Reversible P2Y12 Research Articles

Ticagrelor Plus Aspirin for Stroke or TIA of Atherosclerotic Origin

Ticagrelor is a reversible platelet P2Y12 receptor inhibitor. The recently completed THALES trial, comparing aspirin plus ticagrelor (A+T) versus

Clinical Pharmacology of the Reversible and Potent P2Y12 Receptor Antagonist ACT‐246475 After Single Subcutaneous Administration in Healthy Male Subjects

ACT-246475 is a selective and reversible P2Y12 receptor antagonist inducing inhibition of platelet aggregation (IPA). A randomized, double-blind, placebo-controlled, parallel-design study was performed to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of escalating single subcutaneous doses of ACT-246475 (1, 2, 4, 8, 16, or 32mg) in healthy male subjects (N=8 per dose, 3:1 active:placebo ratio). Pharmacodynamic effects were assessed based on maximum platelet aggregation and P2Y12 reaction units using light transmission aggregometry and VerifyNow® assays, respectively. ACT-246475 was safe and well tolerated up to 32mg based on adverse event data and absence of clinically relevant changes in hematology, biochemistry, vital signs, and electrocardiogram variables. Median time to reach maximum plasma concentration was 0.5-0.75hours, and geometric mean terminal half-life ranged from 1.3 to 9.2hours across the tested dose range. Exposure to ACT-246475 was dose proportional across all dose groups. The maximal %IPA was reached within 30minutes after subcutaneous administration of ACT-246475. A dose-dependent duration and extent of effect were observed based on area under the effect curve and maximum effect data. Similar results were observed for maximum platelet aggregation and P2Y12 reaction units. The %IPA was≥85% at doses≥2mg. This level of %IPA was extended to at least 12hours in the 32-mg dose group. The safety and pharmacokinetic/pharmacokinetic profile with quick onset and adequate duration of IPA support further investigation in patients with coronary artery disease.

The reversible P2Y12 antagonist ACT-246475 causes significantly less blood loss than ticagrelor at equivalent antithrombotic efficacy in rat.

The P2Y12 receptor is a validated target for prevention of major adverse cardiovascular events in patients with acute coronary syndrome. The aim of this study was to compare two direct‐acting, reversible P2Y12 antagonists, ACT‐246475 and ticagrelor, in a rat thrombosis model by simultaneous quantification of their antithrombotic efficacy and surgery‐induced blood loss. Blood flow velocity was assessed in the carotid artery after FeCl3‐induced thrombus formation using a Doppler flow probe. At the same time, blood loss after surgical wounding of the spleen was quantified. Continuous infusions of ACT‐246475 and ticagrelor prevented the injury‐induced reduction of blood flow in a dose‐dependent manner. High doses of both antagonists normalized blood flow and completely abolished thrombus formation as confirmed by histology. Intermediate doses restored baseline blood flow to ≥65%. However, ACT‐246475 caused significantly less increase of blood loss than ticagrelor; the difference in blood loss was 2.6‐fold (P < 0.01) at high doses and 2.7‐fold (P < 0.05) at intermediate doses. Potential reasons for this unexpected difference were explored by measuring the effects of ACT‐246475 and ticagrelor on vascular tone. At concentrations needed to achieve maximal antithrombotic efficacy, ticagrelor compared with ACT‐246475 significantly increased carotid blood flow velocity in vivo (P = 0.003), induced vasorelaxation of precontracted rat femoral arteries, and inhibited contraction of femoral artery induced by electrical field stimulation or by phenylephrine. Overall, ACT‐246475 showed a significantly wider therapeutic window than ticagrelor. The absence of vasodilatory effects due to high selectivity of ACT‐246475 for P2Y12 provides potential arguments for the observed safety advantage of ACT‐246475 over ticagrelor.

Competitive mode and site of interaction of ticagrelor at the human platelet P2Y12‐receptor

The G-protein-coupled P2Y12 -receptor plays a crucial role in platelet aggregation. Recently, ticagrelor was licensed as the first perorally active and reversible P2Y12 -receptor antagonist. The present study investigated the site and the antagonistic mode of action of ticagrelor at wild-type or mutant human P2Y12 -receptors. Recombinant wild-type or mutant human P2Y12 -receptors were stably expressed in Chinese hamster ovary Flp-In cells. Receptor function was assessed by quantification of ADP- and 2-methylthio-ADP-mediated inhibition of forskolin-induced cellular cAMP production either using a [(3) H]cAMP-radioaffinity assay or a cAMP response element-driven luciferase reporter gene assay. The natural agonist ADP inhibited forskolin-induced cAMP formation at the wild-type P2Y12 -receptor with a lower potency (EC50 209 nm) than the synthetic agonist 2-methylthio-ADP (EC50 1.0 nm). Ticagrelor shifted the concentration-response curves of both agonists in a parallel and surmountable manner to the right. Increasing concentrations of ticagrelor caused increasing shifts. Schild-plot analysis revealed pA2 values of 8.85 for ticagrelor against ADP, and 8.69 against 2-methylthio-ADP, and slopes of the regression lines not different from unity. In cells expressing a recombinant C194A(5.43) -mutant P2Y12 -receptor construct, ticagrelor lost antagonistic potency when tested against ADP or 2-methylthio-ADP. The experiments reveal a surmountable and competitive mode of antagonism of ticagrelor at P2Y12 -receptors activated by either the natural agonist ADP or the synthetic agonist 2-methylthio-ADP. Cys194(5.43) is likely to be involved in the interaction of ticagrelor with ADP and 2-methylthio-ADP. The data give new insights into the site and mode of action of ticagrelor at the human P2Y12 -receptor.

Signaling via P2Y12 May Be Critical for Early Stabilization of Platelet Aggregates

P2Y(12) receptor antagonism inhibits platelet aggregation by preventing adenosine diphosphate (ADP)-mediated amplification of activation pathways downstream of primary agonists, such as thrombin and collagen. However, the role of ADP signaling in maintaining aggregate stability and the effects of P2Y(12) antagonists on preestablished aggregates in vitro and arterial thrombus in vivo are not well understood. This study evaluated the impact of P2Y(12) signaling on platelet aggregate stability and early thrombotic occlusion using a reversible P2Y(12) antagonist, ticagrelor. There were 2 study objectives: (1) to determine if there was a time-dependent factor on the capacity of a P2Y(12) antagonist to affect human platelet aggregate stability in vitro using light transmission aggregometry and (2) to evaluate the extent of arterial thrombus reversal in a preclinical model upon administration of ticagrelor in vivo. Platelet aggregates were exposed to ticagrelor after ADP or collagen activation, monitored for stability by aggregometry, and visualized by microscopy. Freshly formed ADP- and collagen-induced platelet aggregates were more rapidly dispersed by a P2Y(12) antagonist than drug carrier control at clinically relevant concentrations (P < 0.05). However, stable aggregates were not noticeably affected. A murine arterial thrombosis model was used to evaluate thrombus stability in an in vivo mouse model. Thrombotic occlusion was induced by FeCl(3), followed by a bolus intravenous administration of ticagrelor or vehicle control. Doppler blood flow was monitored before injury and 30 minutes after bolus administration. Arteries were retrieved for inspection for residual thrombus. Early arterial thrombotic occlusion in vivo was partially reversed by ticagrelor administration. Blood flow through the injured artery increased, and thrombus size within the artery decreased (P < 0.05, n = 3). In conclusion, P2Y(12) antagonism disrupts the stability of newly formed platelet aggregates, promoting disaggregation, and reverses thrombotic vascular occlusion. Thus, in addition to activating platelets, signaling via P2Y(12) seems to be required for stabilizing platelet thrombi.

Rationale and design of the Cangrelor versus standard therapy to acHieve optimal Management of Platelet InhibitiON PHOENIX trial

Despite robust efficacy in the reduction of ischemic events in patients who require percutaneous coronary intervention (PCI), current P2Y(12) inhibitors have limitations. In particular, they require hours to be effective, and they can only be administered orally. Cangrelor is an intravenous, potent, and reversible P2Y(12) inhibitor with fast onset and offset of action. We designed CHAMPION PHOENIX to evaluate the efficacy and safety of cangrelor in patients with atherosclerosis undergoing PCI. The CHAMPION PHOENIX is a randomized, double-blind, double-dummy, superiority trial comparing cangrelor with clopidogrel standard of care in approximately 10,900 patients who have not previously received a P2Y(12) inhibitor and who require PCI, including patients with stable angina and with acute coronary syndromes (with or without ST-segment elevation). The primary objective of the study is to demonstrate that cangrelor will reduce the incidence of the composite of death, myocardial infarction (MI), ischemia-driven revascularization, or stent thrombosis in the 48 hours after randomization compared with clopidogrel without excessive periprocedural bleeding. The key secondary objective is to demonstrate that cangrelor will reduce the incidence of stent thrombosis. Myocardial infarction will be defined according to the universal MI definition, adapting the definition of PCI-related (type 4a) MI. Bleeding will be assessed according to the thrombolysis in myocardial infarction, GUSTO, and Bleeding Academic Research Consortium (BARC) scales. The CHAMPION PHOENIX may establish the role of cangrelor in the care of patients who require PCI across the spectrum of stable and unstable coronary diseases in the setting of current treatment strategies.

Emerging Antiplatelet Therapy for Coronary Artery Disease and Acute Coronary Syndrome

Antiplatelet therapy is used widely with proven benefit for the prevention of further ischemic cardiac complications in patients with known coronary artery disease (CAD) and a history of acute coronary syndrome (ACS). The limitations of conventional antiplatelet therapy with aspirin, clopidogrel, or prasugrel, as well as the fact that rates of recurrent ischemic events still remain high with use of these agents, underscore the need to investigate alternate agents that may further reduce event rates while limiting bleeding risk. The selection of antiplatelet therapy is further influenced by the following: ticagrelor was approved in July 2011 by the United States Food and Drug Administration (FDA), and clopidogrel is slated to become available as a generic productin 2012. We provide an overview of emerging agents for the treatment of CAD and ACS, including the reversible P2Y(12) antagonists ticagrelor, cangrelor, and elinogrel, and a new class of oral protease-activated receptor-1 (PAR-1) inhibitors, vorapaxar and atopaxar.The recently approved P2Y(12) antagonists prasugrel and ticagrelor demonstrate enhanced ability to prevent adverse cardiac outcomes. However, this comes at a cost of a potential increased risk of bleeding. New adverse effects have also emerged, including dyspnea for all of the reversible P2Y(12) antagonists (ticagrelor, cangrelor, and elinogrel) and ventricular pauses for ticagrelor. In addition, the newer P2Y(12) antagonists have a faster onset and offset. Two of these agents, cangrelor and elinogrel, are available as intravenous formulations, which may provide additional benefits in patients who undergo coronary artery bypass graft (CABG) surgery. Trials with the PAR-1 inhibitors have also shown trends toward reductions in cardiac events, but not without the possibility of increased bleeding. More than ever, as the arsenal of antiplatelet therapy expands, health care providers need to understand the pharmacologic and pharmacodynamic differences between conventional and emerging antiplatelet therapies for patients with ACS and CAD. Health care providers must also carefully assess patient-specific factors such as risk of thrombosis, concomitant disease states, age, drug adherence, and aspirin dose, and plan for those patients who will be undergoing CABG when selecting antiplatelet therapy in order to optimally balance bleeding and thrombosis risk.

Bridging Antiplatelet Therapy With Cangrelor in Patients Undergoing Cardiac Surgery

Thienopyridines are among the most widely prescribed medications, but their use can be complicated by the unanticipated need for surgery. Despite increased risk of thrombosis, guidelines recommend discontinuing thienopyridines 5 to 7 days prior to surgery to minimize bleeding. To evaluate the use of cangrelor, an intravenous, reversible P2Y(12) platelet inhibitor for bridging thienopyridine-treated patients to coronary artery bypass grafting (CABG) surgery. Prospective, randomized, double-blind, placebo-controlled, multicenter trial, involving 210 patients with an acute coronary syndrome (ACS) or treated with a coronary stent and receiving a thienopyridine awaiting CABG surgery to receive either cangrelor or placebo after an initial open-label, dose-finding phase (n = 11) conducted between January 2009 and April 2011. Interventions Thienopyridines were stopped and patients were administered cangrelor or placebo for at least 48 hours, which was discontinued 1 to 6 hours before CABG surgery. The primary efficacy end point was platelet reactivity (measured in P2Y(12) reaction units [PRUs]), assessed daily. The main safety end point was excessive CABG surgery-related bleeding. The dose of cangrelor determined in 10 patients in the open-label stage was 0.75 μg/kg per minute. In the randomized phase, a greater proportion of patients treated with cangrelor had low levels of platelet reactivity throughout the entire treatment period compared with placebo (primary end point, PRU <240; 98.8% (83 of 84) vs 19.0% (16 of 84); relative risk [RR], 5.2 [95% CI, 3.3-8.1] P < .001). Excessive CABG surgery-related bleeding occurred in 11.8% (12 of 102) vs 10.4% (10 of 96) in the cangrelor and placebo groups, respectively (RR, 1.1 [95% CI, 0.5-2.5] P = .763). There were no significant differences in major bleeding prior to CABG surgery, although minor bleeding episodes were numerically higher with cangrelor. Among patients who discontinue thienopyridine therapy prior to cardiac surgery, the use of cangrelor compared with placebo resulted in a higher rate of maintenance of platelet inhibition. clinicaltrials.gov Identifier: NCT00767507.

A Clopidogrel-Insensitive Inducible Pool of P2Y12 Receptors Contributes to Thrombus Formation: Inhibition by Elinogrel, a Direct-Acting, Reversible P2Y12 Antagonist

It is known that hepatic metabolism limits the antiaggregatory activity of clopidogrel and, as a consequence, its clinical benefits. In this study, we investigated whether other factors exist that could account for clopidogrel's suboptimal antithrombotic activity. Using an in vivo murine FeCl(3) thrombosis model coupled with intravital microscopy, we found that at equivalent, maximal levels of inhibition of ADP-induced platelet aggregation, clopidogrel (50 mg/kg p.o.) failed to reproduce the phenotype associated with P2Y(12) deficiency. However, elinogrel (60 mg/kg p.o.), a direct-acting reversible P2Y(12) antagonist, achieved maximal levels of inhibition in vivo, and its administration (1 mg/kg i.v.) abolished residual thrombosis associated with clopidogrel dosing. Because elinogrel is constantly present in the plasma, whereas the active metabolite of clopidogrel exists for ∼2 h, we evaluated whether an intracellular pool of P2Y(12) exists that would be inaccessible to clopidogrel and contribute to its limited antithrombotic activity. Using saturation [(3)H]2-(methylthio)ADP ([(3)H]2MeSADP) binding studies, we first demonstrated that platelet stimulation with thrombin and convulxin (mouse) and thrombin receptor activating peptide (TRAP) (human) significantly increased surface expression of P2Y(12) relative to that of resting platelets. We next found that clopidogrel dose-dependently inhibited ADP-induced aggregation, signaling (cAMP), and surface P2Y(12) on resting mouse platelets, achieving complete inhibition at the highest dose (50 mg/kg), but failed to block this inducible pool. Thus, an inducible pool of P2Y(12) exists on platelets that can be exposed upon platelet activation by strong agonists. This inducible pool is not blocked completely by clopidogrel, contributes to thrombosis in vivo, and can be blocked by elinogrel.

The effect of ticagrelor versus clopidogrel on high on-treatment platelet reactivity: Combined analysis of the ONSET/OFFSET and RESPOND studies

The objective of the study was to determine the prevalence of high on-treatment platelet reactivity (HPR) in coronary artery disease patients enrolled in the ONSET/OFFSET and RESPOND studies. HPR has been linked to the occurrence of adverse events after stenting in patients treated with clopidogrel (C) and aspirin. Prevalence of HPR after treatment with ticagrelor (T), a reversible oral P2Y(12) receptor antagonist developed to overcome the limitations of C, is unknown. Patients were treated with T (n = 106) or C (n = 103) on top of aspirin therapy. HPR was defined by published cutoff points associated with post-percutaneous coronary intervention ischemic risk: >59% 20 μM adenosine diphosphate-induced aggregation (light transmittance aggregometry), >235 P2Y12 reaction unit by VerifyNow P2Y(12) assay (VerifyNow, San Diego, CA), and >50% platelet reactivity index by vasodilator-stimulated phosphoprotein phosphorylation assay (VASP-P). Proportion differences for T versus C were analyzed by χ(2) test for each time point. Correlations (R) were analyzed by the Pearson method. Ticagrelor was associated with a significantly lower prevalence of HPR (0%-8%) compared with C (21%-81%) at 2, 4, 8, and 24 hours and ≥2 weeks postdosing (P < .0001, for all assays). The R values between light transmittance aggregometry and VerifyNow/VASP-P were all ≥0.43, P < .0001. The above data represent the largest serial pharmacodynamic evaluation of the comparative effects of T versus C. Ticagrelor was rapidly and consistently associated with a very low prevalence of HPR compared with C, as determined by multiple established methods to measure platelet reactivity. These results provide a mechanism for the lower ischemic event rate associated with T therapy reported in the PLATO trial.

Pharmacochemistry of the platelet purinergic receptors

Platelets contain at least five purinergic G protein-coupled receptors, e.g., the pro-aggregatory P2Y(1) and P2Y(12) receptors, a P2Y(14) receptor (GPR105) of unknown function, and anti-aggregatory A(2A) and A(2B) adenosine receptor (ARs), in addition to the ligand-gated P2X1 ion channel. Probing the structure-activity relationships (SARs) of the P2X and P2Y receptors for extracellular nucleotides has resulted in numerous new agonist and antagonist ligands. Selective agents derived from known ligands and novel chemotypes can be used to help define the subtypes pharmacologically. Some of these agents have entered into clinical trials in spite of the challenges of drug development for these classes of receptors. The functional architecture of P2 receptors was extensively explored using mutagenesis and molecular modeling, which are useful tools in drug discovery. In general, novel drug delivery methods, prodrug approaches, allosteric modulation, and biased agonism would be desirable to overcome side effects that tend to occur even with receptor subtype-selective ligands. Detailed SAR analyses have been constructed for nucleotide and non-nucleotide ligands at the P2Y(1), P2Y(12), and P2Y(14) receptors. The thienopyridine antithrombotic drugs Clopidogrel and Prasugrel require enzymatic pre-activation in vivo and react irreversibly with the P2Y(12) receptor. There is much pharmaceutical development activity aimed at identifying reversible P2Y(12) receptor antagonists. The screening of chemically diverse compound libraries has identified novel chemotypes that act as competitive, non-nucleotide antagonists of the P2Y(1) receptor or the P2Y(12) receptor, and antithrombotic properties of the structurally optimized analogues were demonstrated. In silico screening at the A(2A) AR has identified antagonist molecules having novel chemotypes. Fluorescent and other reporter groups incorporated into ligands can enable new technology for receptor assays and imaging. The A(2A) agonist CGS21680 and the P2Y(1) receptor antagonist MRS2500 were derivatized for covalent attachment to polyamidoamine dendrimeric carriers of MW 20,000, and the resulting multivalent conjugates inhibited ADP-promoted platelet aggregation. In conclusion, a wide range of new pharmacological tools is available to control platelet function by interacting with cell surface purine receptors.

Ticagrelor for the treatment of arterial thrombosis

Importance of the field: High platelet reactivity has been linked to recurrent ischemic events in patients treated with conventional dual antiplatelet therapy, in patients with arterial diseases and particularly in patients treated with coronary artery stenting. The limitations of clopidogrel have served as a major rationale for the development of new P2Y12 blockers that have superior pharmacodynamic profiles uninfluenced by concomitant therapies or specific genotypes. Ticagrelor is the first direct-acting reversibly binding oral P2Y12 receptor antagonist. Extensive Phase II investigations have addressed the pharmacokinetic, pharmacodynamic and safety-related properties of ticagrelor compared with clopidogrel. The recently completed PLATO trial demonstrated promise for ticagrelor as a major treatment strategy for a wide spectrum of patients with acute coronary syndromes. Ticagrelor is now being reviewed by the FDA as a P2Y12 receptor blocker to treat patients with coronary artery disease and, once accepted, will be in widespread use as an antiplatelet agent. Thus, it is both appropriate and timely to review available data and provide a comprehensive review of ticagrelor.Areas covered in this review: We discuss the rationale for the development of ticagrelor, a reversible and potent P2Y12 receptor blocker. The data regarding ticagrelor based on preclinical and clinical studies are examined. We researched articles about ‘AZD6140’ and ‘ticagrelor’ in PubMed from 2006 to 2010 and also reviewed data presented at recent cardiology meetings.What the reader will gain: This is an updated and comprehensive review of ticagrelor. The advantages and disadvantages of ticagrelor and available P2Y12 receptor blockers such as clopidogrel and prasugrel are discussed, thus providing a clear picture to readers.Take home message: Ticagrelor has an important role as an antiplatelet agent in the settings of acute coronary syndrome and percutaneous coronary intervention and once accepted will be in widespread use.

Rationale and design of the randomized, double-blind trial testing INtraveNous and Oral administration of elinogrel, a selective and reversible P2Y12-receptor inhibitor, versus clopidogrel to eVAluate Tolerability and Efficacy in nonurgent Percutaneous Coronary Interventions patients (INNOVATE-PCI)

Despite current dual-antiplatelet therapy with aspirin and clopidogrel, adverse clinical events continue to occur during and after percutaneous coronary intervention (PCI). The failure of clopidogrel to provide optimal protection may be related to delayed onset of action, interpatient variability in its effect, and an insufficient level of platelet inhibition. Furthermore, the irreversible binding of clopidogrel to the P2Y(12) receptor for the life span of the platelet is associated with increased bleeding risk especially during urgent or emergency surgery. Novel antiplatelet agents are required to improve management of patients undergoing PCI. Elinogrel is a potent, direct-acting (ie, non-prodrug), selective, competitive, and reversible P2Y(12) inhibitor available in both intravenous and oral formulations. The INNOVATE-PCI study is a phase 2 randomized, double-blind, clopidogrel-controlled trial to evaluate the safety, tolerability, and preliminary efficacy of this novel antiplatelet agent in patients undergoing nonurgent PCI.

Emerging antiplatelet agents, differential pharmacology, and clinical utility

The aspirin-clopidogrel combination is the current gold standard antiplatelet regimen following percutaneous coronary intervention and for the treatment of acute coronary syndrome. Despite the clinical benefit of this combination, patients continue to have vascular events. Another purinergic (P2Y(12)) receptor antagonist, prasugrel, became available last year. Although prasugrel is superior to clopidogrel in reducing clinical endpoints, a higher bleeding rate has been identified particularly in high-risk patients. Ticagrelor, a reversible P2Y(12) receptor antagonist currently being evaluated for approval, is also more potent than clopidogrel but has a similar bleeding risk. Two additional P2Y(12) antagonists are being investigated that will be available as an intravenous formulation. Apart from the P2Y(12) receptor antagonists, multiple other agents are being developed with unique mechanisms of platelet inhibition. These agents are being studied as an alternative to or in combination with clopidogrel. The antiplatelet agents currently under development include: thrombin receptor antagonists, phosphodiesterase inhibitors, a thromboxane-prostaglandin receptor antagonist, a serotonin receptor blocker, a platelet adhesion antagonist, nitric oxide-releasing aspirin, a glycoprotein VI antagonist, and a cyclooxygenase inhibitor. The purpose of this review is to describe the efficacy and safety profiles of the emerging antiplatelet agents and their role in the treatment of atherosclerotic cardiovascular diseases.

Stabilizing Role of Platelet P2Y12 Receptors in Shear-Dependent Thrombus Formation on Ruptured Plaques

BackgroundIn most models of experimental thrombosis, healthy blood vessels are damaged. This results in the formation of a platelet thrombus that is stabilized by ADP signaling via P2Y12 receptors. However, such models do not predict involvement of P2Y12 in the clinically relevant situation of thrombosis upon rupture of atherosclerotic plaques. We investigated the role of P2Y12 in thrombus formation on (collagen-containing) atherosclerotic plaques in vitro and in vivo, by using a novel mouse model of atherothrombosis.MethodologyPlaques in the carotid arteries from Apoe −/− mice were acutely ruptured by ultrasound treatment, and the thrombotic process was monitored via intravital fluorescence microscopy. Thrombus formation in vitro was assessed in mouse and human blood perfused over collagen or plaque material under variable conditions of shear rate and coagulation. Effects of two reversible P2Y12 blockers, ticagrelor (AZD6140) and cangrelor (AR-C69931MX), were investigated.Principal FindingsAcute plaque rupture by ultrasound treatment provoked rapid formation of non-occlusive thrombi, which were smaller in size and unstable in the presence of P2Y12 blockers. In vitro, when mouse or human blood was perfused over collagen or atherosclerotic plaque material, blockage or deficiency of P2Y12 reduced the thrombi and increased embolization events. These P2Y12 effects were present at shear rates >500 s−1, and they persisted in the presence of coagulation. P2Y12-dependent thrombus stabilization was accompanied by increased fibrin(ogen) binding.Conclusions/SignificancePlatelet P2Y12 receptors play a crucial role in the stabilization of thrombi formed on atherosclerotic plaques. This P2Y12 function is restricted to high shear flow conditions, and is preserved in the presence of coagulation.

Cangrelor for ACS—lessons from the CHAMPION trials

The two CHAMPION trials failed to show superiority of cangrelor (a rapid-acting, reversible intravenous platelet P2Y12 adenosine receptor antagonist) versus clopidogrel in patients with acute coronary syndromes undergoing percutaneous coronary intervention. The CHAMPION PCI trial, however, did show a significant reduction in death and stent thrombosis suggesting benefit in those without clopidogrel pretreatment.

Ticagrelor

Coronary artery disease (CAD) is the single leading cause of death in the U.S. Therapies for CAD have been developed to inhibit platelet aggregation underlying atherogenesis. Clinical benefit has been shown with antagonists of the P2Y(12) receptor, such as clopidogrel. However, concerns over patient resistance to treatment and relatively slow onset and offset of action have indicated the need for further pharmacotherapeutic development. Ticagrelor (formally AZD-6140) is a novel, reversible oral P2Y(12) antagonist developed by AstraZeneca. In vitro and in vivo studies have confirmed that ticagrelor provides rapid, enhanced and maintained antiplatelet effects. These findings have translated to clinical trial investigations with further evidence for a significantly reduced mortality rate associated with cardiovascular events, myocardial infarction (MI) or stroke, and a favourable safety profile. Key clinical trials to date include the DISPERSE, DISPERSE2, PLATO, ONSET/OFFSET and RESPOND. Ticagrelor has been put forward for approval to the European Medical Agency (EMEA) and the Food and Drug Administration (FDA) as an investigational oral antiplatelet treatment for the reduction of major adverse cardiac events in patients with acute coronary syndrome.

Platelet-Directed Therapies and Coronary Artery Bypass Grafting

Coronary artery bypass grafting (CABG) is effective in reducing cardiovascular morbidity and mortality in certain high-risk groups. Despite improvement in surgical technique, hemorrhagic complications are a major concern and are likely to affect perioperative morbidity and mortality, length of stay, and hospital expenditures. The use of platelet-directed therapies in this setting is effective in decreasing ischemic complications, yet these agents simultaneously increase the risk of bleeding. Concern about potential hemorrhagic risk from antiplatelet agents in proximity to CABG may influence physicians to discontinue these agents. The benefit of low-dose aspirin given preoperatively is likely to outweigh any hemorrhagic risk. Dual antiplatelet therapy with aspirin and clopidogrel (or aspirin and prasugrel) is associated with a significant increased risk of bleeding and its complications. Additional research is needed to properly evaluate the ischemic benefit versus bleeding risk of aspirin and clopidogrel. Whether reversible P2Y(12) receptor antagonists will mitigate the bleeding risk is unclear at the present time and will require large prospective studies.

Cangrelor increases the magnitude of platelet inhibition and reduces interindividual variability in clopidogrel-pretreated subjects.

Inadequate platelet inhibition despite aspirin and clopidogrel therapy during and after a percutaneous coronary intervention is associated with an impaired clinical outcome. Cangrelor, a direct and reversible P2Y(12) inhibitor that is currently in development, has the potential to achieve higher levels of inhibition of ADP-induced platelet aggregation than clopidogrel. The aim of the present study was to compare the magnitude of platelet inhibition in clopidogrel-pretreated patients before and after the in vitro addition of a subtherapeutic dose of cangrelor. Blood samples were drawn from patients pretreated with clopidogrel and aspirin who were undergoing elective percutaneous coronary intervention (n=39). Platelet function analysis with 'classical' light transmittance aggregometry (both peak and late aggregation [at 6 min]) was performed before and after the in vitro addition of cangrelor (0.25 mumol/l) to platelet-rich plasma (PRP). After an incubation period of five minutes, platelet aggregation was induced by 5 and 20 mumol/l ADP. The in vitro addition of 0.25mumol/l cangrelor to the PRP from clopidogrel-treated subjects resulted in an additional reduction in ADP-induced platelet aggregation. For ADP concentrations of 5 and 20 mumol/l, peak aggregation showed a decrease of 75 and 85%, respectively (p<0.001 for both), while late aggregation was almost completely diminished (p=0.003 and p<0.001, respectively). Furthermore, the interindividual variation in inhibition of ADP-induced platelet aggregation by clopidogrel was greatly reduced after the addition of cangrelor. We demonstrate that the in vitro addition of even a subtherapeutic dose of cangrelor to the PRP of clopidogrel-pretreated patients results in an additional reduction of ADP-induced platelet aggregation. Moreover, cangrelor was able to diminish the interindividual variation observed in clopidogrel-inhibited platelet aggregation. (Neth Heart J 2009;17:195-8.).

Comparison of ticagrelor, the first reversible oral P2Y 12 receptor antagonist, with clopidogrel in patients with acute coronary syndromes: Rationale, design, and baseline characteristics of the PLATelet inhibition and patient Outcomes (PLATO) trial

Antiplatelet therapy is essential treatment for acute coronary syndromes (ACS). Current therapies, however, have important limitations affecting their clinical success. Ticagrelor, the first reversible oral P2Y(12) receptor antagonist, provides faster, greater, and more consistent adenosine diphosphate-receptor inhibition than clopidogrel. The phase III PLATelet inhibition and patient Outcomes (PLATO) trial is designed to test the hypothesis that ticagrelor compared with clopidogrel will result in a lower risk of recurrent thrombotic events in a broad patient population with ACS. PLATO is an international, randomized, double-blind, event-driven trial involving >18,000 patients hospitalized for ST-elevation ACS with scheduled primary percutaneous coronary intervention or for non-ST-elevation ACS. After loading doses of ticagrelor 180 mg or clopidogrel 300 mg in a double-blind, double-dummy fashion (with provision for additional 300 mg clopidogrel at percutaneous coronary intervention), patients will receive ticagrelor 90 mg twice daily or clopidogrel 75 mg once daily for 6 to 12 months on top of acetylsalicylic acid. The primary efficacy end point is time to first occurrence of death from vascular causes, myocardial infarction, or stroke. The primary safety variable is PLATO-defined major bleeding. An extensive substudy program will explore the pathophysiology of ACS, indicators of prognosis and response to treatment, mechanisms of effect and safety of the study medications, health economics, and quality of life. The PLATO study will provide a pivotal comparison of the efficacy and safety of ticagrelor with those of clopidogrel in ACS patients, together with extensive information on treatment outcomes in different subsets of ACS in a broad patient population.