Insights from In Vitro and Clinical Data to Guide Transition from the Novel P2Y12 Antagonist Selatogrel to Clopidogrel, Prasugrel, and Ticagrelor
Uta SchillingJasper DingemanseMichael DobrowMartine BaumannMarkus A. RiedererPierre‐Éric JuifMike Ufer
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Reduced pharmacodynamic (PD) effects of irreversible oral P2Y12 receptor antagonists have been reported when administered during cangrelor infusion. Therefore, the PD interaction liability of the novel P2Y12 receptor antagonist selatogrel with irreversible (i.e., clopidogrel, prasugrel) and reversible (i.e., ticagrelor) oral P2Y12 receptor antagonists was investigated in vitro and in healthy subjects. In vitro, selatogrel reduced the effects of clopidogrel and prasugrel in a concentration-dependent manner, while additive effects were observed for the combination of selatogrel and ticagrelor. Accordingly, a single-center, randomized, double-blind, two-way crossover study was conducted consisting of six groups. In each group (N = 12), an open-label loading dose of 300 or 600 mg clopidogrel, 60 mg prasugrel, or 180 mg ticagrelor was administered 30 minutes (i.e., at tmax of selatogrel) or 12 hours after a single subcutaneous dose of 16 mg selatogrel or placebo. Inhibition of platelet aggregation (IPA) was assessed at various time points up to 48 hours. Reduced IPA was determined when clopidogrel or prasugrel was administered 30 minutes after selatogrel (∼40 and 70% lower IPA, respectively, at 24 hours postdosing). However, when administering prasugrel 12 hours after selatogrel, IPA was not impacted (>90% IPA) and in the case of clopidogrel reduced effects were partially mitigated. Similar IPA was determined for ticagrelor when administered 30 minutes after selatogrel or placebo. In conclusion, reduced IPA was observed for clopidogrel and prasugrel when administered after selatogrel, which can be mitigated by applying an appropriate time interval. No PD interaction with ticagrelor was observed.Keywords:
Crossover study
Pharmacodynamics
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The thienopyridine clopidogrel, which irreversibly blocks the adenosine diphosphate (ADP) receptor P2Y 12 on platelets, has become an essential component of therapy in patients with acute coronary syndromes. However, clopidogrel has drawbacks which has led to the development of newer more potent antiplatelet agents: prasugrel, and ticagrelor. Prasugrel, a newer thienopyridine, also irreversibly binds to P2Y 12 . Prasugrel has a more rapid onset of action and a stronger inhibitory effect than clopidogrel. Ticagrelor is a new class of antiplatelet which binds reversibly to P2Y with a stronger and more rapid antiplatelet 12 effect than clopidogrel. This article discusses the newer antiplatelet agents and their role in acute coronary syndromes compared to clopidogrel. The article also highlights some of the side effects associated with these newer agents.
Thienopyridine
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Background: A recent study has suggested that ticagrelor 90 mg twice daily (bid) provides stronger platelet inhibition than prasugrel 10mg once daily (od) when measured with the VerifyNow P2Y12 assay (VN-P2Y12), in ACS patients. Aim: To compare the effect of ticagrelor 90mg bid and prasugrel 10mg od on platelet reactivity in STEMI patients using different platelet function tests including the VN-P2Y12 Methods: Platelet reactivity was prospectively evaluated using VN-P2Y12 platelet reaction unit (PRU), light transmission aggregometry (LTA) residual platelet agregation (RPA), and Vasodilator-Stimulated-Phosphoprotein (VASP) platelet reactivity index (PRI) 30 days after an acute STEMI. We studied 92 STEMI patients who received either prasugrel 10mg od (n=54) or ticagrelor 90 mg bid (n=38) after primary coronary stenting. Results: On-treatment platelet reactivity evaluated with the VN-P2Y12 assay (PRU) was lower with ticagrelor compared to prasugrel: 20±4.6 vs 55±8.3 (p=0.001). But these results were not confirmed with the other platelet function tests. The more specific test, VASP PRI (%) was 13.6±2.4 on ticagrelor vs. 18.0±2.1 on prasugrel (p=0.18); the more global test, LTA showed a mean RPA (%) of 12.9±2.0 vs. 9.0±1.7 for ticagrelor and prasugrel, respectively (p=0.15) (Figure). High on-treatment platelet reactivity rates were 2.6% with VASP (defined as PRI>50%) and 0% with VN-P2Y12 (PRU>235) and LTA (% RPA > 46.2%) on ticagrelor, while it was 0% with VASP, 1.8% with VN-P2Y12 and LTA on prasugrel. Pharmacodynamic Evaluation Conclusions: VASP and LTA measurements do not confirm the pharmacological superiority of ticagrelor over prasugrel when measured with VN-P2Y12 in STEMI Patients. These results suggest that VN-P2Y12 assay could overestimate the platelet inhibitory effect of ticagrelor.
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Advances in antiplatelet technologies to improve cardiovascular disease morbidity and mortality: a review of ticagrelor Estella M Davis, Jon T Knezevich, Robyn M Teply Department of Pharmacy Practice, Creighton University School of Pharmacy and Health Professions, Omaha, NE, USA Abstract: Antiplatelet therapy is widely used with proven benefit for the prevention of further ischemic cardiac complications in patients with acute coronary syndrome. Treatment guidelines for acute coronary syndrome and percutaneous coronary intervention now recommend the use of oral antiplatelet agents including ticagrelor, prasugrel, or clopidogrel in combination with aspirin to comprise dual antiplatelet therapy for the prevention of recurrent ischemic events. The limitations of conventional antiplatelet therapy with clopidogrel or prasugrel include the potential for low response to clopidogrel identified through platelet reactivity or genetic testing, increased risk of bleeding with prasugrel, or slower return to normal platelet activity in patients who received either prasugrel or clopidogrel prior to emergent or planned surgical procedures. This review will discuss the pharmacokinetic and pharmacodynamic properties of ticagrelor in comparison to conventional P2Y12 receptor inhibitors and its utility in patients identified as low responders to clopidogrel. Completed clinical studies and substudies comparing ticagrelor to clopidogrel and ongoing clinical trials evaluating ticagrelor in acute coronary syndrome patients will also be reviewed. Keywords: ticagrelor, antiplatelet, acute coronary syndrome, ST elevation myocardial infarction, non-ST elevation MI, percutaneous coronary intervention
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Abstract Today atherothrombotic disease accounts for up to 40% of deaths in Western countries. The role of platelets in the pathogenesis of atherothrombosis disease is well known. Anti-platelet drugs have been shown to prevent formation and progression of thrombosis and are used to prevent complications in acute coronary syndrome. Aspirin and clopidogrel have been the conventional anti-platelet therapy for many years. Despite this, clopidogrel has well known disadvantages that include bleeding, delayed onset, and inter-patient response variability that may equate to negative ischemic outcomes. This has led to the development of alternative oral P2Y12 antagonists such a prasugrel and ticagrelor that have undergone large randomized controlled trials. In these trials, clopidogrel has been compared to the newer oral P2Y12 antagonists in terms of efficacy and safety. Lack of experience with the newer agents, combined with fears about higher rates of bleeding compared with clopidogrel and cost, may have slowed the rate of prasugrel and ticagrelor adoption. In this article we review the pharmacology and individual patient considerations that affect the decision of which P2Y12 antagonist to use.
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Double anti-platelet therapy (DAPT) comprising a combination of acetylsalicylic acid and one of the thrombocyte P2Y12-receptor blockers is considered an obligatory element of the acute coronary syndrome (ACS) therapy [1–5]. Enlargement of the antiplatelet drugs range with active implementation of ticagrelor and prasugrel led to questions in cardiologists who render medical aid to acute coronary syndrome patients. Despite the priority use of these drugs declared in recommendations instead of clopidrogel doctors practically daily face a necessity to choose the optimal P2Y12 blocking agent assessing the expected individual effectiveness, hemorrhagic safety and cost of the rather long-acting therapy. For doctors practicing in the territory of the RF as opposed to doctors in other countries the problem of the P2Y12 blocking agent is less large-scale as they have to choose only between ticagrelor and clopidrogel (prasugrel is not applied in the RF).
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Summary The current standard of antiplatelet therapy of patients after myocardial infarction includes the P2Y12 receptor antagonists clopidogrel, prasugrel or ticagrelor. This study aimed to compare the antiplatelet effect of clopidogrel, prasugrel and ticagrelor in patients after myocardial infarction. In a single-centre registry the antiplatelet effect of clopidogrel, prasugrel and ticagrelor was investigated by aggregometry in patients after myocardial infarction. To assess the overall capacity of platelet aggregation whole blood was induced with thrombin receptor activating peptide (TRAP; 32 μM). To specifically quantify the effect of P2Y12 antagonists, whole blood was stimulated with 6.4 μM adenosine diphophosphate (ADP). Relative ADP induced aggregation (r-ADP-agg) was defined as the ADP-TRAP ratio to reflect an individual degree of P2Y12-dependent platelet inhibition. Platelet function of 238 patients was analysed [clopidogrel (n=58), prasugrel (n=65), ticagrelor (n=115)]. The r-ADP-agg was 35 ± 14% for patients receiving clopidogrel, 28 ± 10% for patients receiving prasugrel and 26 ± 11% for patients receiving ticagrelor. The r-ADP-agg was significantly lower in patients treated with prasugrel (p=0.0024) or ticagrelor (p<0.0001) compared to clopidogrel. There was no significant difference between patients receiving prasugrel or ticagrelor (p=0.2559). In conclusion, prasugrel and ticagrelor provide a stronger platelet inhibition compared to clopidogrel in patients after myocardial infarction. No significant difference in platelet inhibition was detected between prasugrel and ticagrelor. (registry for patients after Myocardial Infarction Treated with AntiPlatelet agents; DRKS00003146).
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The thienopyridine clopidogrel, which irreversibly blocks the adenosine diphosphate (ADP) receptor P2Y12 on platelets, has become an essential component of therapy in patients with acute coronary syndromes. However, clopidogrel has drawbacks which has led to the development of newer more potent antiplatelet agents: prasugrel, and ticagrelor. Prasugrel, a thienopyridine, also irreversibly binds to P2Y12. Prasugrel has a more rapid onset of action and a stronger inhibitory effect than clopidogrel. Ticagrelor is a new class of antiplatelet which binds reversibly to P2Y12 with a stronger and more rapid antiplatelet effect than clopidogrel. This article discusses the newer antiplatelet agents and their role in acute coronary syndromes compared to clopidogrel. The article also highlights some of the side effects associated with these newer agents.
Thienopyridine
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Background Bleeding complications are a common side effect in patients under dual antiplatelet (anti‐ PLT ) therapy. PLT transfusion provides a treatment option for these patients. However it is currently unclear if, and to what extent, P2Y 12 inhibitors influence PLT function of donor PLTs and if patients taking these medications are likely to benefit from PLT transfusions. Study Design and Methods We investigated the effect of blood and plasma of clopidogrel‐, prasugrel‐, and ticagrelor‐treated patients on PLT function of blood from healthy volunteers in flow cytometry, light transmission aggregometry, and multiple electrode aggregometry ( MEA ). Results Our results demonstrate that clopidogrel had no and prasugrel had only mild effects on donor PLT function, but the reversible P2Y 12 inhibitor ticagrelor completely abolished adenosine diphosphate‐mediated PLT activation in all assays tested. We further show that ticagrelor itself and not elevated adenosine concentrations in patient plasma were responsible for the observed effects. Moreover, we show that a modified MEA assay could provide a simple and rapid tool to allow determination of whether patients are likely to benefit from PLT transfusions. Conclusion Our results provide novel insights into potential differences between the P2Y 12 inhibitors on donor PLT function in an in vitro setting, which may provide implications for future PLT transfusion strategies in these patients.
Adenosine diphosphate
Platelet Transfusion
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Since data on the agreement between light transmission aggregometry (LTA) and multiple electrode aggregometry (MEA) in patients on the more potent P2Y 12 inhibitors are missing so far, we investigated if the evaluation of the responsiveness to therapy by LTA can be replaced by MEA in 160 acute coronary syndrome (ACS) patients on dual antiplatelet therapy with aspirin and prasugrel or ticagrelor (n = 80 each). Cut-off values for high on-treatment residual platelet reactivity (HRPR) in response to adenosine diphosphate (ADP) or arachidonic acid (AA) were defined according to previous studies showing an association of HRPR with the occurrence of adverse ischemic outcomes. ADP- inducible platelet aggregation was 33% and 37% ( P = 0.07) by LTA and 19 AU and 20 AU ( P = 0.38) by MEA in prasugrel- and ticagrelor-treated patients, respectively. AA- inducible platelet aggregation was 2% and 3% by LTA and 15 AU and 16 AU by MEA, (all P ≥ 0.3) in patients on prasugrel and ticagrelor, respectively. By LTA, HRPR ADP and HRPR AA were seen in 5%/5% and in 4%/ 13% of patients receiving prasugrel- and ticagrelor, respectively. By MEA, HRPR ADP and HRPR AA were seen in 3%/ 25% and 0%/24% of prasugrel- and ticagrelor-treated patients, respectively. ADP-inducible platelet reactivity by MEA correlated significantly with LTA ADP in prasugrel-treated patients (r = 0.4, P < 0.001), but not in those receiving ticagrelor (r = 0.09, P = 0.45). AA-inducible platelet aggregation by LTA and MEA did not correlate in prasugrel- and ticagrelor-treated patients. Sensitivity/specificity of HRPR by MEA to detect HRPR by LTA were 25%/99% for MEA ADP and 100%/79% for MEA AA in prasugrel-treated patients, and 0%/100% for MEA ADP and 70%/83% for MEA AA in ticagrelor-treated patients. In conclusion, on-treatment residual ADP-inducible platelet reactivity by LTA and MEA shows a significant correlation in prasugrel- but not ticagrelor-treated patients. However, in both groups LTA and MEA revealed heterogeneous results regarding the classification of patients as responders or non-responders to P2Y 12 inhibition.
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