Potent P2Y12 Receptor Inhibitors Research Articles

Immature Platelet Fraction Predicts Adverse Events in Patients With Acute Coronary Syndrome: the ISAR-REACT 5 Reticulated Platelet Substudy.

Immature or reticulated platelets are associated with impaired efficacy of antiplatelet drugs and adverse events in cardiovascular patients. Their role as a predictive biomarker in patients with acute coronary syndrome treated with potent P2Y12 receptor inhibitors is not fully understood. We aimed to prospectively evaluate reticulated platelets as a predictor of the primary end point of the ISAR-REACT 5 trial consisting of death, myocardial infarction, or stroke at 1 year in patients with acute coronary syndrome randomized to prasugrel or ticagrelor. Immature platelet fraction (IPF) was assessed within 48 hours after randomization. Patients were divided based on the IPF median values: the IPFhigh group included patients with IPF>median and the IPFlow group included patients with IPF≤median. Platelet aggregation was assessed using the Multiplate Analyzer and was correlated to IPF. Five hundred seventy-seven patients were included in the study. IPF values in % (median [interquartile range]) within the first 48 hours did not differ between the two study groups: 3.6 (2.5-5.2)% in the prasugrel group and 3.6 (2.5-5.4)% in the ticagrelor group (P=0.882). The incidence of the primary end point was significantly higher in the IPFhigh (IPF>3.6%) group compared with the IPFlow (IPF≤3.6%) group: 13.0% versus 7.2% (HRadj, 1.74 [1.02-3.00]; P=0.044), independently from the assigned drug (Pint=0.159). No significant association between IPF and BARC 3 to 5 bleeding was observed. ADP-induced platelet aggregation correlated significantly with IPF in patients treated with prasugrel (r=0.22; P=0.005) while no correlation was detected in patients treated with ticagrelor (r=0.09; P=0.257). Independently from drug treatment, IPF was associated with the primary end point and therefore is a promising biomarker for the prediction of adverse cardiovascular events in patients with acute coronary syndrome treated with prasugrel or ticagrelor. https://www. gov; Unique identifier: NCT01944800.

Comparative effects of fentanyl versus morphine on platelet inhibition induced by ticagrelor in patients with ST-segment elevation myocardial infarction: Full results of the PERSEUS randomized trial.

BackgroundMorphine reduces absorption and delays action onset of potent oral P2Y12 receptor inhibitors in patients with ST-segment elevation myocardial infarction (STEMI). We sought to determine the differential effects of fentanyl compared to morphine on the pharmacodynamics and pharmacokinetics of ticagrelor in STEMI patients undergoing primary percutaneous coronary intervention (PCI).MethodsPERSEUS (NCT02531165) was a prospective, single-center, open-label, randomized controlled study. Patients with STEMI who required analgesia were randomly assigned in a 1:1 ratio to treatment with intravenous fentanyl or morphine after ticagrelor loading dose (LD) administration. The primary endpoint was platelet reactivity at 2 hours after ticagrelor LD assessed by P2Y12 reaction units (PRU).ResultsThe study was prematurely stopped in June 2017 after enrolment of 38 out of 56 planned patients. PRU at 2 hours following ticagrelor LD was 173.3 ± 89.7 in the fentanyl group and 210.3 ± 76.4 in the morphine group (p = 0.179). At 4 hours, PRU was significantly lower among patients treated with fentanyl as compared to those treated with morphine (90.1 ± 97.4 vs. 168.0 ± 72.2; p = 0.011). Maximal plasma concentrations of ticagrelor and its active metabolite AR-C124910XX tended to be delayed and numerically lower among patients treated with morphine compared to fentanyl. Total exposures to ticagrelor and AR-C124910XX within 6 hours after ticagrelor LD were numerically greater among patients treated with fentanyl compared to those treated with morphine.ConclusionsIn patients with STEMI undergoing primary PCI, fentanyl did not improve platelet inhibition at 2 hours after ticagrelor pre-treatment compared with morphine. Fentanyl may, however, accelerate ticagrelor absorption and increase platelet inhibition at 4 hours compared to morphine.

Current Therapeutic Approach to Acute Myocardial Infarction in Patients with Congenital Hemophilia.

Advances in the treatment of hemophilia have made the life expectancy of hemophiliacs similar to that of the general population. Physicians have begun to face age-related diseases not previously encountered in individuals with hemophilia. Treatment of acute myocardial infarction (AMI) is particularly challenging because the therapeutic strategies influence both the patient’s thrombotic and hemorrhagic risk. As progress has been made in the treatment of AMI over the last decade, we performed an in-depth analysis of the available literature, highlighting the latest advances in the therapy of AMI in hemophiliacs. It is generally accepted that after the optimal substitution therapy has been provided, patients with hemophilia should be treated in the same way as those in the general population. New-generation stents that allow short dual antiplatelet therapy and potent P2Y12 receptor inhibitors have begun to be successfully used. At a time when specific recommendations and relevant data are scarce, our study provides up-to-date information to physicians involved in the treatment of AMI in hemophiliacs.

Survivors of out-of-hospital cardiac arrest treated with percutaneous coronary intervention: Thrombotic and bleeding events among different oral P2Y12 inhibitor regimens

Survivors of out-of-hospital cardiac arrest undergoing percutaneous coronary intervention are at high thrombotic and bleeding risk. The type of antiplatelet that should be used in these patients remains controversial. To compare the impact of the use of more potent P2Y12 receptor inhibitors on thrombotic and bleeding events with that of clopidogrel in survivors of out-of-hospital cardiac arrest undergoing percutaneous coronary intervention. This was an observational study including consecutive patients treated for out-of-hospital cardiac arrest associated with acute coronary syndrome by percutaneous coronary intervention with stent implantation and dual antiplatelet therapy between January 2007 and December 2017. Baseline characteristics, mortality and in-hospital haemorrhagic and thrombotic events were compared between patients who received clopidogrel and those who received more potent P2Y12 receptor inhibitors. Among the 359 included patients, 197 received clopidogrel and 162 received ticagrelor or prasugrel. The primary composite endpoint of death, definite stent thrombosis or major bleeding was similar in the two groups (57.4% in the clopidogrel group vs. 53.7% in the new P2Y12 receptor inhibitors group; P=0.49). Fewer haemorrhagic events occurred in the clopidogrel group (21.8% vs. 31.5%; P=0.04), whereas similar rates of definite stent thrombosis were observed (5.1% vs. 6.2%; P=0.65). The use of more potent P2Y12 receptor inhibitors was an independent predictor of major bleeding (odds ratio 2.69, 95% confidence interval 1.37-5.25; P=0.004). In this specific population, the use of more potent P2Y12 receptor inhibitors was not associated with a reduced thrombosis rate compared with clopidogrel, but with a higher haemorrhagic risk. Prospective studies should be performed on the optimal antithrombotic therapy in this subset of patients.

The East Asian Paradox: An Updated Position Statement on the Challenges to the Current Antithrombotic Strategy in Patients with Cardiovascular Disease.

East Asian patients have reduced anti-ischemic benefits and increased bleeding risk during antithrombotic therapies compared with Caucasian patients. As potent P2Y12 receptor inhibitors (e.g., ticagrelor and prasugrel) and direct oral anticoagulants are commonly used in current daily practice, the unique risk-benefit trade-off in East Asians has been a topic of emerging interest. In this article, we propose updated evidence and future directions of antithrombotic treatment in East Asian patients.

Point-of-Care Platelet Function Monitoring: Implications for Patients With Platelet Inhibitors in Cardiac Surgery

Although most physicians are comfortable managing the limited anticoagulant effect of aspirin, the recent administration of potent P2Y12 receptor inhibitors in patients undergoing cardiac surgery remains a dilemma. Guidelines recommend discontinuation of potent P2Y12 inhibitors 5- to- 7 days before surgery to reduce the risk of postoperative hemorrhage. Such a strategy might not be feasible before urgent surgery, due to ongoing myocardial ischemia or in patients at high risk for thromboembolic events. Recently, different point-of-care devices to assess functional platelet quality have become available for clinical use. The aim of this narrative review was to evaluate the implications and potential benefits of platelet function monitoring in guiding perioperative management and therapeutic options in patients treated with antiplatelets, including aspirin or P2Y12 receptor inhibitors, undergoing cardiac surgery. No objective superiority of one point-of-care device over another was found in a large meta-analysis. Their accuracy and reliability are generally limited in the perioperative period. In particular, preoperative platelet function testing has been used to assess platelet contribution to bleeding after cardiac surgery. However, predictive values for postoperative hemorrhage and transfusion requirements are low, and there is a significant variability between and within these tests. Further, platelet function monitoring has been used to optimize the preoperative waiting period after cessation of dual antiplatelet therapy before urgent cardiac surgery. Furthermore, studies assessing their value in therapeutic decisions in bleeding patients after cardiac surgery are scarce. A general and liberal use of perioperative platelet function testing is not yet recommended.

Personalized antiplatelet therapy in patients with coronary artery disease undergoing percutaneous coronary intervention: A network meta-analysis of randomized clinical trials.

This study aimed to evaluate the efficacy and safety of genotype- and phenotype-guided intensified antiplatelet therapy compared with conventional therapy in patients undergoing stent implantation. Although potent P2Y12 receptor inhibitors are recommended for percutaneous coronary intervention (PCI)-treated acute coronary syndrome, their usage is limited by a high bleeding risk. Therefore, personalized antiplatelet therapy could provide a valuable foundation for selection of antiplatelet therapy in this population. We conducted a Bayesian network meta-analysis for all randomized clinical trials (RCTs) that evaluated genotype- and/or phenotype-guided therapy in PCI-treated coronary artery disease. Thirteen RCTs were included with a total of 6,845 patients. The results showed no significant differences in major adverse cardiovascular events (MACE) between the treatment options ((genotype guided vs. standard of care; OR 0.64; 95% CI: 0.38-1.05) and (phenotype vs. standard of care; OR 0.93; 95% CI: 0.54-1.37)). In addition, no significant differences were demonstrated in bleeding events ((genotype guided vs. standard of care; OR 0.73; 95% CI: 0.45-1.25) and (phenotype vs. standard of care; OR 0.90; 95% CI: 0.62-1.39)). In this mixed treatment meta-analysis of RCTs, neither genotype- nor phenotype-guided antiplatelet therapy in patients with PCI-treated coronary artery disease was superior to conventional therapy.

2018 update of expert consensus statement on antiplatelet therapy in East Asian patients with ACS or undergoing PCI

East Asians are the most populous race in the world and their health status is an important global issue. Compared with Caucasian populations, East Asian patients have a different benefit/risk ratio when using antithrombotic treatment. Despite this observation, treatment strategies in East Asian patients are mostly based on the American and European guidelines. Despite a lower platelet inhibitory response to clopidogrel, East Asian patients show a similar or even a lower rate of ischemic event occurrence and higher bleeding risk compared with Caucasian patients. For potent P2Y12 inhibitors (ticagrelor and prasugrel), East Asian patients have shown less favorable net clinical benefits compared with Caucasian patients, which may be related to differences in pharmacokinetic/pharmacodynamic profiles and therapeutic zone of antiplatelet effect. This updated consensus mainly focuses on state-of-the-art and current controversies in the East Asian population. In addition, when East Asian patients are administered potent P2Y12 receptor inhibitors, the strategies and ongoing trials to overcome the related hurdles are discussed.

Effect of Potent P2Y12 Inhibitors on Ventricular Arrhythmias and Cardiac Dysfunction in Coronary Artery Disease: A Systematic Review and Meta-Analysis.

Background Previous studies have shown that P2Y12 receptor inhibitors might prevent ventricular arrhythmias and cardiac dysfunction in patients with coronary artery disease. However, few studies have focused on comparison of the efficacy of novel oral potent P2Y12 receptor inhibitors with clopidogrel on these outcomes. Methods and Results We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) that were published in electronic databases of MEDLINE, EMBASE, Cochrane Central Register of Clinical Trials, and ClinicalTrials.gov before June 20, 2018. We compared the effect of prasugrel and ticagrelor with clopidogrel on outcomes of ventricular tachycardia (VT), ventricular fibrillation (VF), heart failure (HF), and cardiogenic shock (CS). Data were combined using both the fixed-effects models and the random-effects models, and the heterogeneity was assessed with the I2 statistic. Nine RCTs (6 with prasugrel and 3 with ticagrelor) with 45,227 patients were included. Patients receiving prasugrel were associated with a lower risk of combined VT and VF (rate ratio [RR]: 0.72, 95% confidence interval [CI]: 95% CI: 0.52-0.99, p=0.043), as well as combined HF and CS (RR: 0.81, 95% CI: 0.70-0.94, p=0.005), compared with clopidogrel. Patients receiving ticagrelor were also associated with a reduced risk of VT and VF (RR: 0.85, 95% CI: 0.72-1.02, p=0.077), although without statistical significance, but not of HF and CS (RR: 0.96, 95% CI: 0.81-1.13, p=0.620). Conclusions This meta-analysis of RCTs shows that, compared with clopidogrel, novel oral P2Y12 inhibitors, especially prasugrel, might have better effect on improving ventricular rhythm and cardiac function.

Abstract 17283: De-Escalation of Antiplatelet Therapy in Patients With Coronary Artery Disease Undergoing Percutaneous Coronary Intervention: A Meta-Analysis of Randomized Clinical Trials

Introduction: Potent P2Y 12 -receptor inhibitors are recommended in the management of acute coronary syndrome (ACS) treated with percutaneous coronary intervention (PCI). As the risk of thrombotic complications from an ACS event is highest in the early “ischemic phase,” the greatest benefit of potent P2Y 12 blockade occurs early. However, the risk of bleeding from such therapy tends to occur with chronic treatment during the “maintenance phase.” Therefore, a stage-adapted strategy with the early use of potent P2Y 12 blockade in acute treatment, followed by de-escalation to clopidogrel during the maintenance phase is common. Nevertheless, clinical outcomes supporting this strategy are lacking. Hypothesis: This study aimed to evaluate the safety and efficacy of antiplatelet de-escalation compared with continuation in patients with ACS treated with PCI. Methods: Electronic databases search were conducted for all randomized clinical trials (RCTs) that evaluated the safety and efficacy of antiplatelet de-escalation compared with continuation in patients with ACS treated with PCI. A random-effects model was used to calculate the pooled summary estimates. Results: We included 3 RCTs with 3,391 total patients (median follow-up 12 months). The net clinical outcome (composite of thrombotic or bleeding events) was significantly reduced in the switched group compared with the continued group (8.7% vs 12.1%; risk ratio (RR): 0.64; 95% confidence interval (CI): 0.43-0.97; P=0.03). However, there were no significant differences between groups in major adverse cardiovascular events (RR: 0.78; 95% CI: 0.55-1.11; P=0.17), all BARC (Bleeding Academic Research Consortium) types bleeding (RR: 0.61; 95% CI: 0.33-1.11; P=0.10), or BARC types ≥2 bleeding (RR: 0.49; 95% CI: 0.19-1.26; P=0.14). Conclusions: Our results suggest a net clinical benefit of de-escalation therapy shortly after PCI in ACS patients, without increased risk of MACE or bleeding, though further adequately powered trials are needed to confirm this finding.

Efficacy and safety of potent platelet P2Y12 receptor inhibitors in elderly versus nonelderly patients with acute coronary syndrome: A systematic review and meta-analysis

The use of the potent oral P2Y12 inhibitors prasugrel and ticagrelor in patients with acute coronary syndromes (ACS) has a favorable net clinical effect compared with clopidogrel and is recommended as first-line therapy. However, the impact of these agents on ischemic and bleeding events in elderly ACS patients is not well defined. We performed a systematic review of articles comparing potent P2Y12 inhibitors to clopidogrel in elderly and nonelderly patients (defined according to each study) with ACS in terms of efficacy (composite of cardiovascular death, myocardial infarction, or stroke) and safety (major bleeding) end points. A total of 7,860 elderly and 37,857 nonelderly patients from 7 studies (5 randomized control trials and 2 observational studies) were included. Potent P2Y12 inhibitors significantly reduced efficacy end point in nonelderly patients (relative risk [RR] 0.85, 95% CI 0.79-0.93) and less so in elderly patients (RR 0.95, 95% CI 0.86-1.05). No significant differences were found between potent P2Y12 inhibitors and clopidogrel in terms of safety end point in both elderly (RR 1.19, 95% CI 0.95-1.49) and nonelderly patients (RR 1.16, 95% CI 0.95-1.41). There were no significant interactions between age and treatment effect in both analyses (efficacy Pint=.16; safety Pint=.83). The effect of more potent P2Y12 inhibitors compared with clopidogrel on efficacy and safety end points is consistent in elderly and younger patients. These data imply that potent P2Y12 inhibitors should not be withheld from eligible patients solely because of advanced age.

Prise en charge du risque hémorragique associé aux agents antiplaquettaires

Like all antithrombotic drugs, antiplatelet agents expose to a risk of bleeding complications. Clinical research has extensively focused on the efficacy of these drugs to reduce ischemic events. The bleeding risk associated with them was solely considered as an inevitable and acceptable complication. When two new potent P2Y12-receptor inhibitors, prasugrel and ticagrelor, were marketed, the risk of major bleeding increased. These new agents have modified the balance between the absolute risk reduction in ischemic events and the absolute risk increase in bleeding events. This paper is an update on the bleeding risk assessment associated with antiplatelet agents. It discusses the place of platelet function monitoring, and the optimal management of bleeding complications. It addresses the challenging issue of reversal of antiplatelet therapy, focusing especially on ticagrelor, which pharmacodynamics complicate bleeding management.

Clopidogrel Versus Ticagrelor for Antiplatelet Maintenance in Diabetic Patients Treated With Percutaneous Coronary Intervention

A large proportion of patients with coronary artery disease treated with elective percutaneous coronary intervention have high residual platelet reactivity1 and endothelial dysfunction, which might represent the link to the occurrence of ischemic events.2 This is even more the case for patients with diabetes mellitus, in whom more potent P2Y12 receptor inhibitors have been proposed with promising results in terms of reduced platelet reactivity.3 Nevertheless, whether this enhanced platelet inhibition alsomight be beneficial to the endothelial function is yet unknown. CLOTILDIA (Clopidogrel High Dose Versus Ticagrelor for Antiplatelet Maintenance in Diabetic Patients)4 was a single-center, prospective, randomized, open label, crossover study, enrolling patients with type2 diabetes mellitus and stable coronary artery disease treated with percutaneous coronary intervention and drug-eluting stent implantation. Patients were recruited at least 1month after percutaneous coronary intervention (3.8±2.1 months), while they were still on dual-antiplatelet therapy with aspirin (100 mg/d) and clopidogrel (75 mg/d). At study entry (T0), with the use ofa computer-based randomization system, patients were assigned randomlyto receive either 90 mg ticagrelor twice daily or clopidogrel 150 mg once daily for 14 …

Antiplatelet strategies in elderly people: still a long way to go

Outcomes of patients with acute coronary syndrome undergoing percutaneous coronary intervention have been significantly improved with the potent P2Y12 receptor inhibitors prasugrel and ticagrelor. 1 Wiviott SD Braunwald E McCabe CH et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007; 357: 2001-2015 Crossref PubMed Scopus (5562) Google Scholar , 2 Wallentin L Becker RC Budaj A et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009; 361: 1045-1057 Crossref PubMed Scopus (5545) Google Scholar Elderly patients comprise a growing subset of the acute coronary syndrome population. This subset is characterised by multiple organ changes and various comorbidities, which altogether culminate in an increased risk of both ischaemic and bleeding complications after percutaneous coronary intervention. Platelet function testing has been established and validated to predict ischaemic and bleeding events in patients treated with percutaneous coronary intervention. 3 Aradi D Kirtane A Bonello L et al. Bleeding and stent thrombosis on P2Y12-inhibitors: collaborative analysis on the role of platelet reactivity for risk stratification after percutaneous coronary intervention. Eur Heart J. 2015; 36: 1762-1771 Crossref PubMed Scopus (268) Google Scholar , 4 Tantry US Bonello L Aradi D et al. Consensus and update on the definition of on-treatment platelet reactivity to adenosine diphosphate associated with ischemia and bleeding. J Am Coll Cardiol. 2013; 62: 2261-2273 Summary Full Text Full Text PDF PubMed Scopus (756) Google Scholar However, previous studies, 5 Collet JP Cuisset T Range G et al. Bedside monitoring to adjust antiplatelet therapy for coronary stenting. N Engl J Med. 2012; 367: 2100-2109 Crossref PubMed Scopus (759) Google Scholar , 6 Aradi D Storey RF Komocsi A et al. Expert position paper on the role of platelet function testing in patients undergoing percutaneous coronary intervention. Eur Heart J. 2014; 35: 209-215 Crossref PubMed Scopus (213) Google Scholar enrolling mostly low-risk patients with little use of potent antiplatelet drugs, have been unable to show clinical superiority of strategies that implemented platelet function testing for treatment guidance. Nevertheless, elderly patients undergoing percutaneous coronary intervention represent a high-risk cohort that might derive clinical benefit from platelet function testing to monitor and adjust the level of platelet inhibition. Platelet function monitoring to adjust antiplatelet therapy in elderly patients stented for an acute coronary syndrome (ANTARCTIC): an open-label, blinded-endpoint, randomised controlled superiority trialPlatelet function monitoring with treatment adjustment did not improve the clinical outcome of elderly patients treated with coronary stenting for an acute coronary syndrome. Platelet function testing is still being used in many centres and international guidelines still recommend platelet function testing in high-risk situations. Our study does not support this practice or these recommendations. Full-Text PDF

Ischemic and bleeding events in patients with myocardial infarction undergoing percutaneous coronary intervention who require oral anticoagulation: Insights from the Canadian observational AntiPlatelet sTudy

Since the introduction of newer, more potent P2Y12 receptor inhibitors (P2Y12ris), practice patterns and associated clinical outcomes in patients with myocardial infarction (MI) undergoing percutaneous coronary intervention (PCI) and also requiring oral anticoagulation (OAC) have not been fully characterized. The Canadian Observational Antiplatelet Study was a prospective, multicenter, longitudinal, observational study (26 hospitals, December 2011 to May 2013) describing P2Y12ri treatment patterns and outcomes in patients with ST-elevation and non-ST-elevation MI undergoing PCI. We describe the clinical characteristics, treatment patterns, bleeding, and ischemic outcomes over the 15-month follow-up within and between the subgroups of patients discharged on either dual-antiplatelet therapy (DAPT) (acetyl salicylic acid [ASA]+P2Y12ri) or triple therapy (ASA+P2Y12ri+OAC). Of the 2,034 patients at discharge, 86% (n = 1,757) were on DAPT, whereas 14% (n = 277) were on triple therapy (50% warfarin, 50% non-vitamin K OAC [NOAC]). The frequency of newer P2Y12ri use (prasugrel or ticagrelor) was similar in the DAPT and triple therapy groups (28% vs 26%, respectively). In the triple therapy group, NOAC use was higher in those receiving a new P2Y12ri compared to those receiving clopidogrel (75% vs 41%, respectively, P < .0001). The unadjusted and adjusted events of major cardiovascular event (MACE) and bleeding were higher in the triple therapy group. For patients on triple therapy, the bleeding or MACE events were not significantly different between those on clopidogrel versus those on ticagrelor or prasugrel. In this observational study of MI patients requiring PCI, 1 in 8 were discharged on triple antithrombotic therapy, of whom 26% were on newer P2Y12ris. Patients on triple therapy had higher risk at baseline, with higher unadjusted and adjusted MACE and bleeding events compared to those on DAPT alone. Among triple therapy-treated patients, there was no difference in the MACE and bleeding events regardless of the P2Y12ri used.

Platelet Function Testing and Tailored Antiplatelet Therapy

Dual antiplatelet therapy, consisting of aspirin and a P2Y12 receptor inhibitor, has dramatically reduced the incidence of atherothrombotic events for patients with acute coronary syndrome and those undergoing a percutaneous coronary intervention (PCI). However, the platelet inhibitory effect of clopidogrel, the most commonly used P2Y12 inhibitor, is variable between patients. Patients exhibiting high platelet reactivity (HPR) despite clopidogrel treatment are at higher risk of recurrent atherothrombotic events after PCI. In order to reduce the incidence of HPR, the more potent P2Y12 receptor inhibitors prasugrel and ticagrelor are used. However, these drugs increase the risk of bleeding. As there is evidence of a therapeutic window for platelet inhibition, platelet function tests could be helpful for tailoring antiplatelet therapy based on the patient's thrombotic and bleeding risk. In the present article, we review the most commonly used platelet function tests and the current evidence for tailoring of antiplatelet therapy in PCI patients.

Platelet Function Testing in Patients with Acute Coronary Syndrome

In patients with an acute coronary syndrome (ACS), inhibition of the platelet P2Y12 receptor is standard of care. The shortcomings of the most commonly used P2Y12 receptor inhibitor clopidogrel-that is its delayed onset of action, its interindividual response variability, and the phenomenon of high on-treatment platelet reactivity-led to the development of more potent P2Y12 receptor inhibitors (prasugrel and ticagrelor) that proved their superiority in terms of reducing thrombotic events compared to clopidogrel. Available randomized studies that aimed at investigating the value of a personalized antiplatelet treatment regimen based on platelet function monitoring results were negative with regard to the possible benefits of monitoring but were all limited by mainly enrolling elective and stable patients with coronary artery disease. Thus, it still warrants further investigation if a tailored, platelet function guided, antiplatelet therapy in ACS patients with the available P2Y12 receptor inhibitors prasugrel, ticagrelor, and clopidogrel can lead to improved patients outcome.

Potent P2Y12 receptor inhibitors in patients with acute coronary syndrome

SummaryBlood platelets are highly activated in the setting of an acute coronary syndrome (ACS). This fact mandates the need for potent platelet inhibition in ACS patients and especially in patients undergoing a percutaneous coronary intervention (PCI). The 2nd generation thienopyridine clopidogrel has been the standard of treatment in the past. Due to its pharmacological properties including a delayed onset of action, a large response variability and an insufficient antiplatelet action in some patients (low responsiveness or high on-treatment platelet reactivity), there was a need to develop, to study and to introduce more potent agents with a fast, reliable and potent antiplatelet action. With the 3rd generation thienopyridine prasugrel and with ticagrelor two potent agents for antiplatelet treatment of ACS patients are available now. Both drugs have demonstrated their superiority compared to clopidogrel in terms of thrombotic risk reduction in large-scale randomized trials. However, for these agents and in line with the expectations towards a more potent anti platelet treatment regimen, a higher risk for bleeding was observed for prasugrel and ticagrelor. Further on, the new anti platelet agents have their own and characteristic contraindications and numerous issues to be considered in clinical practice.This review aims to provide an overview on the state of the art P2Y12 receptor directed inhibition in ACS patients with a focus on patients undergoing a coronary stenting procedure.

Role of genotype-based personalized antiplatelet therapy in the era of potent P2Y12 receptor inhibitors

Therapy with clopidogrel and aspirin, commonly known as dual antiplatelet therapy, is a widely adapted secondary prevention strategy among coronary artery disease patients treated with percutaneous coronary intervention. However, in addition to response variability and high on-treatment platelet reactivity and their relation to increased adverse events during clopidogrel therapy, candidate gene studies and genome-wide association studies have highlighted the significance of single nucleotide polymorphisms of genes associated with clopidogrel metabolism in coronary artery disease patients. Genotyping may have an emerging role in personalized antiplatelet therapy, particularly with the advent of new P2Y12 receptor blockers that have more rapid and potent pharmacodynamic properties than clopidogrel. The current review discusses the role of genotyping in personalizing P2Y12 receptor-blocker therapy.

Platelet Hyperreactivity and Stent Thrombosis in Patients Undergoing Coronary Stenting

Stent thrombosis (ST) is a rare but very serious event complicating percutaneous coronary intervention (PCI) procedures. Both procedure- and patient-related factors, including inadequate platelet inhibition are well known predictors of ST. According to the present guidelines, a dual antiplatelet treatment regimen consisting of aspirin and a P2Y12 receptor inhibitor such as clopidogrel, prasugrel or ticagrelor is routinely administered to ACS patients and to patients undergoing PCI in order to prevent thrombotic vessel occlusions. In recent years, evidence has grown that patients showing high on-treatment platelet reactivity (HPR) under clopidogrel intake exhibit a higher risk for the occurrence of ischemic events including ST. For assessing HPR, different platelet function assays are currently available and have already found their way into routine clinical practice in several centers. Along with this development, more potent P2Y12 receptor inhibitors like prasugrel and ticagrelor are substitutes for clopidogrel in specific circumstances such as in ACS patients or in patients who do not adequately respond to standard clopidogrel treatment. Utilizing platelet function monitoring, patients showing HPR can be identified and an optimized antiplatelet treatment regime can be tailored for these patients. This review paper aims to summarize the important facts in relation to ST and antiplatelet therapy with a particular focus on P2Y12 receptor inhibition and its ex vivo assessment in patients undergoing coronary stent placement.