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• W2157731594 abstract "Biomarkers in MedicineVol. 5, No. 1 Themed content: Markers of platelet activation/inhibition - ForewordFree AccessAspirin, P2Y12 blockers, cilostazol, PAR-1 blockers and emerging antiplatelet therapies: can biomarkers guide clinical development and practice?Ian BA MenownIan BA MenownCraigavon Cardiac Centre, Southern Trust, Northern Ireland, UK. Search for more papers by this authorEmail the corresponding author at ian.menown@southerntrust.hscni.netPublished Online:14 Feb 2011https://doi.org/10.2217/bmm.11.6AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail Figure 1. Targets for platelet inhibition showing sites of action of established and emerging therapies.5HT: 5-hydroxytryptamine; GP: Glycoprotein; LMWH: Low-molecular-weight heparin; PAR: Protease-activated receptor; TP: Thromboxane A2/prostaglandin H2; UFH: Unfractionated heparin.Adapted with permission from [10].Over the past two decades, large randomized clinical trials have helped define the current standard of care for patients with acute coronary syndromes, including those undergoing urgent percutaneous coronary intervention [1,2]. For the majority of patients, this will include dual antiplatelet therapy; typically aspirin and a platelet adenosine diphosphate P2Y12 receptor blocker. Some patients may also receive a third antiplatelet therapy, most commonly intravenous glycoprotein IIbIIIa blockade, although clinical experience is growing with the use of other oral antiplatelets on top of conventional dual antiplatelet therapy.While a significant number of ischemic events may still occur despite guideline-based practice, clinical trials with conventional antiplatelet therapies suggest a ceiling has been reached, beyond which further increases in efficacy are associated with unacceptable increases in bleeding.Functional testing of new & established antiplatelet agentsOne approach has been the development of novel antiplatelets as alternatives, or add-ons, to clopidogrel. Advances in understanding of platelet activation, amplification and aggregation has enabled identification of multiple potential therapeutic targets (Figure 1). New therapies include third-generation P2Y12 blockers (e.g., prasugrel, ticagrelor, cangrelor and elinogrel), direct thromboxane A2 antagonists (terutroban and picotamide), inhibition of collagen and ristocetin-mediated platelet function (DZ-697b), the phosphodiesterase III inhibitor (cilostazol) and protease-activated receptor-1 blockers (e.g., vorapaxar and atopaxar). Novel oral antithrombins (including dabigatran) and anti-Xa agents (including rivaroxaban and apixaban), which reduce platelet activation via a reduction in thrombin activation, are also being tested in patients with acute coronary syndrome.Ex vivo and in vivo functional testing, tailored to drug mechanism of action, is increasingly recognized as a useful biomarker to describe drug characteristics and guide both early and later clinical trial programs. In this unique issue of Biomarkers in Medicine, global experts in the field carefully describe the strengths, and the limitations, of functional testing for several established and emerging antiplatelet agents.Measuring antiplatelet activity of aspirinFoo and Oldroyd [3] and Schrör et al.[4] describe multiple methods for evaluating the antiplatelet function of aspirin (an irreversible inhibitor of cyclooxygenase-1-dependent thromboxane A2 formation), including inhibition of arachidonic acid-mediated platelet aggregation, assessing the surface expression of platelet activation markers, such as P-selectin, integrins (glycoprotein IIb/IIIa) or CD40 ligand, and measurement of serum thromboxane B2 or its urinary metabolite, 11-dehydro-thromboxane B2.Assessing response to P2Y12 blockersPrice et al. give a detailed description of the principal methodologies of laboratory-based and point-of-care tests to assess the antiplatelet effect of P2Y12 blockers by ADP-induced platelet aggregation (which acts mainly, but not exclusively, via P2Y12) or more specific measures of P2Y12 receptor reactivity using a vasodilator-stimulated phosphoprotein phosphorylation technique [5]. Application of such methods are key for understanding the clinical antiplatelet effects of clopidogrel in conventional or higher doses (Foo and Oldroyd [3]), prasugrel (Jakubowski [6]) and ticagrelor (Shand et al.[7]).Lippi et al. describe methods for assessing the antiplatelet effect of glycoprotein IIbIIIa inhibitors, including ADP-induced platelet aggregation, closure time (measurement of platelet hemostatic capacity) and platelet activation markers [8].Individualization of therapy?A second emerging approach is greater individualization of therapy. While dose adjustment according to weight, age or renal function (as with some parenteral therapies) is not yet commonplace for oral agents, recent clinical trials have attempted to define patient subgroups in whom dose modification may be of net clinical benefit [9].Foo and Oldroyd [3] and Schrör et al.[4] highlight the considerable inter- and intra-patient variability in aspirin response and the clinical significance of aspirin hyporesponsiveness. However, the absence of standardized methodologies for assessment of aspirin antiplatelet activity, the lack of linear correlation between inhibition of thromboxane A2 formation and platelet function, and the unclear association with clinical outcome means that such biomarkers are not yet ready to guide individualized aspirin therapy and research opportunity remains.Several of this issue’s articles [3,5–7] highlight the considerable inter- and intra-patient variability in the degree of platelet inhibition following clopidogrel with high on-treatment residual ADP-induced platelet aggregation being predictive of further ischemic events. Clopidogrel hyporesponsiveness is probably multifactorial, including genetic, cellular and clinical factors. Clopigogrel is susceptible to polymorphism of the ABCB1 gene (which affects absorption) and cytochrome P450 2C19 and 3A4 genes (which affects levels of active metabolite). Approximately 30% of the population carries a ‘loss-of-function’ 2C19 allele, which is probably of greatest importance in a post-percutaneous coronary intervention setting, particularly if homozygous. The clinical significance of drug interaction with high-dose lipophilic statins or certain proton-pump inhibitors remains unclear, but patient comorbidity, including acute coronary syndromes, diabetes or elevated BMI, has been associated with reduced clopidogrel responsiveness.A practical approachGenetic testing has the advantage of being a fixed and clear result, but as even the commonest polymorphism (2C19) accounts for only a minority of the variability in clopidogrel response, it is best reserved to complement clinical/functional risk assessment rather than as a standalone tool. In the setting of dual therapy with aspirin and clopidogrel, high residual on-treatment platelet reactivity may be associated with poorer outcome. As doubling the dose of clopidogrel only provides a modest pharmacodynamic effect [5], switching to a more potent P2Y12 blocker or adding a third agent, such as cilostazol or a protease activated receptor-1 blocker, may be appropriate providing the patient is not at high bleeding risk. Studies are underway testing the clinical value of such strategies.Financial & competing interests disclosureI Menown receives lecturing and/or advisory board honoraria from Astra Zeneca, Eli-Lilly/Daichii Sankyo, Shering Plough/MSD and Sanofi Aventis. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.Bibliography1 Van de Werf F, Bax J, Betriu A: Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation. Eur. Heart J.29,2909–2945 (2008).Crossref, Medline, CAS, Google Scholar2 Bassand JP, Hamm CW, Ardissino D; Task Force for Diagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary Syndromes of European Society of Cardiology: Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes. Eur. Heart J.28,1598–1660 (2007).Crossref, Medline, CAS, Google Scholar3 Foo F, Oldroyd KG: Clinical value of antiplatelet therapy in patients with acute coronary syndromes and in percutaneous coronary intervention. Biomarkers Med.5(1),9–30 (2011).Link, CAS, Google Scholar4 Schrör K, Huber K, Hohlfeld T: Functional testing methods for the antiplatelet effects of aspirin. Biomarkers Med.5(1),31–42 (2011).Link, Google Scholar5 Price MJ, Barker CM: Functional testing methods for the antiplatelet effect of P2Y12 receptor antagonists. Biomarkers Med.5(1),43–51 (2011).Link, CAS, Google Scholar6 Jakubowski JA: Beyond platelet functional testing: value in the aggregate. Biomarkers Med.5(1),5–8 (2011).Link, Google Scholar7 Shand JA, Menown IBA, Storey RF: Ticagrelor: from concept to clinical evaluation. Biomarkers Med.5(1),53–62 (2011).Link, CAS, Google Scholar8 Lippi G, Montagnana M, Danese E, Favaloro EJ, Franchini M: Glycoprotein IIb/IIIa inhibitors: an update on mechanism of action and use of functional testing methods to assess antiplatelet efficacy. Biomarkers Med.5(1),63–70 (2011).Link, CAS, Google Scholar9 Wiviott SD, Braunwald E, McCabe CH et al.: Prasugrel versus clopidogrel in patients with acute coronary syndromes. N. Engl. J. Med.357,2001–2015 (2007).Crossref, Medline, CAS, Google Scholar10 Storey RF: Biology and pharmacology of the platelet P2Y12 receptor. Curr. Pharm. Des.12,1255–1259 (2006).Crossref, Medline, CAS, Google ScholarFiguresReferencesRelatedDetailsCited ByEvaluation of the F2R IVS-14A/T PAR1 polymorphism with subsequent cardiovascular events and bleeding in patients who have undergone percutaneous coronary intervention7 October 2015 | Journal of Thrombosis and Thrombolysis, Vol. 41, No. 4Advances in cardiology: clinical trial updateAndrew J Howe, James A Shand & Ian BA Menown31 May 2011 | Future Cardiology, Vol. 7, No. 3 Vol. 5, No. 1 Follow us on social media for the latest updates Metrics History Published online 14 February 2011 Published in print February 2011 Information© Future Medicine LtdFinancial & competing interests disclosureI Menown receives lecturing and/or advisory board honoraria from Astra Zeneca, Eli-Lilly/Daichii Sankyo, Shering Plough/MSD and Sanofi Aventis. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download" @default.
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