treatment platelet reactivity (OPR), and analyzed lipid profiles. The primary endpoint was the composite of cardiac death, myocardial infarction, and stent thrombosis at 12 months., Results: PON-1 genotyping data were available in 1336 patients. Since the Q-allele is associated with decreased PON-activity, we analyzed the outcome between patients with QQ/QR (815 patients, 61%) and those with RR-genotype (521 patients, 39%). After adjustment for common cardiac risk factors, the QQ/QR-genotype was an independent predictor of the primary thrombotic endpoint with an 11-fold increased risk (HR 11.6, 95% CI: 1.55-87.0), but not repeat revascularization (HR 1.12, 95% CI: 0.78-1.61). The QQ/QR-genotype was not associated with OPR (QQ/QR: 231±86 PRU vs. RR 236±82 PRU, p = 0.342) but higher small-dense LDL levels (1.20±0.12 mg/dL vs. 0.76±0.15 mg/dL, p = 0.027). The increased risk of thrombotic outcomes was more profound in acute coronary syndrome (ACS) patients compared with non-ACS patients., Conclusion: PON1 Q-allele is an independent predictor of worse cardiovascular outcome independent of platelet function and is associated with significantly higher levels of small dense LDL-C.

Objective: To test the effect of a loss-of-function variation of the cytochrome P450 (CYP) 3A5 on drug-drug interaction between amlodipine and clopidogrel. Amlodipine is a well-known inhibitor of CYP 3A4, an isoenzyme of CYP3A that activates clopidogrel. However, controversy exists regarding whether amlodipine adversely affects clopidogrel response and clinical outcome after percutaneous coronary intervention (PCI). In the presence of CYP3A4 inhibitors such as amlodipine, the genetic variation of CYP3A5, the isoenzyme responsible for the backup CYP3A activity, may play an important role in clopidogrel activation., Design: Post hoc analysis of a prospectively enrolled cohort., Patients: Patients enrolled in the CROSS-VERIFY cohort from June 2006 to June 2010, with successful genotyping of CYP3A5., Main Outcome Measures: The pharmacodynamic analysis end point was clopidogrel on-treatment platelet reactivity (OPR) and the clinical analysis end point was the composite of cardiac death, non-fatal myocardial infarction, ischaemic stroke and stent thrombosis at 12 months post-PCI., Results: 1258 patients had successful genotyping and were categorised as CYP3A5 non-expressers (749 patients) and expressers (509 patients) according to the CYP3A5 genotype. Amlodipine users showed higher OPR versus non-users only in CYP3A5 non-expressers (249 ± 83 vs 228 ± 84 P2Y12 reaction units, p=0.013). These findings was corroborated by clinical outcomes, in which amlodipine users had a higher incidence of events compared with non-users only in CYP3A5 non-expressers (4.6% vs 0.6%, HR 7.731, CI 2.042 to 29.264, p=0.004)., Conclusions: Treatment with amlodipine is associated with increased clopidogrel OPR and increased risk of thrombotic events after PCI, which is dependent on the CYP3A5 genetic status.

Introduction: High posttreatment platelet reactivity to clopidogrel (HPPR) is associated with major adverse cardiac events. However, the clinical predictors of HPPR in Asians have not been studied previously., Aims: We sought to determine clinical predictors of HPPR in Koreans., Results: We measured platelet reactivity with the VerifyNow P2Y12 assay in 1431 consecutive patients undergoing coronary angiography. We used the cut-off value of greater than 275 P2Y12 Reaction Unit (PRU) to define patients with HPPR. The clinical characteristics were compared between patients with HPPR (36.3%) and those without HPPR (63.7%). The mean age (65.4 ± 9.1 vs. 62.2 ± 9.7 years) was higher, hypertension (68.5% vs. 62.0%), diabetes mellitus (35.4% vs. 28.5%), chronic kidney disease (36.3% vs. 22.5%), renal replacement treatment (1.2% vs. 0.2%), and congestive heart failure (1.3% vs. 0.3%) were more common among patients with HPPR, while male gender (72.6% vs. 54.8%) and smoking (19.9% vs. 13.1%) were more common among non-HPPR patients. Mean glomerular filtration rate (63.5 ± 18.6 vs. 69.7 ± 16.1 mL/min/1.73 m(3) ) was lower and C-reactive protein (hs-CRP) (6.6 ± 20.5 mg/L vs. 4.2 ± 12.1 mg/L) level was higher among those with HPPR. Independent predictors of HPPR were female gender (OR 1.90, P≤ 0.001), chronic kidney disease (OR 1.51, 0 = 0.004), diabetes mellitus (OR 1.35, P= 0.024), hs-CRP ≥ 2.0 mg/L (OR 1.31, P= 0.005), and age increase in decades (OR 1.21, P= 0.002), while smoking was negative risk factor (OR 0.63, P= 0.015). The number of risk factors was linearly associated with the risk of HPPR, with most patients having one or two predictors., Conclusion: In Korean population, independent clinical predictors of HPPR included diabetes mellitus, increased age, female gender, chronic kidney disease, and hs-CRP ≥ 2.0 mg/L, while cigarette smoking was associated with better responsiveness. Mean platelet reactivity and HPPR prevalence steadily increased with the number of clinical predictors., (© 2010 Blackwell Publishing Ltd.)

A 58-year-old man presented with unstable angina, for whom drug-eluting stent (DES) was successfully implanted in mid portion of left anterior descending artery and diagonal branch bifurcation. During hospitalization, renal cell carcinoma was incidentally found. Right radical nephrectomy was planned 5 weeks after the DES insertion to minimize thrombotic risk following discontinuation of antiplatelet agents. Seven days and 5 days prior to the operation, clopidogrel and aspirin were withdrawn respectively while platelet activity was serially monitored using VerifyNow Aspirin/P2Y12 assay. According to the results of the assay, the infusion of tirofiban was started from the third day after stopping dual antiplatelet therapy and maintained till 8 h prior to the nephrectomy. With the help of this bridge therapy, the surgery was successfully performed and histology confirmed a renal cell carcinoma. Clopidogrel and aspirin were resumed the next day after the operation. Eight days after his nephrectomy, the patient was discharged without stent thrombosis or bleeding complication., (Copyright © 2009 Elsevier Ireland Ltd. All rights reserved.)

Objective: To evaluate whether the addition of cilostazol to dual antiplatelet therapy (DAT, aspirin plus clopidogrel) can attenuate clopidogrel on-treatment platelet reactivity (OPR) in patients with the CYP2C19 loss-of-function (LOF) allele., Methods: In the CILON-T randomised trial, patients were randomly assigned to either DAT or triple antiplatelet therapy (TAT, DAT plus cilostazol). Genotyping of cytochrome P450 CYP2C19 *2, *3 and *17 was performed and OPR was measured using the VerifyNow P2Y12 assay. Carriers were those with at least one CYP2C19 LOF allele., Results: 474 patients were enrolled; 236 received DAT, 238 TAT. Mean OPR was significantly lower in the TAT compared with the DAT group (207 ± 5 vs 236 ± 5, p<0.001, P2Y12 reaction units, PRU). When grouped according to the presence of the CYP2C19 LOF allele, mean OPR was significantly lower in the TAT compared with the DAT group in only carriers of the LOF allele and not non-carriers (213 ± 6 vs 256 ± 7 PRU, p<0.001 in carriers, 196 ± 9 vs 211 ± 8 PRU, p=0.242 in non-carriers for TAT vs DAT, respectively). The proportion of patients with high OPR was highest in carriers receiving DAT (60.8%) compared with the other three groups. On multivariate analysis, carriers on DAT was an independent predictor of high OPR (OR 2.93, 95% CI 1.64 to 5.21) along with female gender and increasing age., Conclusion: TAT significantly reduced OPR compared with DAT in carriers of the CYP2C19 LOF allele, but not in non-carriers. These data suggest that the addition of cilostazol to DAT may be a good strategy to attenuate CYP2C19 LOF-related high OPR.

Objective: Observational studies have reported enhanced response to clopidogrel in smokers (the smokers' paradox). We examined whether genetic variations in the cytochrome and drug transporter system are associated with the effect of smoking on clopidogrel response., Methods and Results: Clopidogrel on-treatment platelet reactivity (OPR) was measured in 1431 consecutive patients who underwent coronary angiography. Gene samples were available and genotyping was successful in 1123 patients. Nine candidate single-nucleotide polymorphisms in 5 cytochrome genes and 1 drug transporter gene were assessed. The mean OPR of the entire population was 241.9 ± 79.3 (P2Y(12) reaction units). Two hundred forty-nine (17%) smokers had lower OPR compared with 1182 (83%) nonsmokers (227.6 ± 76.0 versus 244.9 ± 79.7, P=0.001). Among the 9 single-nucleotide polymorphisms, only CYP1A2 showed a genotype-dependent change in the effect of smoking on OPR. After adjustment for possible confounding factors, cigarette smoking was associated with a lower OPR by -19 P2Y(12) reaction units (P=0.009) and lower risk for high OPR (odds ratio [OR], 0.48; 95% CI, 0.31 to 0.74) in the AA and CA genotypes but not in the CC genotype., Conclusions: Enhanced clopidogrel response in smokers, known as the smokers' paradox, is not universal but was observed only in cytochrome P450 CYP1A2 (-163C>A) A-allele carriers, suggesting a genotype-dependent effect of smoking on clopidogrel responsiveness.

Aims Dual-antiplatelet therapy (DAPT) with aspirin and a potent P2Y12 inhibitor is the standard treatment for patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). De-escalation of the potent P2Y12 inhibtor is an appealing concept to balance the ischaemic and bleeding risks after PCI. An individual patient data meta-analysis was performed to compare de-escalation versus standard DAPT in patients with ACS. Methods and results Electronic databases, including PubMed, Embase, and the Cochrane database, were searched to identify randomised clinical trials (RCTs) comparing the de-escalation strategy with the standard DAPT after PCI in patients with ACS. Individual patient-level data were collected from the relevant trials. The co-primary endpoints of interest were the ischaemic composite endpoint (a composite of cardiac death, myocardial infarction, and cerebrovascular events) and bleeding endpoint (any bleeding) at 1-year post-PCI. Four RCTs (the TROPICAL-ACS, POPular Genetics, HOST-REDUCE-POLYTECH-ACS, and TALOS-AMI trials) including 10 133 patients were analysed. The ischaemic endpoint was significantly lower in the patients assigned to the de-escalation strategy than in those assigned to the standard strategy (2.3% vs. 3.0%, hazard ratio [HR] 0.761, 95% confidence interval [CI] 0.597-0.972, log rank P = 0.029). Bleeding was also significantly lower in the de-escalation strategy group (6.5% vs. 9.1%, HR 0.701, 95% CI 0.606-0.811, log rank P < 0.001). No significant intergroup differences were observed in terms of all-cause death and major bleeding events. Subgroup analyses revealed that compared to guided de-escalation, unguided de-escalation had a significantly larger impact on bleeding endpoint reduction (P for interaction = 0.007); no intergroup differences were observed for the ischaemic endpoints. Conclusion In this individual patient data meta-analysis, DAPT-based de-escalation was associated with both decreased ischaemic and bleeding endpoints. Reduction in bleeding endpoints was more prominent for the unguided than the guided de-escalation strategy. Study registration number This study was registered in the PROSPERO (ID: CRD42021245477). [ABSTRACT FROM AUTHOR]

Background: Potent P2Y12 inhibitors are recommended for up to 12 months after percutaneous coronary intervention (PCI) in patients diagnosed with acute coronary syndrome (ACS). However, the prescription pattern is diverse in real world practice, which includes various switching between antiplatelet regimens. In this study, we analyzed the prescription patterns of prasugrel, and assessed the safety and effectiveness of P2Y12 inhibitors switching patterns in a real world registry of patients subjected to PCI after ACS. Methods: The EFF-K study included 3077 ACS patients receiving prasugrel-based dual antiplatelet therapy. The cohort was divided into those who were administered with prasugrel as the primary antiplatelet treatment (naïve cohort) or as a substitute agent after clopidogrel or ticagrelor pre-treatment (switch cohort). The primary endpoint was a net adverse clinical event (NACE; a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or TIMI major bleeding unrelated to coronary-artery bypass grafting). Results: A total of 3077 patients diagnosed with ACS were included in the analysis. Among the total population, 726 patients (23.6%) were classed as the naïve cohort and 2351 patients (76.4%) as the switch cohort. Baseline characteristics showed that the switch cohort had more comorbidities, such as hypertension, diabetes mellitus, heart failure and previous PCI. The major cause of switching to prasugrel in the switch cohort was the necessity for a more potent antiplatelet agent (56.3%). During a 12-month follow-up period, 51 patients (1.7%) experienced at least one NACE. The incidence of NACE did not differ between the naïve and switch cohort (1.5% vs. 1.7%, Hazard ratio 1.17, 95% Confidence interval 0.56–2.43, P = 0.677). In subgroup analysis, no significant interaction was observed between the treatment strategy and the incidence of NACE across various subgroups. Conclusions: Dual antiplatelet therapy with prasugrel seems to be safe and effective both as a primary treatment and as a substitute for other P2Y12 inhibitors in a real world registry of Asian ACS patients receiving PCI. Trial registration: KCT0002356, registered June 13, 2017. [ABSTRACT FROM AUTHOR]

Clopidogrel was superior to aspirin monotherapy in secondary prevention after percutaneous coronary intervention (PCI). The purpose of this study was to evaluate the benefits of clopidogrel across high-risk subgroups This was a post hoc analysis of the HOST-EXAM (Harmonizing Optimal Strategy for Treatment of coronary artery diseases-EXtended Antiplatelet Monotherapy) trial that randomly assigned patients who were event free for 6 to 18 months post-PCI on dual antiplatelet therapy (DAPT) to clopidogrel or aspirin monotherapy. Two clinical risk scores were used for risk stratification: the DAPT score and the Thrombolysis In Myocardial Infarction Risk Score for Secondary Prevention (TRS 2°P) (the sum of age ≥75 years, diabetes, hypertension, current smoking, peripheral artery disease, stroke, coronary artery bypass grafting, heart failure, and renal dysfunction). The primary composite endpoint was a composite of all-cause death, nonfatal myocardial infarction, stroke, readmission because of acute coronary syndrome, and major bleeding (Bleeding Academic Research Consortium type ≥3) at 2 years after randomization. Among 5,403 patients, clopidogrel monotherapy showed a lower rate of the primary composite endpoint than aspirin monotherapy (HR: 0.73; 95% CI: 0.59-0.90). The benefit of clopidogrel over aspirin was consistent regardless of TRS 2°P (high TRS 2°P [≥3] group: HR: 0.65 [95% CI: 0.44-0.96]; and low TRS 2°P [<3] group: HR: 0.77 [95% CI: 0.60-0.99]) (P for interaction = 0.454) and regardless of DAPT score (high DAPT score [≥2] group: HR: 0.68 [95% CI: 0.46-1.00]; and low DAPT score [<2] group: HR: 0.75 [95% CI: 0.59-0.96]) (P for interaction = 0.662). The association was similar for the individual outcomes. The beneficial effect of clopidogrel over aspirin monotherapy was consistent regardless of clinical risk or relative ischemic and bleeding risks compared with aspirin monotherapy. (Harmonizing Optimal Strategy for Treatment of Coronary Artery Stenosis- EXtended Antiplatelet Monotherapy [HOST-EXAM]; NCT02044250) [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Limited data are available on short-term dual antiplatelet therapy (DAPT) after percutaneous coronary intervention using third-generation drug-eluting stents with ultrathin struts and advanced polymer technology. We investigated whether 3- to 6-month DAPT was noninferior to 12-month DAPT after implantation of drug-eluting stents with ultrathin struts and advanced polymer technology. Methods: We performed an open-label, randomized trial at 37 centers in South Korea. We enrolled patients undergoing percutaneous coronary intervention using the Orsiro biodegradable-polymer sirolimus-eluting stents or the Coroflex ISAR polymer-free sirolimus-eluting stents. Patients with ST-segment–elevation myocardial infarction were excluded. Patients were randomly assigned to receive either 3- to 6-month or 12-month DAPT after percutaneous coronary intervention. The choice of antiplatelet medications was at the physician's discretion. The primary outcome was a net adverse clinical event, a composite of cardiac death, target vessel myocardial infarction, clinically driven target lesion revascularization, stent thrombosis, or major bleeding, defined as Bleeding Academic Research Consortium type 3 or 5 at 12 months. The major secondary outcomes were target lesion failure, a composite of cardiac death, target vessel myocardial infarction, clinically driven target lesion revascularization, and major bleeding. Results: A total of 2013 patients (mean age, 65.7±10.5 years; 1487 males [73.9%]; 1110 [55.1%] presented with acute coronary syndrome) were randomly assigned to 3- to 6-month DAPT (n=1002) or 12-month DAPT (n=1011). The primary outcome occurred in 37 (3.7%) patients in the 3- to 6-month DAPT group and 41 (4.1%) in the 12-month DAPT group. The noninferiority of the 3- to 6-month DAPT group to the 12-month DAPT group was met (absolute risk difference, –0.4% [1-sided 95% CI, –∞% to 1.1%]; P <0.001 for noninferiority). There were no significant differences in target lesion failure (hazard ratio, 0.98 [95% CI, 0.56–1.71], P =0.94) or major bleeding (hazard ratio, 0.82 [95% CI, 0.41–1.61], P =0.56) between the 2 groups. Across various subgroups, the treatment effect of 3- to 6-month DAPT was consistent for net adverse clinical event. Conclusions: Among patients undergoing percutaneous coronary intervention using third-generation drug-eluting stents, 3- to 6-month DAPT was noninferior to 12-month DAPT for net adverse clinical event. Further research is needed to generalize this finding to other populations and to determine the ideal regimen for 3- to 6-month DAPT. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02601157. [ABSTRACT FROM AUTHOR]

Background: Long term outcomes of antiplatelet monotherapy in patients who receive percutaneous coronary intervention (PCI) are unknown. The HOST-EXAM Extended study reports the post-trial follow-up results of the original HOST-EXAM trial. Methods: From March 2014 through May 2018, 5438 patients who maintained dual antiplatelet therapy without clinical events for 12±6 months after PCI with drug-eluting stents (DES) were randomly assigned in a 1:1 ratio to receive clopidogrel 75mg once daily or aspirin 100mg once daily. The primary endpoint (a composite of all-cause death, nonfatal myocardial infarction (MI), stroke, readmission due to acute coronary syndrome (ACS), and BARC type ≥3 bleeding), secondary thrombotic endpoint (cardiac death, non-fatal MI, ischemic stroke, readmission due to ACS, and definite or probable stent thrombosis), bleeding endpoint (BARC type ≥2 bleeding) were analyzed during the extended follow-up period. Analysis was performed on the per-protocol population (2431 patients in the clopidogrel group and 2286 patients in the aspirin group). Results: During median follow-up of 5.8 years (interquartile range, 4.8 and 6.2 years), the primary endpoint occurred in 12.8% and 16.9% in the clopidogrel and aspirin groups, respectively (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.63 to 0.86, p<0.001). The clopidogrel group had a lower risk for the secondary thrombotic endpoint (7.9% vs. 11.9%; HR 0.66, 95% CI 0.55 to 0.79, p<0.001) and secondary bleeding endpoint (4.5% vs. 6.1%; HR 0.74, 95% CI 0.57 to 0.94, p=0.016). There was no significant difference in the incidence of all-cause death between the two groups (6.2% vs. 6.0%; HR 1.04, 95% CI 0.82 to 1.31, p=0.742). Landmark analysis at 2 years showed that the beneficial effect of clopidogrel was consistent throughout the follow-up period. Conclusions: During an extended follow-up of over 5 years after randomization, clopidogrel monotherapy as compared with aspirin monotherapy was associated with lower rates of the composite net clinical outcome in patients without clinical events for 12±6 months after PCI with DES. [ABSTRACT FROM AUTHOR]

Background: Optimal antiplatelet monotherapy during the chronic maintenance period in patients who undergo coronary stenting is unknown. We aimed to compare head to head the efficacy and safety of aspirin and clopidogrel monotherapy in this population.Methods: We did an investigator-initiated, prospective, randomised, open-label, multicentre trial at 37 study sites in South Korea. We enrolled patients aged at least 20 years who maintained dual antiplatelet therapy without clinical events for 6-18 months after percutaneous coronary intervention with drug-eluting stents (DES). We excluded patients with any ischaemic and major bleeding complications. Patients were randomly assigned (1:1) to receive a monotherapy agent of clopidogrel 75 mg once daily or aspirin 100 mg once daily for 24 months. The primary endpoint was a composite of all-cause death, non-fatal myocardial infarction, stroke, readmission due to acute coronary syndrome, and Bleeding Academic Research Consortium (BARC) bleeding type 3 or greater, in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02044250.Findings: Between March 26, 2014, and May 29, 2018, we enrolled 5530 patients. 5438 (98·3%) patients were randomly assigned to either the clopidogrel group (2710 [49·8%]) or to the aspirin group (2728 [50·2%]). Ascertainment of the primary endpoint was completed in 5338 (98·2%) patients. During 24-month follow-up, the primary outcome occurred in 152 (5·7%) patients in the clopidogrel group and 207 (7·7%) in the aspirin group (hazard ratio 0·73 [95% CI 0·59-0·90]; p=0·0035).Interpretation: Clopidogrel monotherapy, compared with aspirin monotherapy during the chronic maintenance period after percutaneous coronary intervention with DES significantly reduced the risk of the composite of all-cause death, non-fatal myocardial infarction, stroke, readmission due to acute coronary syndrome, and BARC bleeding type 3 or greater. In patients requiring indefinite antiplatelet monotherapy after percutaneous coronary intervention, clopidogrel monotherapy was superior to aspirin monotherapy in preventing future adverse clinical events.Funding: ChongKunDang, SamJin, HanMi, DaeWoong, and the South Korea Ministry of Health and Welfare. [ABSTRACT FROM AUTHOR]