Yongwhi Park

Novel Antiplatelet Agents: The Current State and What Is Coming Down the Pike

Antiplatelet therapy is the cornerstone of treatment for patients with acute coronary syndrome (ACS) or undergoing percutaneous coronary intervention (PCI). Despite the use of dual antiplatelet therapy with aspirin and clopidogrel, a considerable number of patients still experience atherothrombotic events, which may be explained at least in part by inadequate platelet inhibition induced by this treatment regimen. This underscores the need for more potent antithrombotic strategies for the acute and long-term treatment of ischemic complications, especially in high-risk patients. These include novel generation P2Y12 receptor antagonists, such as prasugrel, ticagrelor and cangrelor, or adjunctive antiplatelet agents targeting different pathways, such as the thrombin protease-activated receptors-1 receptor inhibitor vorapaxar. Moreover, since ischemic events accrue over time after an acute event, prolonging intensified antiplatelet therapy beyond 1-year has also been investigated. This manuscript provides an overview on the current status and future directions of antithrombotic therapies for the treatment of patients with ACS or treated with PCI, mainly focusing on novel agents.

Antithrombotic Therapy for Secondary Prevention in Patients With Diabetes Mellitus and Coronary Artery Disease

Diabetes mellitus (DM) is a key risk factor for recurrent atherothrombotic events in patients with acute coronary syndrome (ACS) and in those undergoing percutaneous coronary intervention (PCI). The prothrombotic milieu that characterizes patients with DM underscores the importance of oral antithrombotic therapy for secondary prevention of recurrent events in these patients. Indeed, dual antiplatelet therapy (DAPT) with aspirin and the P2Y12inhibitor clopidogrel, which has represented the mainstay of treatment for many years, has significantly reduced the incidence of recurrent atherothrombotic events. However, recurrence rates in DM patients still remain high despite this treatment regimen, which may be partly related to inadequate platelet inhibition induced by standard DAPT with aspirin and clopidogrel. This underpins the need for more potent antithrombotic treatment regimens for secondary prevention of atherothrombotic events in DM patients following ACS or PCI. The development of antiplatelet therapies associated with more potent oral platelet P2Y12receptor inhibition, including prasugrel and ticagrelor, as well as platelet inhibitors blocking alternative pathways, such as thrombin-mediated platelet inhibition with vorapaxar, may represent potential treatment options in DM patients. Moreover, with the introduction of the target-specific oral anticoagulants, there has been a reappraisal of the use of anticoagulation in addition to antiplatelet therapy for secondary prevention in patients with ACS. This review provides an update on the recent advances and limitations of oral antithrombotic agents used for secondary prevention in DM patients following ACS or PCI.

Platelet thrombin receptor antagonism with vorapaxar: pharmacology and clinical trial development

Oral antiplatelet therapies for secondary prevention of ischemic recurrences in patients with atherosclerotic disease manifestations include aspirin and P2Y12 receptor antagonists. Despite the use of these therapies, patients remain at risk for recurrent ischemic events, which may be attributed to other platelet signaling pathways which continue to be activated. More intense antithrombotic strategies have been investigated, including identifying additional targets to modulate platelet activation. Among these, thrombin-mediated platelet activation through PAR-1 has been subject to broad clinical investigation. Vorapaxar is the only PAR-1 receptor antagonists that completed large-scale clinical investigations and is approved for clinical use. This manuscript provides an overview of the pharmacology and clinical trial development of vorapaxar as well as its role in clinical practice.

Dual antiplatelet therapy after coronary stenting

ABSTRACT Introduction: Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor represents the mainstay of pharmacotherapy in patients undergoing coronary stenting. Currently, three P2Y12 receptor inhibitors are approved for clinical use, including clopidogrel, prasugrel, and ticagrelor, with the latter two being preferred in patients presenting with an acute coronary syndrome. The introduction into clinical practice of newer-generation drug-eluting stent (DES) with safer profiles (i.e. less stent thrombosis) compared with earlier platforms have led recent guideline updates to re-evaluate the optimal duration of DAPT therapy, which are now based on evidence of a multitude of randomized clinical trials, registries, and meta-analysis and take into consideration the ischemic and bleeding risk profile of the patients. Areas covered: Most recent updates on DAPT duration from professional societies in the United States and Europe are discussed. Moreover, an assessment of clinical trials, registries, and meta-analysis leading to changes on practice guidelines analyzed. Expert opinion: The widespread introduction into clinical practice of newer-generation DES allows for shortening DAPT duration as also endorsed by practice guidelines. However, the optimal duration of DAPT therapy varies according to the individuals’ risk of ischemic and bleeding complications, with longer or shorter durations of treatment, respectively, that may be considered.

A Safety Evaluation of Cangrelor in Patients Undergoing PCI

ABSTRACT Introduction: Dual antiplatelet therapy with aspirin and an oral ADP P2Y12 receptor antagonist is the standard-of-care for treatment of patients undergoing percutaneous coronary intervention (PCI). However, oral P2Y12 receptor antagonists have several limitations, including inter- and intra-individual response variability, drug-drug interactions, slow onset and offset of action and delayed platelet inhibition in high-risk clinical settings, such as patients with ST-segment elevation myocardial infarction. Areas covered: Cangrelor is an intravenous, direct-acting, reversible, potent P2Y12 receptor antagonist. It rapidly achieves near complete platelet inhibition and has a very short half-life and a fast offset of action. We conducted a systematic review searching PubMed/MEDLINE for pharmacodynamic/pharmacokinetic studies and clinical trials in which cangrelor was investigated, published from any time up to November 1st 2015. For clinical trials, those investigating cangrelor in the setting of PCI were considered for discussion. Expert opinion: Cangrelor is approved by drug regulating authorities worldwide as adjunctive antithrombotic therapy for the full spectrum of patients undergoing PCI, not pre-treated with a P2Y12 receptor inhibitor and not with intent to receive a glycoprotein IIb/IIIa inhibitor. Its unique pharmacological properties and its favorable safety and efficacy profile make it an attractive treatment strategy, especially in clinical settings where immediate platelet inhibition is required.

Update on oral antithrombotic therapy for secondary prevention following non-ST segment elevation myocardial infarction

Patients with non-ST segment elevation myocardial infarction (NSTEMI) are at high risk for atherothrombotic recurrences. Dual antiplatelet therapy (DAPT) with aspirin and the P2Y12 receptor inhibitor clopidogrel significantly reduces the ischemic events in NSTEMI patients and has represented the mainstay of treatment for over a decade. However, a considerable number of patients continue to experience thrombotic complications, which may be in part due to inadequate platelet inhibition induced by this treatment regimen. This underscores the need for more potent antithrombotic treatment regimens for the long-term prevention of atherothrombotic events in NSTEMI patients. These include novel generation P2Y12 receptor blockers, such as prasugrel and ticagrelor, or adjunctive antiplatelet or anticoagulant therapies, such as vorapaxar [a protease-activated receptors (PAR)-1 receptor inhibitor] or rivaroxaban (a factor Xa inhibitor), respectively. Since ischemic events accrue over time in NSTEMI patients, prolonging intensified antiplatelet therapy beyond 1 year has also been investigated. However, although intensified and prolonged antithrombotic treatment regimens reduce ischemic events, this occurs at the expense of an increased risk of bleeding complications. This article encompasses the current state of the art on antithrombotic therapies for the secondary prevention of atherothrombotic events in patients with NSTEMI.

IN VITRO PHARMACODYNAMIC EFFECTS OF CANGRELOR ON PLATELET P2Y12 RECEPTOR MEDIATED SIGNALING IN TICAGRELOR TREATED PATIENTS

Variability in the onset of platelet inhibitory effects induced by oral P2Y12 receptor antagonists, including ticagrelor, has been shown in high-risk settings. These findings underscore the need for intravenous P2Y12 inhibiting therapies, such as cangrelor, with immediate effects. However, to date