Potent P2Y12 Inhibitors Research Articles

Potent P2Y12 inhibitors in patients with acute myocardial infarction and cardiogenic shock

BackgroundAlthough potent P2Y12 inhibitors, such as ticagrelor and prasugrel, are standard treatment in patients with acute myocardial infarction (AMI), evidence for their efficacy and safety compared with clopidogrel is limited in patients with AMI complicated by cardiogenic shock.MethodsAmong 28,949 patients from the nationwide pooled registry of KAMIR-NIH and KAMIR-V, a total of 1482 patients (5.1%) with AMI and cardiogenic shock who underwent percutaneous coronary intervention of the culprit vessel were selected. Primary outcome was major adverse cardiovascular event (MACE, a composite of cardiac death, MI, repeat revascularization and definite stent thrombosis) and major secondary outcome was Bleeding Academic Research Consortium (BARC) type 2 or greater bleeding at 2 years.ResultsAmong the study population, 537 patients (36.2%) received potent P2Y12 inhibitors and 945 patients (63.8%) received clopidogrel after index procedure. The risk of MACE was significantly lower in the potent P2Y12 inhibitors group than in the clopidogrel group (16.6% versus 24.7%; adjusted hazard ratio [HR], 0.76 [95% CI 0.59–0.99]; P = 0.046). Regarding BARC type 2 or greater bleeding, there was no significant difference between the potent P2Y12 inhibitors group and the clopidogrel group (12.5% versus 10.7%; adjusted HR, 1.36 [95% CI 0.98–1.88]; P = 0.064). Significant interaction was observed in patients aged ≥ 75 years (interaction P = 0.021) or venoarterial extracorporeal membrane oxygenator (VA-ECMO) use (interaction P = 0.015) for significantly increased risk of BARC type 2 or greater bleeding following the use of potent P2Y12 inhibitors.ConclusionsIn patients with AMI complicated by cardiogenic shock, the use of potent P2Y12 inhibitors was associated with a lower risk of MACE compared with clopidogrel, without an increased risk of BARC type 2 or greater bleeding. The current data supports the use of potent P2Y12 inhibitors in patients with AMI and cardiogenic shock, except in patients aged ≥ 75 years or receiving VA-ECMO support.Graphical abstract

STEMI Antithrombotic Therapy: The Evolving Role of P2Y12 Inhibitor Pretreatment in Contemporary Practice.

The P2Y12 receptor plays a central role in platelet activation, secretion, and procoagulant activity. The CURE (clopidogrel in unstable angina to prevent recurrent events) trial, conducted in 2001, was the first to effectively demonstrate the benefit of dual anti-aggregation therapy with aspirin and clopidogrel in patients with acute coronary syndromes (ACS) undergoing invasive treatment. Since then, the field of interventional cardiology has changed considerably. The introduction of drug-eluting stents (DES) and the development of new, potent P2Y12 inhibitors such as ticagrelor, prasugrel and cangrelor have revolutionized the treatment of ACS. Nevertheless, ST-elevation myocardial infarction (STEMI) remains a critical condition that requires rapid and effective intervention. The use of P2Y12 receptor antagonists as part of the pretreatment strategy is an interesting topic to optimize outcomes in STEMI patients. This review summarizes the existing evidence on the efficacy and safety of pretreatment with P2Y12 receptor antagonists in STEMI, and emphasizes the importance of making pretreatment decisions based on individual clinical characteristics. The review also looks to the future, pointing to the potential role of artificial intelligence (AI) in improving STEMI diagnosis and treatment decisions, suggesting a future where technology could improve the accuracy and timeliness of care for STEMI patients.

The Comparative Effectiveness of Potent P2Y12 Inhibitors Versus Clopidogrel in Patients with Acute Myocardial Infarction Undergoing PCI: National Registry Data.

Dual antiplatelet therapy (DAPT), which is essential in AMI management, combines aspirin with a P2Y12 receptor antagonist. This study compared the effectiveness of potent P2Y12 inhibitors versus clopidogrel in AMI patients treated with percutaneous coronary intervention (PCI). Methods: 65,986 AMI patients included in a nationwide prospective registry who underwent PCI and received DAPT were studied. In total, 9,014 patients received potent P2Y12 inhibitors, and 56,074 received clopidogrel. This study focused on mortality, recurrent myocardial infarction, stroke, repeat revascularization, and major adverse cardiovascular events (MACE) over seven years. The analysis utilized unadjusted models and inverse probability of treatment weighting (IPTW) to compare prognosis, and decision curve analyses were constructed to aid clinical decision making. Results: Potent P2Y12 inhibitors significantly reduced mortality risk (unadjusted hazard ratio (HR): 0.58; IPTW HR: 0.68) and MACE (unadjusted HR: 0.66; IPTW HR: 0.78). Diabetic patients showed greater benefits (HR:0.45). In patients at high bleeding risk, the mortality rate was 13% (HR: 0.87, p = 0.08). For patients aged 75-79, the HR for mortality was 0.82, whereas for those aged >80 years, it was 0.79, indicating significant mortality risk reduction. Similar trends were observed for MACE. Conclusion: This study demonstrated that potent P2Y12 inhibitors are more effective than clopidogrel in reducing mortality and MACE in patients with AMI and underscored their potential role in improving outcomes across diverse patient subgroups. The trend was consistent even during the COVID-19 pandemic. These findings highlight the need for personalized DAPT strategies, particularly for high-bleeding-risk patients, and challenge current guidelines favoring clopidogrel use in older patients.

Safety and effectiveness of glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: insights from the SPUM-ACS study

Abstract Aims Data on Glycoprotein IIb/IIIa inhibitors (GPI) use in real world ACS patients following the introduction of potent P2Y12 inhibitors and newer generation stents are scant. Here, we aimed to assess the utilization, effectiveness, and safety of GPI in a large prospective cohort of contemporary ACS patients. Methods SPUM-ACS is a prospective, multicentre study in which ACS patients between 2009 and 2017 were recruited. The primary endpoint of the present study was major adverse cardiovascular events (MACE), a composite of all-cause death, non-fatal myocardial infarction (MI) and non-fatal stroke at one year. Any bleeding events, BARC 3-5 bleeding, and net adverse cardiovascular events (NACE) comprised the secondary endpoints. Results A total of 4395 ACS patients were included in the analysis. GPI-treated patients had more total coronary artery occlusion (56% vs 35%, p<0.001) and thrombus (60% vs 35%, p<0.001) at angiography. Among the propensity score matched (PSM) population (1992 patients equally split into two groups), GPI-treated patients showed lower MACE risk (PSM adjusted HR 0.70, 95% CI 0.49-0.99) but a higher risk of any (PSM adj HR 1.46, 95% CI 1.06-1.99) and major bleedings (PSM adj HR 1.73, 95% CI 1.09-2.76), resulting in a neutral effect on NACE (PSM adj HR 0.87, 95% CI 0.65-1.17). These results remained consistent across all subgroups. When including only patients treated with potent P2Y12, the incidence of MACE was not different between the two groups, (log rank p=0.50 and PSM adjusted HR 0.94, 95% CI 0.60-1.48). In the PSM population, GPI use (HR 0.76, 95% CI 0.59-0.99, p=0.04), TIMI 3 at the end of the procedure (HR 0.16, 95% CI 0.08-0.30, p<0.001) and potent P2Y12 inhibitor use (HR 0.70, 95% CI 0.49-0.99, p=0.04) were protective independent predictors of MACE at follow-up, while oral anticoagulation at discharge (4.48, 95% CI 2.10-9.52, p<0.001), multivessel disease (HR 1.95, 95% CI 1.09-3.48, p=0.02) and KILLIP class ≥ 2 at admission (HR 1.98, 95% CI 0.99-3.95, p=0.05) were adverse independent predictors. Conclusion In ACS patients undergoing PCI and broadly treated with potent P2Y12 inhibitors, GPI use reduced the risk of MACE at 1 year, while increasing the risk of major bleedings, with a neutral effect on NACE. The routine use of these pharmacological agents should be discouraged, while in selected patients GPI use should be considered following personalized balancing between ischaemic and bleeding risk.Events in PSM populationEvents in PSM population

Elderly patients are hyperresponsive to potent P2Y12 inhibitors

Abstract Background Aging has recently been associated with increased basal platelet activation and adenosine diphosphate (ADP) hyperreactivity on the one hand, but decreased platelet response to thrombin receptor stimulation on the other hand in individuals without antiplatelet therapy. In the current study, we investigated platelet response to agonist stimulation in elderly patients (70 years or older) on dual antiplatelet therapy with potent P2Y12 inhibitors. Methods Platelet aggregation in response to arachidonic acid (AA), ADP, collagen, the protease-activated receptor (PAR)-1 agonist SFLLRN and the PAR-4 agonist AYPGKF was assessed by multiple electrode aggregometry in 79 prasugrel- and 77 ticagrelor-treated patients 3 days after acute percutaneous coronary intervention. Results In the overall study population (n=156), patients aged ≥70 years (n=33) had lower platelet aggregation in response to AA, ADP and SFLLRN than younger patients (all p<0.05). In prasugrel-treated patients (n=79), those aged ≥70 years (n=13) showed significantly lower platelet aggregation in response to all agonists compared to younger patients (all p<0.05). In contrast, in ticagrelor-treated patients (n=77), those aged ≥70 years (n=20) only had significantly lower ADP-inducible platelet aggregation than younger patients (p=0.03), whereas platelet aggregation in response to AA, collagen, SFLLRN and AYPGKF was similar between elderly and younger patients on ticagrelor (all p>0.05). Among patients aged ≥70 years, prasugrel-treated patients showed significantly lower platelet aggregation in response to AA, collagen and AYPGKF than those receiving ticagrelor (all p<0.05). Conclusion Patients aged ≥70 years on potent P2Y12 inhibitors exhibit increased inhibition of ADP-inducible platelet aggregation. In addition, elderly patients on prasugrel show a significantly lower response to AA, collagen, SFLLRN and AYPGKF than younger patients.Platelet aggregation prasugrel patientsPlatelet aggregation ticagrelor patients

The impact of body mass on cardiovascular outcomes in patients with acute coronary syndrome

Abstract Background Patients with acute coronary syndrome (ACS) and extreme body weights exhibit varying risks of bleeding and thrombotic outcomes. Furthermore, extreme body weights can influence the pharmacodynamic response to potent P2Y12 inhibitors (ticagrelor/prasugrel) and clopidogrel. Purpose This study aims to assess the impact of extreme body weights on cardiovascular outcomes, as well as the comparative efficacy and safety of potent P2Y12 inhibitors versus clopidogrel. Methods Data was extracted from the FORCE-ACS registry, a prospective, multicentre, registry, enrolling patients with ACS. Patients were stratified (in kg/m2) into the categories: underweight (body mass index [BMI] ≤20.0), normal weight (20.1–24.9), overweight (25.0–29.9), class 1 (30.0–34.9) and class 2 obesity (≥35.0). The primary thrombotic endpoint was major adverse cardiac events (MACE), a composite of cardiovascular death, myocardial infarction (MI), or stroke. The primary bleeding endpoint was defined as Bleeding Academic Research Consortium (BARC) 2, 3 or 5 bleeding. Cox proportional hazard models and Kaplan-Meier survival curves were used to estimate the risk of clinical events across the BMI categories. Restricted cubic splines were made to assess the continuous association of BMI with the risk of the primary endpoints, stratified for P2Y12-inhibitor therapy (potent vs. clopidogrel) and gender. Results The total included population consisted of 5,864 patients with ACS (mean age 65.2 years, 72.4% men), and were stratified into underweight (N=112 [2%]), normal weight (N=1,627 [28%]), overweight (N=2,697 [46%]), class 1 obesity (N=1,081 [18%]) and class 2 obesity (N=347 [6%]). Compared with normal weight (10.8%), the rate of primary bleeding outcome was higher in underweight (15.2%) patients, but lower in the overweight (8.9%), class 1 obesity (7.9%) and class 2 obesity (6.3%) categories. MACE occurred in 9.8% for the underweight group, 7.9% for normal weight, 7.0% for overweight, 8.0% for class, and 6.1% for class 2 obesity. After adjusting for confounding factors such as age, gender, cardiovascular risk factors, access site, and medical therapy, each unit increase in BMI was associated with a decreased bleeding risk (hazard ratio [HR] 0.97, 95% CI 0.95-0.99, p = 0.02), with no significant association found for MACE. Similar findings are demonstrated in the Kaplan Meier analysis (Figure 1A-1B). Subgroup analysis regarding bleeding risk and BMI did not show a significant interaction for potent P2Y12-inhibitor therapy versus clopidogrel and gender (P-value for interaction: 0.04 and 0.32, respectively)(Figure 2A-2D). Conclusions Our findings indicate a stronger correlation between BMI and bleeding risk compared to thrombotic risk, showing an increased risk for bleeding in patients with a low BMI. These results underscore the importance of careful monitoring and tailored interventions to mitigate bleeding risk in underweight patients.

Association of P2Y12 inhibitor pretreatment strategy with short and long term ischemic and bleeding outcomes in NSTE-ACS patients

Abstract Background and Aims Oral P2Y12 inhibitors form the basis of both short and long term antiplatelet therapy in NSTE-ACS patients. While reducing thrombogenic activity and ischemic risk is the basis of routine P2Y12 inhibitor pretreatment in NSTE-ACS patients, timing of treatment became controversial as a result of studies showing routine P2Y12 inhibitor pretreatment is associated with an increased risk of bleeding. Even though routine pretreatment is no longer recommended in the ESC guidelines, the inadequacies in RCTs combining all treatment modalities have been noted. Our study aims to determine the relationship between P2Y12 inhibitor pretreatment strategy and short and long-term ischemic and bleeding events. Methods The study was designed as a single-center, prospective and observational study. 2602 patients, aged between 18 and 85, diagnosed with NSTE-ACS in accordance with ESC guidelines were included in the study. 2189 patients were administered with P2Y12 inhibitor pretreatment while 413 patients weren't. Demographic data, CVD risk factors, ECG, echocardiography and laboratory findings at the time of admission, interventional procedural details, type of antiplatelet and anticoagulant treatment and application time were recorded. Patients were divided into two groups as pretreatment and no-pretreatment according to the time of administration of P2Y12 inhibitor loading dose. In the no-pretreatment group choice of P2Y12 inhibitor was left to operator in the cath lab before proceeding to PCI. Post-procedural in-hospital and long term follow up (1 year) were obtained through hospital and national registry systems and patient survey. Results In the no-pretreatment group 91.3% of patients underwent coronary angiography and PCI was performed in 51.8%. In patients proceeding to PCI, 58.5% were given clopidogrel and 41.5% were given a potent P2Y12 inhibitor. In the pretreatment group, clopidogrel was the drug of choice in 93.8% of patients. In the pretreatment group, the primary composite endpoint (MACE and bleeding events) were more common during in-hospital follow-up and this difference was due to a significant increase in both BARC class I & II and class III, IV & V bleedings (Table 1). In the long-term follow up, statistically significant difference was only seen in BARC class I & II bleedings in the pretreatment group. There were no difference in MACE rates in neither in-hospital or long-term follow up (Table 2). Also in multivariate regression analysis, pretreatment with a P2Y12 inhibitor was found to be an independent predictor of short term primary composite endpoints and long-term all-cause mortality. Conclusion The results of our study investigating the effects of the P2Y12 inhibitor pretreatment strategy on ischemic and bleeding endpoints in NSTE-ACS patients showed that the pretreatment strategy did not lead to an improvement in MACE rates in in-hospital and long-term follow-up but caused on overall increase in bleeding events.Kaplan-Meier Survival Analysis

The real-world safety of ticagrelor among older adults (above 75 years): a pharmacovigilance study from the FDA data

Abstract Introduction Potent P2Y12 inhibitors are recommended in conjunction with Aspirin for the treatment of acute coronary syndrome. Since Prasugrel is relatively contraindicated in patients older than 75 years, Ticagrelor remains the primary potent P2Y12 inhibitor option for this age group. However, its safety profile among older adults has not been adequately examined. Purpose To examine Ticagrelor safety profile among older adults (≥75 years) patients Methods We conducted a retrospective pharmacovigilance study utilizing the FDA Adverse Event Reporting System (FAERS) database. We employed disproportionality analysis comparing Ticagrelor to Clopidogrel. We evaluated the reporting of predefined adverse events (dyspnea, bradyarrhythmia, complete AV block [CAVB], intracranial hemorrhage, gastrointestinal hemorrhage, acute kidney injury [AKI], and gout) in adults (<75 years) and older adults (≥75 years). For each group, we calculated reporting odds ratio (ROR) and its 95% confidence interval and compared them by calculating P for interaction. Results The FAERS database encompassed 6,476 adverse event reports for Ticagrelor; 4,795 (74%) adults and 1,681 (26%) older adults. Among older adults and compared to Clopidogrel, Ticagrelor was not associated with an increased reporting for dyspnea (ROR 3.3 [2.7-3.9] vs. 3.9 [3.5-4.5]), bradyarrhythmia (ROR 4.1 [2.5 – 6.7] vs 5.4 [3.9 – 7.6]) intracranial hemorrhage (ROR 1.1 [0.7-1.7] vs. 1.1[0.8-1.5]), CAVB (ROR 11.5 [3.1–42.4] vs. ROR 27.8 [6.7-116.3]), and gout (ROR 3.8 [0.5-27] vs. 3.9 [2-7.5]). AKI was reported more frequently among older adults (ROR 2.3 [1.5-3.6] vs. 0.6 [0.4-0.9]). Ticagrelor was not associated with an increased reporting of GI hemorrhage. Conclusion According to the FAERS, Ticagrelor is generally safe for use in older adults (≥75 years) with no significant increase in the reporting of major adverse events compared to adults (<75 years), except for a higher reporting of AKI.

One-year clinical outcome of aspirin-free prasugrel monotherapy following stent implantation in patients with chronic coronary syndrome: insight from ASET-JAPAN study

Abstract Background Single antiplatelet therapy with a potent P2Y12 inhibitor without aspirin after coronary stent implantation may provide an adequate balance between ischemic and bleeding risks in selected patients. The 3-month follow-up of the Acetyl-Salicylic Elimination Trial (ASET)-Japan pilot study demonstrated the feasibility and safety of Prasugrel monotherapy without aspirin after successful percutaneous coronary intervention (PCI) in selected patients with chronic coronary syndrome (CCS). Purpose The current study aimed to evaluate the 1-year clinical outcome in the ASET-Japan. Methods The ASET-Japan pilot study was designed to demonstrate the feasibility and safety of the approved dose of prasugrel monotherapy in Japan without aspirin after optimal PCI with a platinum-chromium everolimus-eluting stent in CCS population. After successful procedure, all patients were treated with a locally approved maintenance dose of 3.75 mg/day of Prasugrel monotherapy up to 3-month. After 3-month, the choice of antiplatelet therapy was left to the discretion of the investigators. Patients were followed up to 1 year. The target lesion-related endpoint was a composite of cardiac death, spontaneous target-vessel myocardial infarction (MI) >48 h after the index PCI or clinical-driven target lesion revascularisation. Patient-Oriented Composite Endpoint (POCE) was defined as a composite of all cause mortality, any stroke, any MI and any revascularisation. Spontaneous MI was defined according to Forth universal definition. The event rate was estimated by the Kaplan-Meier method. The event was adjudicated by an independent clinical event committee. Results A total of 208 patients were enrolled in the study. The average anatomical SYNTAX score was 7.96 (±4.6). After procedure, prasugrel monotherapy was immediately initiated. After 3-month, Prasugrel monotherapy was continued in 88.6% up to 1-year. Aspirin monotherapy was prescribed to 10 patients (5.0%), while 6 patients (3.0%) were on DAPT at 1-year. All-cause mortality rate was 1.49%, with no occurrence of cardiovascular death. Revascularisation occurred in 4.0% (n=8) with no occurrence of TLR, while one patient (0.5%) underwent a clinical driven target vessel revascularisation. In summary, 7 out of 8 revascularisations were non-target vessel revascularisation (6 clinically-driven non-TVR). Spontaneous non TV-MI occured in 0.5% (n=1) of patients. There was no definite/probable stent thrombosis up to 1 year. The target lesion related endpoint rate at 1-year was 0%, whereas 1-year POCE rate was 7.0% (n=14). Conclusion Discontinuation of Aspirin and Prasugrel monotherapy at a low maintenance dose of 3.75 mg/day following an angiographically successful stent deployment was feasible and safe in selected patients with CCS and low SYNTAX score. This safety profile is confirmed at 1 year while the investigators, in their large majority and at their own discretion, had maintained the prasugrel treatment.

Cangrelor use in ticagrelor-loaded ST-elevation myocardial infarction patients with high residual platelet reactivity: a randomized controlled trial

Abstract Background Despite the use of potent P2Y12 inhibitor, many patients still present with high platelet reactivity (HPR) at the time of primary percutaneous coronary intervention (PCI). HPR is associated with impaired myocardial reperfusion and the subsequent poor outcome. Purpose We sought to determine the impact of Cangrelor -a rapid and potent intravenous P2Y12 inhibitor- on myocardial reperfusion in patients with HPR admitted for primary PCI in a randomized trial. Methods Patients pre-treated with ticagrelor and aspirin with residual HPR (baseline platelet reactivity unit (PRU) > 208) were randomly assigned in a 1:1 ratio to receive cangrelor (experimental group) or not (control group) just before PCI. The primary endpoint was optimal myocardial reperfusion defined as a final myocardial blush grade (MBG) 3 assessed by an independent core laboratory. Results After screening of 128 patients, a total of 60 patients were with HPR were enrolled and randomized. The ticagrelor loading dose to PRU measurement times were 83 ± 32 and 90 ± 47 minutes in the experimental and control groups, respectively. Baseline PRU were 245 ± 30 and 252 ± 35 in the experimental and standard group, respectively. A final MBG 3 was observed in 21/30 (55%) and 17/30 (45%) the experimental and standard groups (p=0.29). A final TIMI flow grade 3 was observed in 30/30 (100%) and 27/30 (90%) the experimental and standard groups (p=0.24). Peak troponin levels after PCI were 51381 ± 50047 and 51078 ± 63960 ng/L (p=0.98) in the experimental and standard group, respectively. At the end of the PCI, control PRU were 36 ± 57 and 198 ± 107 (p<0.0001) in the experimental and standard group, respectively. One patient of the experimental group presented an in-hospital major bleeding (BARC 3). Conclusion In ticagrelor-loaded STEMI patients with residual HPR at the time of PCI, cangrelor use was associated with a more effective platelet inhibition but failed to significantly improve the rates of optimal final myocardial blush grades.

From bench to bedside and back to bench: investigating the role of platelet heterogeneity in coronary artery disease

Abstract Background/Introduction Platelets exhibit considerable heterogeneity in RNA content, size, and thrombogenicity. Our preliminary investigation of the transcriptome of the RNA-rich reticulated platelets(RPs) in healthy donors revealed an enrichment of prothrombotic transcripts compared to mature platelets(MPs). Recently, we validated the prognostic role of elevated RPs at clinical level in a modern cohort of ACS patients treated with potent P2Y12 inhibitors. However, the pathophysiology of RP hyperreactivity remains unclear, particularly its correlation with adverse events and cardiovascular death. Purpose To study the biology of RPs in patients with chronic coronary syndrome(CCS) and to elucidate their role in disease progression. Methods RPs were isolated from peripheral blood of CCS patients(N=20) and compared with MPs. Cell viability and reactivity of RPs were quantified by FACS. Deep transcriptomic profiling was performed using post-sorting bulk RNA sequencing of RPs and MPs and analyzed with ad-hoc bioinformatic pipelines. Proteomic profiling using mass cytometry(CyTOF) was used to validate the transcriptomic findings with single cell resolution. Results FACS analysis confirmed RPs hyperreactivity showing increased P-Selectin expression upon activation with TRAP, ADP and Collagen(Fig. 1A). Total RNA-sequencing detected 2213 differentially regulated genes with an enrichment in RPs of key functional transcript such as, the von Willebrand Factor VWF(p=3.06*10-33), the thromboxane receptor TBXA2R(p=2.07*10-29) and the collagen receptor GP6(p=1.29*10-38, Fig. 1B-C). Gene ontology and gene set enrichment analyses detected an upregulation of relevant categories as "Regulation of platelet activation" and "Platelet aggregation"(Fig. 1D-F). In addition, we detected a novel alternative splicing event on the collagen receptor transcript GP6 upregulated in RPs(Fig. 1G). We detected 33 differentially regulated miRNAs, including miR-409, miR-134 and miR-432, which have been already linked to prothrombotic phenotypes(Fig. 1H). Additionally, we detected an enrichment of circular RNAs in RPs compared to MPs with several circular RNA upregulated in RPs, that have not been described before(Fig. 1I-K). Mass cytometry detected a significant upregulation in RPs of relevant proteins including the collagen receptor GPVI(p=8.98*10-12, Fig.2) and the thrombin receptor PAR1(p=5.21*10-11). Validation assays in an independent cohort detected an upregulation of the PI3K/AKT pathway in RPs which is downstream of the receptor PAR1 and GP6. Conclusion This study represents the first comprehensive multiomic characterization of RPs in CCS patients, providing insights into their prothrombotic phenotype and into their correlation with cardiovascular events. These findings suggest potential avenues for tailored therapeutic interventions targeting the identified upregulated pathways in patients with elevated RPs, warranting further investigation at the clinical level.

The impact of targeted bleeding source treatment on the risk of recurrent bleeding after percutaneous coronary intervention among patients with a history of prior bleeding

Abstract Background Prior bleeding is one of the strongest predictors for bleeding after percutaneous coronary intervention (PCI). Whether targeted treatment of the prior bleeding site affects the risk of bleeding after PCI is unknown to date. Methods From an all-comers population undergoing PCI between 2009-2019, patients with BARC 2-4 bleeding prior to index PCI were identified. Among those, the recurrence of BARC 2-5 bleeding at the same bleeding site, any BARC 2-5 bleeding, and mortality were compared throughout 1 year after PCI between patients with vs. without targeted treatment at the prior bleeding site. Targeted treatment was defined as medical, interventional, or surgical therapy targeted to cure the cause of bleeding. Adjusted hazard ratios (HRadj) were extracted from Cox regressions. Inverse probability weights were computed from a logistic regression with targeted treatment as dependent variable, and the following covariates: ARC-HBR variables associated with ≥4% 1-year bleeding risk in this registry (including oral anticoagulation), aspirin, potent P2Y12 inhibitor treatment, and prior bleeding site. Results Out of 18’510 patients enrolled from 2009-2019, 845 (4.6%) had a history of prior BARC 2-4 bleeding before PCI. Mean age was 71.6 years, 25% were female, and 52% presented with acute coronary syndrome. Patients with targeted treatment were significantly younger (70.3 vs. 72.5 years, p=0.005) and had more frequently malignancies (25% vs. 18%, p=0.012). 26/344 (7.6%) of patients with targeted treatment vs. 31/501 (6.2%) of patients without targeted treatment experienced recurrent BARC 2-5 bleeding at the same bleeding site (HRadj 1.35, 95% CI 0.79-2.30, p=0.268). 45/344 (13.1%) of patients with targeted treatment vs. 59/501 (11.8%) of patients without targeted treatment experienced any recurrent BARC 2-5 bleeding (HRadj 1.16, 95% CI 0.78-1.72, p=0.473). The rate of mortality was also similar between the groups (targeted treatment 13.7% vs. no targeted treatment 12.4%, HRadj 1.13, 95% CI 0.76-1.67, p=0.549). Conclusions Among patients with a bleeding history before PCI, half of the recurrent bleeding events throughout 1-year after PCI occurred at the same bleeding site, regardless of whether the bleeding source underwent targeted treatment. These findings imply that targeted treatment is not protective for recurrent bleeding events after PCI and that prior bleeding represents rather a systemic than local bleeding risk.Frequency of bleeding sitesKaplan Meier curves

Short-Term Dual Antiplatelet Therapy After Drug-Eluting Stenting in Patients With Acute Coronary Syndromes

The optimal duration of dual antiplatelet therapy (DAPT) in patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI) remains under debate. To analyze the efficacy and safety of DAPT strategies in patients with ACS using a bayesian network meta-analysis. MEDLINE, Embase, Cochrane, and LILACS databases were searched from inception to April 8, 2024. Randomized clinical trials (RCTs) comparing DAPT duration strategies in patients with ACS undergoing PCI were selected. Short-term strategies (1 month of DAPT followed by P2Y12 inhibitors, 3 months of DAPT followed by P2Y12 inhibitors, 3 months of DAPT followed by aspirin, and 6 months of DAPT followed by aspirin) were compared with conventional 12 months of DAPT. This systematic review and network meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. The risk ratio (RR) with a 95% credible interval (CrI) was calculated within a bayesian random-effects network meta-analysis. Treatments were ranked using surface under the cumulative ranking (SUCRA). The primary efficacy end point was major adverse cardiac and cerebrovascular events (MACCE); the primary safety end point was major bleeding. A total of 15 RCTs randomizing 35 326 patients (mean [SD] age, 63.1 [11.1] years; 26 954 male [76.3%]; 11 339 STEMI [32.1%]) with ACS were included. A total of 24 797 patients (70.2%) received potent P2Y12 inhibitors (ticagrelor or prasugrel). Compared with 12 months of DAPT, 1 month of DAPT followed by P2Y12 inhibitors reduced major bleeding (RR, 0.47; 95% CrI, 0.26-0.74) with no difference in MACCE (RR, 1.00; 95% CrI, 0.70-1.41). No significant differences were observed in MACCE incidence between strategies, although CrIs were wide. SUCRA ranked 1 month of DAPT followed by P2Y12 inhibitors as the best for reducing major bleeding and 3 months of DAPT followed by P2Y12 inhibitors as optimal for reducing MACCE (RR, 0.85; 95% CrI, 0.56-1.21). Results of this systematic review and network meta-analysis reveal that, in patients with ACS undergoing PCI with DES, 1 month of DAPT followed by potent P2Y12 inhibitor monotherapy was associated with a reduction in major bleeding without increasing MACCE when compared with 12 months of DAPT. However, an increased risk of MACCE cannot be excluded, and 3 months of DAPT followed by potent P2Y12 inhibitor monotherapy was ranked as the best option to reduce MACCE. Because most patients receiving P2Y12 inhibitor monotherapy were taking ticagrelor, the safety of stopping aspirin in those taking clopidogrel remains unclear.

Can CYP2C19 genotyping improve antiplatelet therapy efficacy in real-life practice? Recent advances.

Clopidogrel remains the most widely used P2Y12 receptor inhibitor worldwide and is often used in combination with aspirin for secondary prevention in patients with arterial disease. The drug is associated with a wide variation in responses, with one in 3 patients exhibiting little or no inhibition of adenosine diphosphate-induced platelet aggregation. It is a prodrug that is mainly metabolized by hepatic cytochrome P450 (CYP) 2C19. Patients who carry a CYP2C19 loss-of-function (LoF) allele have reduced metabolism of clopidogrel, which is associated with reduced platelet inhibition compared to non-carriers and an increased risk for thrombotic event occurrences, particularly stent thrombosis. The United States Food and Drug Administration (FDA) issued a 'black box warning' on the clopidogrel label highlighting the importance of the presence of CYP2C19 LOF allele during insufficient metabolism of clopidogrel and the availability of alternate potent P2Y12 inhibitors for the treatment in CYP2C19 poor metabolizers. Clinical trials have conclusively demonstrated greater anti-ischemic benefits of prasugrel/ticagrelor in the treatment of patients carrying the CYP2C19 LoF allele. However, uniform use of these more potent P2Y12 inhibitors has been associated with greater bleeding and higher cost, and lower adherence. This latter information provides a strong rationale for personalizing P2Y12 inhibitor therapy based on the laboratory determination of the CYP2C19 genotype. However, cardiologists have been slow to take up pharmacogenetic testing, possibly due to a lack of provider and patient education, clear cardiology guidelines and lack of positive results from adequately sized randomized clinical trials. However, current evidence strongly supports genotyping of patients who are candidates for clopidogrel. Physicians should strongly consider performing genetic tests to identify LoF carriers and treat these patients with more pharmacodynamically predictable P2Y12 inhibitors than clopidogrel.

Ticagrelor monotherapy in ST-elevation myocardial infarction: An individual patient-level meta-analysis from TICO and T-PASS trials.

Patients with ST-elevation myocardial infarction (STEMI) tend to be excluded or under-represented in randomized clinical trials evaluating the effects of potent P2Y12 inhibitor monotherapy after short-term dual antiplatelet therapy (DAPT). Individual patient data were pooled from randomized clinical trials that included STEMI patients undergoing drug-eluting stent (DES) implantation and compared ticagrelor monotherapy after short-term (≤3months) DAPT versus ticagrelor-based 12-month DAPT in terms of centrally adjudicated clinical outcomes. The co-primary outcomes were efficacy outcome (composite of all-cause death, myocardial infarction, or stroke) and safety outcome (Bleeding Academic Research Consortium type 3 or 5 bleeding) at 1 year. The pooled cohort contained 2,253 patients with STEMI. The incidence of the primary efficacy outcome did not differ between the ticagrelor monotherapy group and the ticagrelor-based DAPT group (1.8% versus 2.0%; hazard ratio [HR]= 0.88; 95% confidence interval [CI]= 0.49-1.61; p= 0.684). There was no difference in cardiac death between the groups (0.6% versus 0.7%; HR= 0.89; 95% CI= 0.32-2.46; p= 0.822). The incidence of the primary safety outcome was significantly lower in the ticagrelor monotherapy group (2.3% versus 4.0%; HR= 0.56; 95% CI= 0.35-0.92; p= 0.020). No heterogeneity of treatment effects was observed for the primary outcomes across subgroups. In patients with STEMI treated with DES implantation, ticagrelor monotherapy after short-term DAPT was associated with lower major bleeding without an increase in the risk of ischemic events compared with ticagrelor-based 12-month DAPT. Further research is necessary to extend these findings to non-Asian patients. This study was funded by Biotronik (Bülach, Switzerland).

Duration of triple antithrombotic therapy and clinical outcomes after percutaneous coronary intervention in atrial fibrillation

ABSTRACT Background Triple antithrombotic therapy (TAT) with aspirin, a P2Y12 inhibitor, and oral anticoagulation in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) raises concerns about increased bleeding. Regimens incorporating more potent P2Y12 inhibitors over clopidogrel have not been investigated adequately. Research design and methods A retrospective observational study was performed on 387 patients with AF receiving TAT for 1 month (n = 236) or ≤1 week (n = 151) after PCI. Major and clinically relevant non-major bleeding and major adverse cardiac and cerebrovascular events (MACCE) were assessed up to 30 days post-procedure. Results Bleeding was less frequent with ≤1 week versus 1 month of TAT (3.3 vs 9.3%; p = 0.025) while MACCE were similar (4.6 vs 4.7%; p = 0.998). No differences in bleeding or MACCE were observed between ticagrelor/prasugrel and clopidogrel regimens. For patients receiving ≤1 week of TAT, no excess of MACCE was seen in the subgroup given no further aspirin post-PCI compared with those given aspirin for up to 1 week (3.6 vs 5.2%). Conclusions TAT post-PCI for ≤1 week was associated with less bleeding despite greater use of ticagrelor/prasugrel but similar MACCE versus 1-month TAT. These findings support further studies on safety and efficacy of dual therapy with ticagrelor/prasugrel immediately after PCI.

CYP2C19 Genetic Testing for Oral P2Y12 Inhibitor Therapy: A Scientific Statement From the American Heart Association.

There is significant variability in the efficacy and safety of oral P2Y12 inhibitors, which are used to prevent ischemic outcomes in common diseases such as coronary and peripheral arterial disease and stroke. Clopidogrel, a prodrug, is the most used oral P2Y12 inhibitor and is activated primarily after being metabolized by a highly polymorphic hepatic cytochrome CYP2C219 enzyme. Loss-of-function genetic variants in CYP2C219 are common, can result in decreased active metabolite levels and increased on-treatment platelet aggregation, and are associated with increased ischemic events on clopidogrel therapy. Such patients can be identified by CYP2C19 genetic testing and can be treated with alternative therapy. Conversely, universal use of potent oral P2Y12 inhibitors such as ticagrelor or prasugrel, which are not dependent on CYP2C19 for activation, has been recommended but can result in increased bleeding. Recent clinical trials and meta-analyses have demonstrated that a precision medicine approach in which loss-of-function carriers are prescribed ticagrelor or prasugrel and noncarriers are prescribed clopidogrel results in reducing ischemic events without increasing bleeding risk. The evidence to date supports CYP2C19 genetic testing before oral P2Y12 inhibitors are prescribed in patients with acute coronary syndromes or percutaneous coronary intervention. Clinical implementation of such genetic testing will depend on among multiple factors: rapid availability of results or adoption of the concept of performing preemptive genetic testing, provision of easy-to-understand results with therapeutic recommendations, and seamless integration in the electronic health record.

Clopidogrel resistance and its relevance: Current concepts

ABSTRACT Clopidogrel is the most widely used P2Y12 receptor inhibitor (P2Y12i) as a part of dual antiplatelet therapy along with aspirin. Clopidogrel is a pro-drug and is metabolized to its active metabolite by the hepatic enzyme cytochrome P4502C19 (CYP2C19). This active metabolite is responsible for the antiplatelet action of clopidogrel. Recent studies have demonstrated that single nucleotide polymorphisms in the CYP2C19 gene, including CYP2C19*2,*3,*4, and *5 alleles, result in reduced production of the active metabolite of clopidogrel, and hence reduced inhibition of platelet aggregation. This in turn enhances the incidence of stent thrombosis and recurrent cardiovascular (CV) events. We report a case of coronary stent thrombosis due to clopidogrel resistance proven by CYP2C19 genotyping. We then review the literature on clopidogrel resistance and its impact on CV outcomes. Subsequently, we discuss the methods of diagnosis of resistance, evidence from clinical trials for tailoring clopidogrel therapy, the role of potent P2Y12 inhibitors, the current guidelines, and future directions.

De-escalation of dual antiplatelet therapy for patients with acute coronary syndrome after percutaneous coronary intervention: a systematic review and network meta-analysis

ObjectivesTo compare dual antiplatelet therapy (DAPT) de-escalation with five alternative DAPT strategies in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI).DesignWe conducted a systematic review and network...

Ticagrelor monotherapy for acute coronary syndrome: an individual patient data meta-analysis of TICO and T-PASS trials.

In patients with acute coronary syndrome (ACS), dual antiplatelet therapy (DAPT) with aspirin and a potent P2Y12 inhibitor is recommended for 12 months after drug-eluting stent (DES) implantation. Monotherapy with a potent P2Y12 inhibitor after short-term DAPT is an attractive option to better balance the risks of ischaemia and bleeding. Therefore, this study evaluated the efficacy and safety of ticagrelor monotherapy after short-term DAPT, especially in patients with ACS. Electronic databases were searched from inception to 11 November 2023, and for the primary analysis, individual patient data were pooled from the relevant randomized clinical trials comparing ticagrelor monotherapy after short-term (≤3 months) DAPT with ticagrelor-based 12-month DAPT, exclusively in ACS patients undergoing DES implantation. The co-primary endpoints were ischaemic endpoint (composite of all-cause death, myocardial infarction, or stroke) and bleeding endpoint [Bleeding Academic Research Consortium (BARC) type 3 or 5 bleeding] at 1 year. Individual patient data from two randomized clinical trials including 5906 ACS patients were analysed. At 1 year, the primary ischaemic endpoint did not differ between the ticagrelor monotherapy and ticagrelor-based DAPT groups [1.9% vs. 2.5%; adjusted hazard ratio (HR) 0.79; 95% confidence interval (CI) 0.56-1.13; P = .194]. The incidence of the primary bleeding endpoint was lower in the ticagrelor monotherapy group (2.4% vs. 4.5%; adjusted HR 0.54; 95% CI 0.40-0.72; P < .001). The results were consistent in a secondary aggregate data meta-analysis including the ACS subgroup of additional randomized clinical trials which enrolled patients with ACS as well as chronic coronary syndrome. In ACS patients undergoing DES implantation, ticagrelor monotherapy after short-term DAPT was associated with less major bleeding without a concomitant increase in ischaemic events compared with ticagrelor-based 12-month DAPT. PROSPERO (ID: CRD42023476470).