Ana Muniz-Lozano

Update on platelet glycoprotein IIb/IIIa inhibitors: recommendations for clinical practice

Antiplatelet therapy is the cornerstone of treatment for patients with acute coronary syndrome (ACS) and undergoing percutaneous coronary intervention (PCI). Glycoprotein IIb/IIIa receptors mediate platelet aggregation, representing the final common pathway of platelet-mediated thrombosis. Therefore, agents blocking this pathway may be desirable for the treatment of patients with ACS and PCI. Glycoprotein IIb/IIIa receptor inhibitors have been widely investigated and have been key to the pharmacological advancements in the field. However, although GPIs have been important to reduce ischemic complications, their elevated risk of bleeding complications remains a major limitation. The poor prognostic implications, including increased mortality, associated with bleeding complication underscores the need for alternative treatment options. Over the past years there have been several advancements in antithrombotic pharmacology which have led to changes in recommendations for GPI usage in clinical practice. This is an overview of the most recent clinical trial data on GPIs, and provides practical insight on their modern day use in ACS therapy.

A head-to-head pharmacodynamic comparison of prasugrel vs. ticagrelor after switching from clopidogrel in patients with coronary artery disease: results of a prospective randomized study

AIMS Pharmacodynamic (PD) studies comparing prasugrel and ticagrelor have reached inconsistent findings. Therefore, a comprehensive investigation comparing the PD effects of prasugrel vs. ticagrelor after switching from clopidogrel therapy, exploring both loading dose (LD) and maintenance dose (MD) regimens represented the aim of this study. METHODS AND RESULTS Patients (n = 110) with coronary artery disease were randomized to prasugrel (60 mg LD/10 mg MD q.d.) or ticagrelor (180 mg LD/90 mg MD b.i.d) therapy for 1 week. Pharmacodynamic assessments were conducted using three assays (vasodilator-stimulated phosphoprotein, VerifyNow P2Y12, and light transmittance aggregometry, LTA) at baseline, 30 min, 2, 24 h, and 1 week. The impact of initiating ticagrelor MD 12 vs. 24 h after LD administration was also assessed. Switching clopidogrel-treated patients to an LD of prasugrel or ticagrelor was associated with a reduction in platelet reactivity at 30 min and was sustained at all time points up to 1 week with the MD (P < 0.001 for all assays). Platelet reactivity was similar with prasugrel and ticagrelor with all assays at 30 min, 2 h, and 1 week (P > 0.05 for all time points), with the exception of LTA at 30 min (lower with prasugrel; P = 0.003). At 24 h, platelet reactivity was lower among patients initiating ticagrelor MD after 12 vs. 24 h post-LD. Rates of high platelet reactivity (HPR) were markedly reduced and similar between groups. CONCLUSION Prasugrel and ticagrelor exert similar levels of P2Y12 inhibition achieving more potent PD effects and reduced HPR rates compared with clopidogrel which are reached promptly following LD and sustained with MD. CLINICALTRIALSGOV IDENTIFIER NCT01852175.

Cangrelor: a review on pharmacology and clinical trial development

Dual antiplatelet therapy with aspirin and an oral ADP P2Y12 receptor antagonist is the standard-of-care for the prevention of ischemic events in patients with acute coronary syndrome or undergoing percutaneous coronary intervention (PCI). However, currently available ADP P2Y12 receptor antagonists have several limitations, such as interindividual response variability, drug–drug interactions, slow onset/offset and only oral availability. Cangrelor is a reversible, potent, intravenous, competitive inhibitor of the ADP P2Y12 receptor that rapidly achieves near complete and predictable platelet inhibition. Along with reversible binding to the receptor cangrelor also has a very short half-life (3–5 min), which in turn results in a rapid offset of action. These properties make cangrelor a promising drug for clinical use in patients undergoing PCI or patients waiting for major surgery but still require antiplatelet protection. This manuscript provides an update of the current status of knowledge on cangrelor, focusing on its pharmacologic properties and clinical trial development, including the BRIDGE and CHAMPION-PHOENIX trials.

Pharmacodynamic effects of cangrelor on platelet P2Y12 receptor-mediated signaling in prasugrel-treated patients.

OBJECTIVES The purpose of this study was to assess the in vitro P2Y12 receptor inhibitory effects of cangrelor on platelets from patients on maintenance prasugrel therapy treated with 2 reloading dose regimens. BACKGROUND Despite its more potent and rapid antiplatelet effects compared with clopidogrel, recent studies have shown variability in prasugrel-mediated P2Y12 receptor inhibition, particularly in high-risk settings. Cangrelor is a potent intravenous P2Y12 receptor inhibitor. METHODS A total of 60 patients with coronary artery disease on maintenance prasugrel (10 mg/day) therapy were randomized to a 30- or 60-mg reload of prasugrel. The platelet reactivity index (PRI), as assessed by whole-blood vasodilator-stimulated phosphoprotein, was measured with and without in vitro incubation of cangrelor (500 nM) at baseline, and at 1 and 4 h after reload. RESULTS In the absence of cangrelor, prasugrel reloading reduced PRI (p < 0.001 for both doses), although a 60-mg reload had greater platelet inhibition compared with a 30-mg reload at 4 h (p = 0.001). Cangrelor was associated with a reduction in PRI values during the overall study time course in patients reloaded with 30 mg (p = 0.001) and 60 mg (p < 0.001) of prasugrel. In patients reloaded with 30 mg prasugrel, cangrelor decreased PRI at each time point (baseline, p < 0.001; 1 h, p = 0.013; 4 h, p = 0.001). In patients reloaded with 60 mg prasugrel, cangrelor decreased PRI at baseline (p < 0.001) and 1 h (p = 0.002); levels of platelet reactivity comparable to those achieved with cangrelor were observed only at 4 h (p = 0.325). The intergroup comparisons with cangrelor were not significant at any time point. CONCLUSIONS In patients on maintenance prasugrel therapy exposed to a reloading dose (30 or 60 mg) of prasugrel, in vitro cangrelor is associated with further platelet P2Y12 receptor inhibitory effects.

Platelet Function Profiles in Patients with Diabetes Mellitus

Patients with diabetes mellitus (DM) are at high risk for several cardiovascular disorders such as coronary heart disease, stroke, peripheral arterial disease, and congestive heart failure. DM has reached epidemic proportions and its strong association with coronary artery disease is responsible for increased cardiovascular morbidity and mortality. DM patients are characterized by platelet hyperreactivity, which contribute to the enhanced atherothrombotic risk of these subjects. Several mechanisms are involved in the hyperreactive platelet phenotype characterizing DM patients. Furthermore, a large proportion of DM patients show inadequate response to standard antiplatelet treatments and high rate of adverse recurrent cardiovascular events despite compliance with standard antiplatelet treatment regimens. Therefore, new antiplatelet treatment regimens are warranted in DM patients to reduce their atherothrombotic risk. The present manuscript provides an overview on the current status of knowledge on platelet function profiles in patients with DM and therapeutic considerations.

Pharmacodynamic Effects of Ticagrelor Dosing Regimens in Patients on Maintenance Ticagrelor Therapy : Results From a Prospective, Randomized, Double-Blind Investigation

OBJECTIVES The aim of this study was to assess the impact of ticagrelor dosing regimens on pharmacodynamic (PD) profiles in patients on maintenance ticagrelor therapy. BACKGROUND Many patients on maintenance P2Y12-inhibiting therapies may require coronary revascularization procedures, raising a common clinical question with regard to the dosing regimen of the P2Y12-inhibiting agent to be used. To date, investigations assessing dosing regimens of P2Y12 receptor inhibitors in patients on maintenance therapy have been only assessed with thienopyridines, but not with ticagrelor. METHODS This was a prospective, randomized, double-blind, placebo-controlled study assessing the PD effects of 2 dosing regimens of ticagrelor in patients on standard aspirin and ticagrelor maintenance therapy. A total of 60 patients were randomized to either 90 mg (maintenance dose [MD] group) or 180 mg (loading dose [LD] group) dose of ticagrelor. PD assessments were conducted at 3 time points (baseline, 1 h and 4 h). PD assessments were defined according to the platelet reactivity index (PRI) (vasodilator-stimulated phosphoprotein phosphorylation assay), P2Y12 reaction unit (VerifyNow P2Y12 assay) and adenosine diphosphate-induced platelet aggregation by light transmittance aggregometry. RESULTS There were no differences in baseline levels of platelet reactivity with all assays. Intergroup comparisons by means of repeated-measures analysis adjusted for baseline PRI values showed that the LD group had significantly lower PRI levels compared with the MD group during the overall study time course (p = 0.031). Consistent findings were found for P2Y12 reaction unit (p = 0.026) and light transmittance aggregometry (p = 0.004). Intragroup comparisons showed that a more prompt and sustained platelet inhibitory effect was achieved more consistently with an LD regimen compared with a MD regimen. CONCLUSIONS In patients on maintenance ticagrelor therapy, a 180-mg LD regimen of ticagrelor is associated with more potent and prompt platelet inhibition compared with a 90-mg MD. (Impact of Ticagrelor Re-Load Pharmacodynamic Profiles; NCT01731041).

Impact of aspirin dose on adenosine diphosphate-mediated platelet activities. Results of an in vitro pilot investigation.

Different aspirin dosing regimens have been suggested to impact outcomes when used in combination with adenosine diphosphate (ADP) P2Y12 receptor antagonists. Prior investigations have shown that not only aspirin, but also potent ADP P2Y12 receptor blockade can inhibit thromboxane A2-mediated platelet activation. The impact of aspirin dosing on ADP mediated platelet activities is unknown and represents the aim of this in vitro pilot pharmacodynamic (PD) investigation. Twenty-six patients with stable coronary artery disease on aspirin 81 mg/day and P2Y12 naïve were enrolled. PD assessments were performed at baseline, while patients were on 81 mg/day aspirin and after switching to 325 mg/day for 7 ± 2 days with and without escalating concentrations (vehicle, 1, 3, and 10 μM) of prasugrels active metabolite (P-AM). PD assays included flow cytometric assessment of VASP to define the platelet reactivity index (PRI) and the Multiplate Analyzer (MEA) using multiple agonists [ADP, ADP + prostaglandin (PGE1), arachidonic acid (AA), and collagen]. Escalating P-AM concentrations showed incremental platelet P2Y12 inhibition measured by VASP-PRI (p<0.001). However, there were no differences according to aspirin dosing regimen at any P-AM concentration (vehicle: p=0.899; 1 μM: p=0.888; 3 μM: p=0.524; 10 μM: p=0.548). Similar findings were observed in purinergic markers assessed by MEA (ADP and ADP+PGE1). P-AM addition significantly reduced AA and collagen induced platelet aggregation (p<0.001 for all measures), irrespective of aspirin dose. In conclusion, aspirin dosing does not appear to affect PD measures of ADP-mediated platelet reactivity irrespective of the degree of P2Y12 receptor blockade. P2Y12 receptor blockade modulates platelet reactivity mediated by alternative activators.

PHARMACODYNAMIC EFFECTS OF SKIPPING TICAGRELOR MAINTENANCE DOSING FOLLOWING LOADING DOSE ADMINISTRATION

methods: Patients (n=27) on maintenance aspirin (81 mg/qd) and clopidogrel (75 mg/qd) were prospectively enrolled in a two phase study. In phase 1, patients received a morning 180 mg ticagrelor LD, but not the evening 90 mg MD. After a 15-day wash-out period (patients resumed clopidogrel), phase 2 was performed in which the morning 180 mg ticagrelor LD was followed by the evening 90 mg MD. PD assessments (VerifyNow, LTA and VASP) were performed at baseline, and 2 and 24 hrs after LD.

Anticoagulation Therapy. Heparins, Factor II and Factor Xa Inhibitors

The use of anticoagulant therapy plays an important role particularly in the early management of patients with acute coronary syndrome (ACS) and in those undergoing percutaneous coronary interventions (PCI). These include a variety of agents available for parenteral administration which may be chosen depending on the level of ischemic and hemorrhagic risk of the patient as well as the planned early management (conservative vs. invasive). Indeed, not only the choice of therapy by also timing of administration and cessation are key determinant of short and long-term outcomes of anticoagulant therapies in the setting of ACS and PCI. Given that ACS patients persist with elevated thrombin levels following an ACS event, there also has been an emerging interest on adding oral anticoagulant therapy to standard antiplatelet regiment for long-term secondary prevention of ischemic event. The present chapter is an overview of the different options of anticoagulant therapy that are available for use in ACS and PCI patients. In particular, the basic principles of pharmacology, rationale for use, indications, contraindications, dosing considerations and side effects of currently available anticoagulant therapies are summarized and recent advances in the field provided.

Antithrombotic Issues in Women

Despite the numerous randomized trials that have evaluated the use of antithrombotic therapy in the setting of acute coronary syndromes (ACS) and atrial fibrillation (AF), the heterogeneity of the population enrolled in the majority of these studies represents an important limitation and extrapolating data to underrepresented populations does not come without concerns. In particular, women are underrepresented in most trials [1–4]. In line with this, in general gender differences in clinical response to antithrombotic therapies, in terms of thrombosis and bleeding risks, remains poorly understood. Accordingly, the association between possible sex differences in platelet biology and pharmacodynamic response to antithrombotic therapies warrants further understanding [5–7]. Table 15.1 provides a detailed description of the existing sex-related features regarding antiplatelet and anticoagulant therapies and the main studies conducted, which will be better outlined in the sections below [8–38]. The present chapter provides an overview on the impact of antithrombotic therapy, from bench to bedside, thus evaluating basic aspects of biology of thrombosis, response to antithrombotic therapies, and their impact in various clinic setting in which these are utilized.