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Review

Clinical pharmacology of antiplatelet drugs

ORCID Icon & ORCID Icon
Pages 1177-1197 | Received 18 Mar 2022, Accepted 31 Aug 2022, Published online: 11 Sep 2022

References

  • Mortality GBD, Causes of Death C. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the global burden of disease study 2013. Lancet. 2015 Jan 10;385(9963): 117–171.
  • Brass LF, Stalker TJ, Woulfe DS. Platelets. 2nd. Michelson AD, editor. San Diego: Elsevier/Academic Press; 2007.
  • Rendu F, Brohard-Bohn B. The platelet release reaction: granules’ constituents, secretion and functions. Platelets. 2001 Aug;12(5):261–273.
  • Koupenova M, Clancy L, Corkrey HA, et al. Circulating platelets as mediators of immunity, inflammation, and thrombosis. Circ Res. 2018 Jan 19;122(2):337–351.
  • Broos K, Feys HB, De Meyer SF, et al. Platelets at work in primary hemostasis. Blood Rev. 2011 Jul;25(4):155–167.
  • Smith WL. Prostanoid biosynthesis and mechanisms of action. Am J Physiol. 1992 Aug;263(2 Pt 2):F181–91.
  • Morita I, Schindler M, Regier MK, et al. Different intracellular locations for prostaglandin endoperoxide H synthase-1 and −2. J Biol Chem. 1995 May 5;270(18):10902–10908.
  • Roth GJ, Majerus PW. The mechanism of the effect of aspirin on human platelets. I. acetylation of a particulate fraction protein. J Clin Invest. 1975 Sep;56(3):624–632.
  • Loll PJ, Picot D, Garavito RM. The structural basis of aspirin activity inferred from the crystal structure of inactivated prostaglandin H2 synthase. Nat Struct Biol. 1995 Aug;2(8):637–643.
  • Patrono C, Coller B, Dalen JE, et al. Platelet-active drugs: the relationships among dose, effectiveness, and side effects. Chest. 1998 Nov;114(5 Suppl):470S–488S.
  • Vane JR, Bakhle YS, Botting RM. Cyclooxygenases 1 and 2. Annu Rev Pharmacol Toxicol. 1998;38(1):97–120.
  • Driver B, Marks DC, van der Wal DE. Not all (N)SAID and done: effects of nonsteroidal anti-inflammatory drugs and paracetamol intake on platelets. Res Pract Thromb Haemost. 2020 Jan;4(1):36–45.
  • Cattaneo M, Gachet C. ADP receptors and clinical bleeding disorders. Arterioscler Thromb Vasc Biol. 1999 Oct;19(10):2281–2285.
  • Becker RC, Gurbel PA. Platelet P2Y12 receptor antagonist pharmacokinetics and pharmacodynamics: a foundation for distinguishing mechanisms of bleeding and anticipated risk for platelet-directed therapies. Thromb Haemost. 2010 Mar;103(3):535–544.
  • Eckly A, Gendrault JL, Hechler B, et al. Differential involvement of the P2Y1 and P2YT receptors in the morphological changes of platelet aggregation. Thromb Haemost. 2001 Apr;85(4):694–701.
  • Cattaneo M, Canciani MT, Lecchi A, et al. Released adenosine diphosphate stabilizes thrombin-induced human platelet aggregates. Blood. 1990 Mar 1;75(5):1081–1086.
  • Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, et al. Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives. J Am Coll Cardiol. 2007 Apr 10;49(14):1505–1516.
  • Cattaneo M, Zighetti ML, Lombardi R, et al. Role of ADP in platelet aggregation at high shear: studies in a patient with congenital defect of platelet responses to ADP. Br J Haematol. 1994 Dec;88(4):826–829.
  • Goto S, Tamura N, Eto K, et al. Functional significance of adenosine 5’-diphosphate receptor (P2Y(12)) in platelet activation initiated by binding of von Willebrand factor to platelet GP Ibalpha induced by conditions of high shear rate. Circulation. 2002 May 28;105(21):2531–2536.
  • Cattaneo M, Lombardi R, Bettega D, et al. Shear-induced platelet aggregation is potentiated by desmopressin and inhibited by ticlopidine. Arterioscler Thromb. 1993 Mar;13(3):393–397.
  • Turner NA, Moake JL, McIntire LV. Blockade of adenosine diphosphate receptors P2Y(12) and P2Y(1) is required to inhibit platelet aggregation in whole blood under flow. Blood. 2001 Dec 1;98(12):3340–3345.
  • Nergiz-Unal R, Cosemans JM, Feijge MA, et al. Stabilizing role of platelet P2Y(12) receptors in shear-dependent thrombus formation on ruptured plaques. PLoS One. 2010 Apr 12;5(4):e10130.
  • Bhatt DL, Topol EJ. Scientific and therapeutic advances in antiplatelet therapy. Nat Rev Drug Discov. 2003 Jan;2(1):15–28.
  • Topol EJ, Byzova TV, Plow EF. Platelet GPIIb-IIIa blockers. Lancet. 1999 Jan 16;353(9148):227–231.
  • Michelson AD. Antiplatelet therapies for the treatment of cardiovascular disease. Nat Rev Drug Discov. 2010 Feb;9(2):154–169.
  • Coughlin SR. Protease-activated receptors in hemostasis, thrombosis and vascular biology. J Thromb Haemost. 2005 Aug;3(8):1800–1814.
  • Franchi F, Angiolillo DJ. Novel antiplatelet agents in acute coronary syndrome. Nat Rev Cardiol. 2015 Jan;12(1):30–47.
  • Angiolillo DJ, Capodanno D, Goto S. Platelet thrombin receptor antagonism and atherothrombosis. Eur Heart J. 2010 Jan;31(1):17–28.
  • Vu TK, Hung DT, Wheaton VI, et al. Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell. 1991 Mar 22;64(6):1057–1068.
  • Steinhoff M, Buddenkotte J, Shpacovitch V, et al. Proteinase-activated receptors: transducers of proteinase-mediated signaling in inflammation and immune response. Endocr Rev. 2005 Feb;26(1):1–43.
  • Henriksen RA, Hanks VK. PAR-4 agonist AYPGKF stimulates thromboxane production by human platelets. Arterioscler Thromb Vasc Biol. 2002 May 1;22(5):861–866.
  • Covic L, Singh C, Smith H, et al. Role of the PAR4 thrombin receptor in stabilizing platelet-platelet aggregates as revealed by a patient with Hermansky-Pudlak syndrome. Thromb Haemost. 2002 Apr;87(4):722–727.
  • Lova P, Campus F, Lombardi R, et al. Contribution of protease-activated receptors 1 and 4 and glycoprotein Ib-IX-V in the G(i)-independent activation of platelet Rap1B by thrombin. J Biol Chem. 2004 Jun 11;279(24):25299–25306.
  • Smith CC, Wilson AP, Prichard BN, et al. Stimulus-induced release of endogenous catecholamines from human washed platelets. Clin Sci (Lond). 1986 May;70(5):495–500.
  • Henn V, Slupsky JR, Grafe M, et al. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature. 1998 Feb 5;391(6667):591–594.
  • Stenberg PE, McEver RP, Shuman MA, et al. A platelet alpha-granule membrane protein (GMP-140) is expressed on the plasma membrane after activation. J Cell Biol. 1985 Sep;101(3):880–886.
  • Shattil SJ, Kashiwagi H, Pampori N. Integrin signaling: the platelet paradigm. Blood. 1998 Apr 15;91(8):2645–2657.
  • Offermanns S, Toombs CF, Hu YH, et al. Defective platelet activation in G alpha(q)-deficient mice. Nature. 1997 Sep 11;389(6647):183–186.
  • Andersen H, Greenberg DL, Fujikawa K, et al. Protease-activated receptor 1 is the primary mediator of thrombin-stimulated platelet procoagulant activity. Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):11189–11193.
  • Goldsack NR, Chambers RC, Dabbagh K, et al. Thrombin. Int J Biochem Cell Biol. 1998 Jun;30(6):641–646.
  • Chackalamannil S. Thrombin receptor (protease activated receptor-1) antagonists as potent antithrombotic agents with strong antiplatelet effects. J Med Chem. 2006 Sep 7;49(18):5389–5403.
  • FitzGerald GA, Wood AJJ, FitzGerald GA. Dipyridamole. N Engl J Med. 1987 May 14;316(20):1247–1257.
  • Gresele P, Momi S, Falcinelli E. Anti-platelet therapy: phosphodiesterase inhibitors. Br J Clin Pharmacol. 2011 Oct;72(4):634–646.
  • Bender AT, Beavo JA. Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use. Pharmacol Rev. 2006 Sep;58(3):488–520.
  • Smith SCsJr., Benjamin EJ, Bonow RO, et al. AHA/ACCF secondary prevention and risk reduction therapy for patients with coronary and other atherosclerotic vascular disease: 2011 update: a guideline from the American heart association and American college of cardiology foundation. Circulation. 2011 Nov 29;124(22):2458–2473.
  • Latini R, Cerletti C, de Gaetano G, et al. Comparative bioavailability of aspirin from buffered, enteric-coated and plain preparations. Int J Clin Pharmacol Ther Toxicol. 1986 Jun;24(6):313–318.
  • Jimenez AH, Stubbs ME, Tofler GH, et al. Rapidity and duration of platelet suppression by enteric-coated aspirin in healthy young men. Am J Cardiol. 1992 Jan 15;69(3):258–262.
  • Burch JW, Stanford N, Majerus PW. Inhibition of platelet prostaglandin synthetase by oral aspirin. J Clin Invest. 1978 Feb;61(2):314–319.
  • Bradlow BA, Chetty N. Dosage frequency for suppression of platelet function by low dose aspirin therapy. Thromb Res. 1982 Jul 1;27(1):99–110.
  • Patrono C, Ciabattoni G, Patrignani P, et al. Clinical pharmacology of platelet cyclooxygenase inhibition. Circulation. 1985 Dec;72(6):1177–1184.
  • Li C, Hirsh J, Xie C, et al. Reversal of the anti-platelet effects of aspirin and clopidogrel. J Thromb Haemost. 2012 Apr;10(4):521–528.
  • Fuchs I, Spiel AO, Frossard M, et al. Platelet hyperfunction is decreased by additional aspirin loading in patients presenting with myocardial infarction on daily aspirin therapy. Crit Care Med. 2010 Jun;38(6):1423–1429.
  • Patrignani P, Filabozzi P, Patrono C. Selective cumulative inhibition of platelet thromboxane production by low-dose aspirin in healthy subjects. J Clin Invest. 1982 Jun;69(6):1366–1372.
  • Weksler BB, Pett SB, Alonso D, et al. Differential inhibition by aspirin of vascular and platelet prostaglandin synthesis in atherosclerotic patients. N Engl J Med. 1983 Apr 7;308(14):800–805.
  • Homoncik M, Jilma B, Hergovich N, et al. Monitoring of aspirin (ASA) pharmacodynamics with the platelet function analyzer PFA-100. Thromb Haemost. 2000 Feb;83(2):316–321.
  • Tohgi H, Konno S, Tamura K, et al. Effects of low-to-high doses of aspirin on platelet aggregability and metabolites of thromboxane A2 and prostacyclin. Stroke. 1992 Oct;23(10):1400–1403.
  • Rao GH, Johnson GG, Reddy KR, et al. Ibuprofen protects platelet cyclooxygenase from irreversible inhibition by aspirin. Arteriosclerosis. 1983 Jul-Aug;3(4):383–388.
  • Schuijt MP, Huntjens-Fleuren HW, de Metz M, et al. The interaction of ibuprofen and diclofenac with aspirin in healthy volunteers. Br J Pharmacol. 2009 Jul;157(6):931–934.
  • Catella-Lawson F, Reilly MP, Kapoor SC, et al. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N Engl J Med. 2001 Dec 20;345(25):1809–1817.
  • MacDonald TM, Wei L. Effect of ibuprofen on cardioprotective effect of aspirin. Lancet. 2003 Feb 15;361(9357):573–574.
  • Polzin A, Richter S, Schror K, et al. Prevention of dipyrone (metamizole) induced inhibition of aspirin antiplatelet effects. Thromb Haemost. 2015 Jul;114(1):87–95.
  • Scharf RE. Drugs that affect platelet function. Semin Thromb Hemost. 2012 Nov;38(8):865–883.
  • Mackenzie IS, Coughtrie MW, MacDonald TM, et al. Antiplatelet drug interactions. J Intern Med. 2010 Dec;268(6):516–529.
  • Antman EM, DeMets D, Loscalzo J. Cyclooxygenase inhibition and cardiovascular risk. Circulation. 2005 Aug 2;112(5):759–770.
  • Juni P, Nartey L, Reichenbach S, et al. Risk of cardiovascular events and rofecoxib: cumulative meta-analysis. Lancet. 2004 Dec 4-10;364(9450):2021–2029.
  • Puri RN, Colman RW, Liberman MA. ADP-induced platelet activation. Crit Rev Biochem Mol Biol. 1997;32(6):437–502.
  • Jacobson AK. Platelet ADP receptor antagonists: ticlopidine and clopidogrel. Best Pract Res Clin Haematol. 2004 Mar;17(1):55–64.
  • Wallentin L. P2Y(12) inhibitors: differences in properties and mechanisms of action and potential consequences for clinical use. Eur Heart J. 2009 Aug;30(16):1964–1977.
  • Gill S, Majumdar S, Brown NE, et al. Ticlopidine-associated pancytopenia: implications of an acetylsalicylic acid alternative. Can J Cardiol. 1997 Oct;13(10):909–913.
  • Quinn MJ, Fitzgerald DJ. Ticlopidine and clopidogrel. Circulation. 1999 Oct 12;100(15):1667–1672.
  • Pharmaceuticals SP. US Prescribing Information [CLO-FPLR-SL-MAR21]. 2021.
  • Zhu HJ, Wang X, Gawronski BE, et al. Carboxylesterase 1 as a determinant of clopidogrel metabolism and activation. J Pharmacol Exp Ther. 2013 Mar;344(3):665–672.
  • Bonello L, Tantry US, Marcucci R, et al. Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate. J Am Coll Cardiol. 2010 Sep 14;56(12):919–933.
  • Kazui M, Nishiya Y, Ishizuka T, et al. Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. Drug Metab Dispos. 2010 Jan;38(1):92–99.
  • Jiang XL, Samant S, Lesko LJ, et al. Clinical pharmacokinetics and pharmacodynamics of clopidogrel. Clin Pharmacokinet. 2015 Feb;54(2):147–166.
  • Bouman HJ, Schomig E, van Werkum JW, et al. Paraoxonase-1 is a major determinant of clopidogrel efficacy. Nat Med. 2011 Jan;17(1):110–116.
  • Sibbing D, Aradi D, Alexopoulos D, et al. Updated expert consensus statement on platelet function and genetic testing for guiding P2Y12 Receptor inhibitor treatment in percutaneous coronary intervention. JACC Cardiovasc Interv. 2019 Aug 26;12(16):1521–1537.
  • Galli M, Franchi F, Rollini F, et al. Genetic testing in patients undergoing percutaneous coronary intervention: rationale, evidence and practical recommendations. Expert Rev Clin Pharmacol. 2021 Aug;14(8):963–978.
  • Lewis JP, Stephens SH, Horenstein RB, et al. The CYP2C19*17 variant is not independently associated with clopidogrel response. J Thromb Haemost. 2013 Sep;11(9):1640–1646.
  • Danese E, Fava C, Beltrame F, et al. Relationship between pharmacokinetics and pharmacodynamics of clopidogrel in patients undergoing percutaneous coronary intervention: comparison between vasodilator-stimulated phosphoprotein phosphorylation assay and multiple electrode aggregometry. J Thromb Haemost. 2016 Feb;14(2):282–293.
  • Price MJ, Walder JS, Baker BA, et al. Recovery of platelet function after discontinuation of prasugrel or clopidogrel maintenance dosing in aspirin-treated patients with stable coronary disease: the recovery trial. J Am Coll Cardiol. 2012 Jun 19;59(25):2338–2343.
  • Li XQ, Andersson TB, Ahlstrom M, et al. Comparison of inhibitory effects of the proton pump-inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450 activities. Drug Metab Dispos. 2004 Aug;32(8):821–827.
  • Howden CW. Clinical pharmacology of omeprazole. Clin Pharmacokinet. 1991 Jan;20(1):38–49.
  • Bates ER, Lau WC, Angiolillo DJ. Clopidogrel-drug interactions. J Am Coll Cardiol. 2011 Mar 15;57(11):1251–1263.
  • Gilard M, Arnaud B, Cornily JC, et al. Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized, double-blind OCLA (omeprazole clopidogrel aspirin) study. J Am Coll Cardiol. 2008 Jan 22;51(3):256–260.
  • Cuisset T, Frere C, Quilici J, et al. Comparison of omeprazole and pantoprazole influence on a high 150-mg clopidogrel maintenance dose the PACA (proton pump inhibitors and clopidogrel association) prospective randomized study. J Am Coll Cardiol. 2009 Sep 22;54(13):1149–1153.
  • Sibbing D, Morath T, Stegherr J, et al. Impact of proton pump inhibitors on the antiplatelet effects of clopidogrel. Thromb Haemost. 2009 Apr;101(4):714–719.
  • Neubauer H, Engelhardt A, Kruger JC, et al. Pantoprazole does not influence the antiplatelet effect of clopidogrel-a whole blood aggregometry study after coronary stenting. J Cardiovasc Pharmacol. 2010 Jul;56(1):91–97.
  • Ferreiro JL, Ueno M, Capodanno D, et al. Pharmacodynamic effects of concomitant versus staggered clopidogrel and omeprazole intake: results of a prospective randomized crossover study. Circ Cardiovasc Interv. 2010 Oct;3(5):436–441.
  • Angiolillo DJ, Gibson CM, Cheng S, et al. Differential effects of omeprazole and pantoprazole on the pharmacodynamics and pharmacokinetics of clopidogrel in healthy subjects: randomized, placebo-controlled, crossover comparison studies. Clin Pharmacol Ther. 2011 Jan;89(1):65–74.
  • Siller-Matula JM, Spiel AO, Lang IM, et al. Effects of pantoprazole and esomeprazole on platelet inhibition by clopidogrel. Am Heart J. 2009 Jan;157(1):148 e1–5.
  • Siller-Matula JM, Jilma B, Schror K, et al. Effect of proton pump inhibitors on clinical outcome in patients treated with clopidogrel: a systematic review and meta-analysis. J Thromb Haemost. 2010 Dec;8(12):2624–2641.
  • Farid NA, Payne CD, Small DS, et al. Cytochrome P450 3A inhibition by ketoconazole affects prasugrel and clopidogrel pharmacokinetics and pharmacodynamics differently. Clin Pharmacol Ther. 2007 May;81(5):735–741.
  • Suh JW, Koo BK, Zhang SY, et al. Increased risk of atherothrombotic events associated with cytochrome P450 3A5 polymorphism in patients taking clopidogrel. Cmaj. 2006 Jun 6;174(12):1715–1722.
  • Siller-Matula JM, Lang I, Christ G, et al. Calcium-channel blockers reduce the antiplatelet effect of clopidogrel. J Am Coll Cardiol. 2008 Nov 4;52(19):1557–1563.
  • Gremmel T, Steiner S, Seidinger D, et al. Calcium-channel blockers decrease clopidogrel-mediated platelet inhibition. Heart. 2010 Feb;96(3):186–189.
  • Sibbing D, von Beckerath N, Morath T, et al. Oral anticoagulation with coumarin derivatives and antiplatelet effects of clopidogrel. Eur Heart J. 2010 May;31(10):1205–1211.
  • Judge HM, Patil SB, Buckland RJ, et al. Potentiation of clopidogrel active metabolite formation by rifampicin leads to greater P2Y12 receptor blockade and inhibition of platelet aggregation after clopidogrel. J Thromb Haemost. 2010 Aug;8(8):1820–1827.
  • Lau WC, Welch TD, Shields T, et al. The effect of St John’s Wort on the pharmacodynamic response of clopidogrel in hyporesponsive volunteers and patients: increased platelet inhibition by enhancement of CYP3A4 metabolic activity. J Cardiovasc Pharmacol. 2011 Jan;57(1):86–93.
  • Bliden KP, Dichiara J, Lawal L, et al. The association of cigarette smoking with enhanced platelet inhibition by clopidogrel. J Am Coll Cardiol. 2008 Aug 12;52(7):531–533.
  • Lev EI, Arikan ME, Vaduganathan M, et al. Effect of caffeine on platelet inhibition by clopidogrel in healthy subjects and patients with coronary artery disease. Am Heart J. 2007 Oct;154(4):694 e1–7.
  • Angiolillo DJ, Capranzano P, Goto S, et al. A randomized study assessing the impact of cilostazol on platelet function profiles in patients with diabetes mellitus and coronary artery disease on dual antiplatelet therapy: results of the OPTIMUS-2 study. Eur Heart J. 2008 Sep;29(18):2202–2211.
  • Farid NA, Smith RL, Gillespie TA, et al. The disposition of prasugrel, a novel thienopyridine, in humans. Drug Metab Dispos. 2007 Jul;35(7):1096–1104.
  • Rehmel JL, Eckstein JA, Farid NA, et al. Interactions of two major metabolites of prasugrel, a thienopyridine antiplatelet agent, with the cytochromes P450. Drug Metab Dispos. 2006 Apr;34(4):600–607.
  • Brandt JT, Payne CD, Wiviott SD, et al. A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation. Am Heart J. 2007 Jan;153(1):66 e9–16.
  • Sugidachi A, Ogawa T, Kurihara A, et al. The greater in vivo antiplatelet effects of prasugrel as compared to clopidogrel reflect more efficient generation of its active metabolite with similar antiplatelet activity to that of clopidogrel’s active metabolite. J Thromb Haemost. 2007 Jul;5(7):1545–1551.
  • Wallentin L, Varenhorst C, James S, et al. Prasugrel achieves greater and faster P2Y12receptor-mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirin-treated patients with coronary artery disease. Eur Heart J. 2008 Jan;29(1):21–30.
  • Angiolillo DJ, Bates ER, Bass TA. Clinical profile of prasugrel, a novel thienopyridine. Am Heart J. 2008 Aug;156(2 Suppl):S16–22.
  • Jakubowski JA, Matsushima N, Asai F, et al. A multiple dose study of prasugrel (CS-747), a novel thienopyridine P2Y12 inhibitor, compared with clopidogrel in healthy humans. Br J Clin Pharmacol. 2007 Apr;63(4):421–430.
  • Mega JL, Simon T. Pharmacology of antithrombotic drugs: an assessment of oral antiplatelet and anticoagulant treatments. Lancet. 2015 Jul 18;386(9990):281–291.
  • Duggan ST, Keating GM. Prasugrel: a review of its use in patients with acute coronary syndromes undergoing percutaneous coronary intervention. Drugs. 2009 Aug 20;69(12):1707–1726.
  • Vang JJ, Nilsson L, Berntsson P, et al. Ticagrelor binds to human P2Y(12) independently from ADP but antagonizes ADP-induced receptor signaling and platelet aggregation. J Thromb Haemost. 2009 Sep;7(9):1556–1565.
  • Husted S, van Giezen JJ. Ticagrelor: the first reversibly binding oral P2Y12 receptor antagonist. Cardiovasc Ther. 2009;27(4):259–274. Winter.
  • Zhou D, Andersson TB, Grimm SW. In vitro evaluation of potential drug-drug interactions with ticagrelor: cytochrome P450 reaction phenotyping, inhibition, induction, and differential kinetics. Drug Metab Dispos. 2011 Apr;39(4):703–710.
  • Teng R, Butler K. Pharmacokinetics, pharmacodynamics, tolerability and safety of single ascending doses of ticagrelor, a reversibly binding oral P2Y(12) receptor antagonist, in healthy subjects. Eur J Clin Pharmacol. 2010 May;66(5):487–496.
  • Teng R, Oliver S, Hayes MA, et al. Absorption, distribution, metabolism, and excretion of ticagrelor in healthy subjects. Drug Metab Dispos. 2010 Sep;38(9):1514–1521.
  • Teng R. Ticagrelor: pharmacokinetic, pharmacodynamic and pharmacogenetic profile: an update. Clin Pharmacokinet. 2015 Nov;54(11):1125–1138.
  • Teng R, Mitchell PD, Butler K. Lack of significant food effect on the pharmacokinetics of ticagrelor in healthy volunteers. J Clin Pharm Ther. 2012 Aug;37(4):464–468.
  • Teng R, Mitchell PD, Butler KA. Pharmacokinetic interaction studies of co-administration of ticagrelor and atorvastatin or simvastatin in healthy volunteers. Eur J Clin Pharmacol. 2013 Mar;69(3):477–487.
  • Teng R, Butler K. Effect of the CYP3A inhibitors, diltiazem and ketoconazole, on ticagrelor pharmacokinetics in healthy volunteers. J Drug Assess. 2013;2(1):30–39.
  • Bartko J, Schoergenhofer C, Schwameis M, et al. Morphine interaction with aspirin: a double-blind, crossover trial in healthy volunteers. J Pharmacol Exp Ther. 2018 May;365(2):430–436.
  • Hobl EL, Stimpfl T, Ebner J, et al. Morphine decreases clopidogrel concentrations and effects: a randomized, double-blind, placebo-controlled trial. J Am Coll Cardiol. 2014 Feb 25;63(7):630–635.
  • Parodi G, Valenti R, Bellandi B, et al. Comparison of prasugrel and ticagrelor loading doses in ST-segment elevation myocardial infarction patients: RAPID (rapid activity of platelet inhibitor drugs) primary pci study. J Am Coll Cardiol. 2013 Apr 16;61(15):1601–1606.
  • Hobl EL, Reiter B, Schoergenhofer C, et al. Morphine interaction with prasugrel: a double-blind, cross-over trial in healthy volunteers. Clin Res Cardiol. 2016 Apr;105(4):349–355.
  • Kubica J, Adamski P, Ostrowska M, et al. Morphine delays and attenuates ticagrelor exposure and action in patients with myocardial infarction: the randomized, double-blind, placebo-controlled IMPRESSION trial. Eur Heart J. 2016 Jan 14;37(3):245–252.
  • Hobl EL, Reiter B, Schoergenhofer C, et al. Morphine decreases ticagrelor concentrations but not its antiplatelet effects: a randomized trial in healthy volunteers. Eur J Clin Invest. 2016 Jan;46(1):7–14.
  • Giannopoulos G, Deftereos S, Kolokathis F, et al. P2Y12 receptor antagonists and morphine: a dangerous liaison? Circ Cardiovasc Interv. 2016 Sep;9(9). doi:10.1161/CIRCINTERVENTIONS.116.004229.
  • Nimmo WS, Heading RC, Wilson J, et al. Inhibition of gastric emptying and drug absorption by narcotic analgesics. Br J Clin Pharmacol. 1975 Dec;2(6):509–513.
  • Gue YX, Spinthakis N, Farag M, et al. Impact of preadmission morphine on reinfarction in patients with ST-elevation myocardial infarction treated with percutaneous coronary intervention: a meta-analysis. Clin Pharmacol Ther. 2020 Jul;108(1):54–62.
  • Ibanez B, James S, Agewall S, et al. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the task force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the european society of cardiology (ESC). Eur Heart J. 2018 Jan 7;39(2):119–177.
  • Meine TJ, Roe MT, Chen AY, et al. Association of intravenous morphine use and outcomes in acute coronary syndromes: results from the CRUSADE Quality Improvement Initiative. Am Heart J. 2005 Jun;149(6):1043–1049.
  • Sikora J, Niezgoda P, Baranska M, et al. METoclopramide administration as a strategy to overcome morphine-ticagrelor interaction in patients with unstable angina pectoris-the METAMORPHOSIS trial. Thromb Haemost. 2018 Dec;118(12):2126–2133.
  • Saad M, Meyer-Saraei R, de Waha-thiele S, et al. Impact of morphine treatment with and without metoclopramide coadministration on ticagrelor-induced platelet inhibition in acute myocardial infarction: the randomized monami trial. Circulation. 2020 Apr 21;141(16):1354–1356.
  • Siller-Matula JM, Specht S, Kubica J, et al. Abciximab as a bridging strategy to overcome morphine-prasugrel interaction in STEMI patients. Br J Clin Pharmacol. 2016 Nov;82(5):1343–1350.
  • Storey RF, Oldroyd KG, Wilcox RG. Open multicentre study of the P2T receptor antagonist AR-C69931MX assessing safety, tolerability and activity in patients with acute coronary syndromes. Thromb Haemost. 2001 Mar;85(3):401–407.
  • Greenbaum AB, Grines CL, Bittl JA, et al. Initial experience with an intravenous P2Y12 platelet receptor antagonist in patients undergoing percutaneous coronary intervention: results from a 2-part, phase II, multicenter, randomized, placebo- and active-controlled trial. Am Heart J. 2006 Mar;151(3):689 e1–689 e10.
  • Dovlatova NL, Jakubowski JA, Sugidachi A, et al. The reversible P2Y antagonist cangrelor influences the ability of the active metabolites of clopidogrel and prasugrel to produce irreversible inhibition of platelet function. J Thromb Haemost. 2008 Jul;6(7):1153–1159.
  • Herrman JP, Hermans WR, Vos J, et al. Pharmacological approaches to the prevention of restenosis following angioplasty the search for the Holy Grail? (Part I). Drugs. 1993 Jul;46(1):18–52.
  • Coller BS, Scudder LE, Beer J, et al. Monoclonal antibodies to platelet glycoprotein IIb/IIIa as antithrombotic agents. Ann N Y Acad Sci. 1991;614(1):193–213.
  • Ibbotson T, McGavin JK, Goa KL. Abciximab: an updated review of its therapeutic use in patients with ischaemic heart disease undergoing percutaneous coronary revascularisation. Drugs. 2003;63(11):1121–1163.
  • Faulds D, Sorkin EM. Abciximab (c7E3 Fab). A review of its pharmacology and therapeutic potential in ischaemic heart disease. Drugs. 1994 Oct;48(4):583–598.
  • Simoons ML, de Boer MJ, van den Brand MJ, et al. Randomized trial of a GPIIb/IIIa platelet receptor blocker in refractory unstable angina. European Cooperative Study Group. Circulation. 1994 Feb; 89(2): 596–603.
  • Investigators E. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. N Engl J Med. 1994 Apr 7;330(14):956–961.
  • Hartman GD, Egbertson MS, Halczenko W, et al. Non-peptide fibrinogen receptor antagonists 1 discovery and design of exosite inhibitors. J Med Chem. 1992 Nov 27;35(24):4640–4642.
  • Kondo K, Umemura K. Clinical pharmacokinetics of tirofiban, a nonpeptide glycoprotein IIb/IIIa receptor antagonist: comparison with the monoclonal antibody Abciximab. Clin Pharmacokinet. 2002;41(3):187–195.
  • Yang M, Huo X, Miao Z, et al. Platelet glycoprotein IIb/IIIa receptor inhibitor tirofiban in acute ischemic stroke. Drugs. 2019 Apr;79(5):515–529.
  • Scarborough RM. Development of eptifibatide. Am Heart J. 1999 Dec;138(6 Pt 1):1093–1104.
  • Gould RJ, Polokoff MA, Friedman PA, et al. Disintegrins: a family of integrin inhibitory proteins from viper venoms. Proc Soc Exp Biol Med. 1990 Nov;195(2):168–171.
  • Scarborough RM, Rose JW, Hsu MA, et al. Barbourin A GPIIb-IIIa-specific integrin antagonist from the venom of sistrurus m. barbouri. J Biol Chem. 1991 May 25;266(15):9359–9362.
  • Harrington RA, Kleiman NS, Kottke-Marchant K, et al. Immediate and reversible platelet inhibition after intravenous administration of a peptide glycoprotein IIb/IIIa inhibitor during percutaneous coronary intervention. Am J Cardiol. 1995 Dec 15;76(17):1222–1227.
  • Goa KL, Noble S. Eptifibatide: a review of its use in patients with acute coronary syndromes and/or undergoing percutaneous coronary intervention. Drugs. 1999 Mar;57(3):439–462.
  • Uthoff K, Zehr KJ, Geerling R, et al. Inhibition of platelet adhesion during cardiopulmonary bypass reduces postoperative bleeding. Circulation. 1994 Nov;90(5 Pt 2):II269–74.
  • O’Shea JC, Tcheng JE. Eptifibatide: a potent inhibitor of the platelet receptor integrin glycoprotein IIb/IIIa. Expert Opin Pharmacother. 2002 Aug;3(8):1199–1210.
  • Abrams CS, Cines DB. Thrombocytopenia after treatment with platelet glycoprotein IIb/IIIa inhibitors. Curr Hematol Rep. 2004 Mar;3(2):143–147.
  • Coons JC, Barcelona RA, Freedy T, et al. Eptifibatide-associated acute, profound thrombocytopenia. Ann Pharmacother. 2005 Feb;39(2):368–372.
  • Huynh T, Piazza N, DiBattiste PM, et al. Analysis of bleeding complications associated with glycoprotein IIb/IIIa receptors blockade in patients with high-risk acute coronary syndromes: insights from the PRISM-PLUS study. Int J Cardiol. 2005 Apr 8;100(1):73–78.
  • Aster RH. Immune thrombocytopenia caused by glycoprotein IIb/IIIa inhibitors. Chest. 2005 Feb;127(2 Suppl):53S–59S.
  • Aster RH, Bougie DW. Drug-induced immune thrombocytopenia. N Engl J Med. 2007 Aug 9;357(6):580–587.
  • Bougie DW, Wilker PR, Wuitschick ED, et al. Acute thrombocytopenia after treatment with tirofiban or eptifibatide is associated with antibodies specific for ligand-occupied GPIIb/IIIa. Blood. 2002 Sep 15;100(6):2071–2076.
  • Billheimer JT, Dicker IB, Wynn R, et al. Evidence that thrombocytopenia observed in humans treated with orally bioavailable glycoprotein IIb/IIIa antagonists is immune mediated. Blood. 2002 May 15;99(10):3540–3546.
  • Peterson JA, Nelson TN, Kanack AJ, et al. Fine specificity of drug-dependent antibodies reactive with a restricted domain of platelet GPIIIA. Blood. 2008 Feb 1;111(3):1234–1239.
  • Bougie DW, Rasmussen M, Zhu J, et al. Antibodies causing thrombocytopenia in patients treated with RGD-mimetic platelet inhibitors recognize ligand-specific conformers of alphaIIb/beta3 integrin. Blood. 2012 Jun 28;119(26):6317–6325.
  • Gao C, Boylan B, Bougie D, et al. Eptifibatide-induced thrombocytopenia and thrombosis in humans require FcgammaRIIa and the integrin beta3 cytoplasmic domain. J Clin Invest. 2009 Mar;119(3):504–511.
  • Said SM, Hahn J, Schleyer E, et al. Glycoprotein IIb/IIIa inhibitor-induced thrombocytopenia: diagnosis and treatment. Clin Res Cardiol. 2007 Feb;96(2):61–69.
  • Rousan TA, Aldoss IT, Cowley BDsJr., et al. Recurrent acute thrombocytopenia in the hospitalized patient: sepsis, DIC, HIT, or antibiotic-induced thrombocytopenia. Am J Hematol. 2010 Jan;85(1):71–74.
  • Jenkins LA, Lau S, Crawford M, et al. Delayed profound thrombocytopenia after c7E3 Fab (Abciximab) therapy. Circulation. 1998 Mar 31;97(12):1214–1215.
  • Reddy MS, Carmody TJ, Kereiakes DJ. Severe delayed thrombocytopenia associated with Abciximab (ReoPro) therapy. Catheter Cardiovasc Interv. 2001 Apr;52(4):486–488.
  • Curtis BR, Divgi A, Garritty M, et al. Delayed thrombocytopenia after treatment with Abciximab: a distinct clinical entity associated with the immune response to the drug. J Thromb Haemost. 2004 Jun;2(6):985–992.
  • Leonardi S, Tricoci P, Becker RC. Thrombin receptor antagonists for the treatment of atherothrombosis: therapeutic potential of vorapaxar and E-5555. Drugs. 2010 Oct 1;70(14):1771–1783.
  • Franchi F, Rollini F, Park Y, et al. Platelet thrombin receptor antagonism with vorapaxar: pharmacology and clinical trial development. Future Cardiol. 2015 Sep;11(5):547–564.
  • Bliden K, Chaudhary R, Kuliopulos A, et al. Effects of vorapaxar on clot characteristics, coagulation, inflammation, and platelet and endothelial function in patients treated with mono- and dual-antiplatelet therapy. J Thromb Haemost. 2020 Jan;18(1):23–35.
  • Schoergenhofer C, Schwameis M, Gelbenegger G, et al. Inhibition of protease-activated receptor (PAR1) reduces activation of the endothelium, coagulation, fibrinolysis and inflammation during human endotoxemia. Thromb Haemost. 2018 Jul;118(7):1176–1184.
  • Kosoglou T, Reyderman L, Tiessen RG, et al. Pharmacodynamics and pharmacokinetics of the novel PAR-1 antagonist vorapaxar (formerly SCH 530348) in healthy subjects. Eur J Clin Pharmacol. 2012 Mar;68(3):249–258.
  • Ghosal A, Lu X, Penner N, et al. Identification of human liver cytochrome P450 enzymes involved in the metabolism of SCH 530348 (Vorapaxar), a potent oral thrombin protease-activated receptor 1 antagonist. Drug Metab Dispos. 2011 Jan;39(1):30–38.
  • Kosoglou T, Statkevich P, Kumar B, et al. The effect of multiple doses of ketoconazole or rifampin on the single- and multiple-dose pharmacokinetics of vorapaxar. J Clin Pharmacol. 2013 May;53(5):540–549.
  • Angiolillo DJ, Capranzano P. Pharmacology of emerging novel platelet inhibitors. Am Heart J. 2008 Aug;156(2 Suppl):S10–5.
  • Rollini F, Franchi F, Cho JR, et al. 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. Eur Heart J. 2016 Sep 14;37(35):2722–2730.
  • Angiolillo DJ, Saucedo JF, Deraad R, et al. Increased platelet inhibition after switching from maintenance clopidogrel to prasugrel in patients with acute coronary syndromes: results of the SWAP (switching anti platelet) study. J Am Coll Cardiol. 2010 Sep 21;56(13):1017–1023.
  • Gurbel PA, Bliden KP, Butler K, et al. Response to ticagrelor in clopidogrel nonresponders and responders and effect of switching therapies: the RESPOND study. Circulation. 2010 Mar 16;121(10):1188–1199.
  • Angiolillo DJ, Rollini F, Storey RF, et al. International expert consensus on switching platelet P2Y12 receptor-inhibiting therapies. Circulation. 2017 Nov 14;136(20):1955–1975.
  • Angiolillo DJ, Curzen N, Gurbel P, et al. Pharmacodynamic evaluation of switching from ticagrelor to prasugrel in patients with stable coronary artery disease: results of the SWAP-2 study (switching anti platelet-2). J Am Coll Cardiol. 2014 Apr 22;63(15):1500–1509.
  • Franchi F, Faz GT, Rollini F, et al. Pharmacodynamic effects of switching from prasugrel to ticagrelor: results of the prospective, Randomized SWAP-3 study. JACC Cardiovasc Interv. 2016 Jun 13;9(11):1089–1098.
  • Steinhubl SR, Oh JJ, Oestreich JH, et al. Transitioning patients from cangrelor to clopidogrel: pharmacodynamic evidence of a competitive effect. Thromb Res. 2008;121(4):527–534.
  • Schneider DJ, Agarwal Z, Seecheran N, et al. Pharmacodynamic effects when clopidogrel is given before cangrelor discontinuation. J Interv Cardiol. 2015 Oct;28(5):415–419.
  • Schneider DJ, Seecheran N, Raza SS, et al. Pharmacodynamic effects during the transition between cangrelor and prasugrel. Coron Artery Dis. 2015 Jan;26(1):42–48.
  • Franchi F, Rollini F, Muniz-Lozano A, et al. Cangrelor: a review on pharmacology and clinical trial development. Expert Rev Cardiovasc Ther. 2013 Oct;11(10):1279–1291.
  • Schneider DJ, Agarwal Z, Seecheran N, et al. Pharmacodynamic effects during the transition between cangrelor and ticagrelor. JACC Cardiovasc Interv. 2014 Apr;7(4):435–442.
  • Franchi F, Rollini F, Rivas A, et al. Platelet inhibition with cangrelor and crushed ticagrelor in patients with st-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention. Circulation. 2019 Apr 2;139(14):1661–1670.
  • Angiolillo DJ, Firstenberg MS, Price MJ, et al. Bridging antiplatelet therapy with cangrelor in patients undergoing cardiac surgery: a randomized controlled trial. JAMA. 2012 Jan 18;307(3):265–274.
  • Galli M, Franchi F, Rollini F, et al. Role of platelet function and genetic testing in patients undergoing percutaneous coronary intervention. Trends Cardiovasc Med. 2021 Dec 20. DOI:10.1016/j.tcm.2021.12.007.
  • Galli M, Benenati S, Capodanno D, et al. Guided versus standard antiplatelet therapy in patients undergoing percutaneous coronary intervention: a systematic review and meta-analysis. Lancet. 2021 Apr 17;397(10283):1470–1483.
  • Stone GW, Witzenbichler B, Weisz G, et al. Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents (ADAPT-DES): a prospective multicentre registry study. Lancet. 2013 Aug 17;382(9892):614–623.
  • Campo G, Parrinello G, Ferraresi P, et al. Prospective evaluation of on-clopidogrel platelet reactivity over time in patients treated with percutaneous coronary intervention relationship with gene polymorphisms and clinical outcome. J Am Coll Cardiol. 2011 Jun 21;57(25):2474–2483.
  • Sibbing D, Schulz S, Braun S, et al. Antiplatelet effects of clopidogrel and bleeding in patients undergoing coronary stent placement. J Thromb Haemost. 2010 Feb;8(2):250–256.
  • Bonello L, Mancini J, Pansieri M, et al. Relationship between post-treatment platelet reactivity and ischemic and bleeding events at 1-year follow-up in patients receiving prasugrel. J Thromb Haemost. 2012 Oct;10(10):1999–2005.
  • Gurbel PA, Bliden KP, Navickas IA, et al. Adenosine diphosphate-induced platelet-fibrin clot strength: a new thrombelastographic indicator of long-term poststenting ischemic events. Am Heart J. 2010 Aug;160(2):346–354.
  • Lordkipanidze M. Platelet function tests. Semin Thromb Hemost. 2016 Apr;42(3):258–267.
  • Franchi F, Rollini F, Rivas J, et al. Prasugrel versus ticagrelor in patients with CYP2C19 loss-of-function genotypes: results of a Randomized pharmacodynamic study in a feasibility investigation of rapid genetic testing. JACC Basic Transl Sci. 2020 May;5(5):419–428.
  • Pereira NL, Farkouh ME, So D, et al. Effect of genotype-guided oral P2Y12 inhibitor selection vs conventional clopidogrel therapy on Ischemic outcomes after percutaneous coronary intervention: the TAILOR-Pci randomized clinical trial. JAMA. 2020 Aug 25;324(8):761–771.
  • Zheng YY, Wu TT, Yang Y, et al. Personalized antiplatelet therapy guided by a novel detection of platelet aggregation function in stable coronary artery disease patients undergoing percutaneous coronary intervention: a randomized controlled clinical trial. Eur Heart J Cardiovasc Pharmacother. 2020 Jul 1;6(4):211–221.
  • Sibbing D, Aradi D, Jacobshagen C, et al. Guided de-escalation of antiplatelet treatment in patients with acute coronary syndrome undergoing percutaneous coronary intervention (TROPICAL-ACS): a randomised, open-label, multicentre trial. Lancet. 2017 Oct 14;390(10104):1747–1757.
  • Claassens DMF, Vos GJA, Bergmeijer TO, et al. A genotype-guided strategy for oral P2Y12 inhibitors in primary pci. N Engl J Med. 2019 Oct 24;381(17):1621–1631.
  • Galli M, Benenati S, Franchi F, et al. Comparative effects of guided vs. potent P2Y12 inhibitor therapy in acute coronary syndrome: a network meta-analysis of 61 898 patients from 15 randomized trials. Eur Heart J. 2022 Mar 7;43(10):959–967.
  • Pereira NL, Rihal C, Lennon R, et al. Effect of CYP2C19 genotype on ischemic outcomes during oral P2Y12 inhibitor therapy: a meta-analysis. JACC Cardiovasc Interv. 2021 Apr 12;14(7):739–750.
  • Cuisset T, Deharo P, Quilici J, et al. Benefit of switching dual antiplatelet therapy after acute coronary syndrome: the TOPIC (timing of platelet inhibition after acute coronary syndrome) randomized study. Eur Heart J. 2017 Nov 1;38(41):3070–3078.
  • Kim HS, Kang J, Hwang D, et al. Prasugrel-based de-escalation of dual antiplatelet therapy after percutaneous coronary intervention in patients with acute coronary syndrome (HOST-REDUCE-POLYTECH-ACS): an open-label, multicentre, non-inferiority randomised trial. Lancet. 2020 Oct 10;396(10257):1079–1089.
  • Kim CJ, Park MW, Kim MC, et al. Unguided de-escalation from ticagrelor to clopidogrel in stabilised patients with acute myocardial infarction undergoing percutaneous coronary intervention (TALOS-AMI): an investigator-initiated, open-label, multicentre, non-inferiority, randomised trial. Lancet. 2021 Oct 9;398(10308):1305–1316.
  • Baber U, Zafar MU, Dangas G, et al. Ticagrelor with or without aspirin after pci: the TWILIGHT platelet substudy. J Am Coll Cardiol. 2020 Feb 18;75(6):578–586.
  • Armstrong PC, Leadbeater PD, Chan MV, et al. In the presence of strong P2Y12 receptor blockade, aspirin provides little additional inhibition of platelet aggregation. J Thromb Haemost. 2011 Mar;9(3):552–561.
  • Capodanno D, Mehran R, Valgimigli M, et al. Aspirin-free strategies in cardiovascular disease and cardioembolic stroke prevention. Nat Rev Cardiol. 2018 Aug;15(8):480–496.
  • Vranckx P, Valgimigli M, Juni P, et al. Ticagrelor plus aspirin for 1 month, followed by ticagrelor monotherapy for 23 months vs aspirin plus clopidogrel or ticagrelor for 12 months, followed by aspirin monotherapy for 12 months after implantation of a drug-eluting stent: a multicentre, open-label, randomised superiority trial. Lancet. 2018 Sep 15;392(10151):940–949.
  • Watanabe H, Domei T, Morimoto T, et al. Effect of 1-month dual antiplatelet therapy followed by clopidogrel vs 12-month dual antiplatelet Therapy on cardiovascular and bleeding events in patients receiving pci: the STOPDAPT-2 randomized clinical trial. JAMA. 2019 Jun 25;321(24):2414–2427.
  • Hahn JY, Song YB, Oh JH, et al. Effect of P2Y12 inhibitor monotherapy vs dual antiplatelet therapy on cardiovascular events in patients undergoing percutaneous coronary intervention: the SMART-CHOICE randomized clinical trial. JAMA. 2019 Jun 25;321(24):2428–2437.
  • Mehran R, Baber U, Sharma SK, et al. Ticagrelor with or without aspirin in high-risk patients after pci. N Engl J Med. 2019 Nov 21;381(21):2032–2042.
  • Kim BK, Hong SJ, Cho YH, et al. Effect of ticagrelor monotherapy vs ticagrelor with aspirin on major bleeding and cardiovascular events in patients with acute coronary syndrome: the TICO randomized clinical trial. JAMA. 2020 Jun 16;323(23):2407–2416.
  • Watanabe H, Morimoto T, Natsuaki M, et al. Comparison of clopidogrel monotherapy after 1 to 2 months of dual antiplatelet therapy with 12 months of dual antiplatelet therapy in patients with acute coronary syndrome: the STOPDAPT-2 ACS randomized clinical trial. JAMA Cardiol. 2022 Apr 1;7(4):407–417.
  • O’Donoghue ML, Murphy SA, Sabatine MS. The safety and efficacy of aspirin discontinuation on a background of a P2Y12 inhibitor in patients after percutaneous coronary intervention: a systematic review and meta-analysis. Circulation. 2020 Aug 11;142(6):538–545.
  • Gelbenegger G, Schoergenhofer C, Jilma B, et al. Efficacy and safety of ticagrelor monotherapy in patients undergoing percutaneous coronary intervention: a meta-analysis. Clin Pharmacol Ther. 2021 Aug;110(2):424–431.
  • Valgimigli M, Gragnano F, Branca M, et al. P2Y12 inhibitor monotherapy or dual antiplatelet therapy after coronary revascularisation: individual patient level meta-analysis of randomised controlled trials. BMJ. 2021 Jun 16;373(1332). DOI:10.1136/bmj.n1332.
  • Angiolillo DJ, Galli M, Collet JP, et al. Antiplatelet therapy after percutaneous coronary intervention. EuroIntervention. 2022 Apr 1;17(17):e1371–e1396.
  • Costa F, van Klaveren D, James S, et al. Derivation and validation of the predicting bleeding complications in patients undergoing stent implantation and subsequent dual antiplatelet therapy (PRECISE-DAPT) score: a pooled analysis of individual-patient datasets from clinical trials. Lancet. 2017 Mar 11;389(10073):1025–1034.
  • Urban P, Mehran R, Colleran R, et al. Defining high bleeding risk in patients undergoing percutaneous coronary intervention. Circulation. 2019 Jul 16;140(3):240–261.
  • Knuuti J, Wijns W, Saraste A, et al. 2019 ESC guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J. 2020 Jan 14;41(3):407–477.
  • Collet JP, Thiele H, Barbato E, et al. 2020 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J. 2021 Apr 7;42(14):1289–1367.
  • Piccolo R, Oliva A, Avvedimento M, et al. Mortality after bleeding versus myocardial infarction in coronary artery disease: a systematic review and meta-analysis. EuroIntervention. 2021 Sep 20;17(7):550–560.
  • Leonardi S, Gragnano F, Carrara G, et al. Prognostic implications of declining hemoglobin content in patients hospitalized with acute coronary syndromes. J Am Coll Cardiol. 2021 Feb 2;77(4):375–388.
  • Costa F, Van Klaveren D, Feres F, et al. Dual antiplatelet therapy duration based on ischemic and bleeding risks after coronary stenting. J Am Coll Cardiol. 2019 Feb 26;73(7):741–754.
  • Aradi D, Kirtane A, Bonello L, et al. Bleeding and stent thrombosis on P2Y12-inhibitors: collaborative analysis on the role of platelet reactivity for risk stratification after percutaneous coronary intervention. Eur Heart J. 2015 Jul 14;36(27):1762–1771.
  • Tantry US, Bonello L, Aradi D, et al. Consensus and update on the definition of on-treatment platelet reactivity to adenosine diphosphate associated with ischemia and bleeding. J Am Coll Cardiol. 2013 Dec 17;62(24):2261–2273.
  • Fox KA, Goodman SG, Klein W, et al. Management of acute coronary syndromes. Variations in practice and outcome; findings from the global registry of acute coronary events (GRACE). Eur Heart J. 2002 Aug;23(15):1177–1189.
  • Kristensen SD, Laut KG, Fajadet J, et al. Reperfusion therapy for ST elevation acute myocardial infarction 2010/2011: current status in 37 ESC countries. Eur Heart J. 2014 Aug 1;35(29):1957–1970.
  • Valgimigli M, Bueno H, Byrne RA, et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: the task force for dual antiplatelet therapy in coronary artery disease of the European society of cardiology (ESC) and of the European association for cardio-thoracic surgery (EACTS). Eur Heart J. 2018 Jan 14;39(3):213–260.
  • Alexopoulos D, Theodoropoulos KC, Stavrou EF, et al. Prasugrel versus high dose clopidogrel to overcome early high on clopidogrel platelet reactivity in patients with ST elevation myocardial infarction. Cardiovasc Drugs Ther. 2012 Oct;26(5):393–400.
  • Alexopoulos D, Xanthopoulou I, Gkizas V, et al. Randomized assessment of ticagrelor versus prasugrel antiplatelet effects in patients with ST-segment-elevation myocardial infarction. Circ Cardiovasc Interv. 2012 Dec;5(6):797–804.
  • Holm M, Tornvall P, Henareh L, et al. The MOVEMENT Trial. J Am Heart Assoc. 2019 Jan 22;8(2):e010152.
  • Parodi G, Bellandi B, Xanthopoulou I, et al. Morphine is associated with a delayed activity of oral antiplatelet agents in patients with ST-elevation acute myocardial infarction undergoing primary percutaneous coronary intervention. Circ Cardiovasc Interv. 2015 Jan;8(1). doi:10.1161/CIRCINTERVENTIONS.114.001593.
  • Trip MD, Cats VM, van Capelle FJ, et al. Platelet hyperreactivity and prognosis in survivors of myocardial infarction. N Engl J Med. 1990 May 31;322(22):1549–1554.
  • Funck-Jensen KL, Dalsgaard J, Grove EL, et al. Increased platelet aggregation and turnover in the acute phase of ST-elevation myocardial infarction. Platelets. 2013;24(7):528–537.
  • Montalescot G, van ‘t Hof AW, Lapostolle F, et al. Prehospital ticagrelor in ST-segment elevation myocardial infarction. N Engl J Med. 2014 Sep 11;371(11):1016–1027.
  • Bhatt DL, Stone GW, Mahaffey KW, et al. Effect of platelet inhibition with cangrelor during Pci on ischemic events. N Engl J Med. 2013 Apr 4;368(14):1303–1313.
  • Kar P, Jones KL, Horowitz M, et al. Measurement of gastric emptying in the critically ill. Clin Nutr. 2015 Aug;34(4):557–564.
  • Deitchman AN, Derendorf H. Measuring drug distribution in the critically ill patient. Adv Drug Deliv Rev. 2014 Nov 20;77:22–26.
  • Roberts DJ, Hall RI. Drug absorption, distribution, metabolism and excretion considerations in critically ill adults. Expert Opin Drug Metab Toxicol. 2013 Sep;9(9):1067–1084.
  • Freynhofer MK, Gruber SC, Grove EL, et al. Antiplatelet drugs in patients with enhanced platelet turnover: biomarkers versus platelet function testing. Thromb Haemost. 2015 Aug 31;114(3):459–468.
  • Schoergenhofer C, Hobl EL, Schwameis M, et al. Acetylsalicylic acid in critically ill patients: a cross-sectional and a randomized trial. Eur J Clin Invest. 2017 Jul;47(7):504–512.
  • Schoergenhofer C, Hobl EL, Schellongowski P, et al. Clopidogrel in Critically Ill Patients. Clin Pharmacol Ther. 2018 Feb;103(2):217–223.
  • Schoergenhofer C, Hobl EL, Staudinger T, et al. Prasugrel in critically ill patients. Thromb Haemost. 2017 Aug 1;117(8):1582–1587.
  • Frontera JA, Lewin JJs3rd, Rabinstein AA, et al. Guideline for reversal of antithrombotics in intracranial hemorrhage: a statement for healthcare professionals from the neurocritical care society and society of critical care medicine. Neurocrit Care. 2016 Feb;24(1):6–46.
  • Baharoglu MI, Cordonnier C, Al-Shahi Salman R, et al. Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral haemorrhage associated with antiplatelet therapy (PATCH): a randomised, open-label, phase 3 trial. Lancet. 2016 Jun 25;387(10038):2605–2613.
  • Baharoglu MI, Al-Shahi Salman R, Cordonnier C, et al. PATCH trial: explanatory analyses. Blood. 2020 Apr 16;135(16):1406–1409.
  • Zakko L, Rustagi T, Douglas M, et al. No benefit from platelet transfusion for gastrointestinal bleeding in patients taking antiplatelet agents. Clin Gastroenterol Hepatol. 2017 Jan;15(1):46–52.
  • Pandit TN, Sarode R. Blood component support in acquired coagulopathic conditions: is there a method to the madness? Am J Hematol. 2012 May;87(1):S56–62.
  • Sarode R. How do I transfuse platelets (PLTs) to reverse anti-PLT drug effect? quiz 694. Transfusion. 2012 Apr;52(4):695–701.
  • Slichter SJ. Evidence-based platelet transfusion guidelines. Hematology Am Soc Hematol Educ Program. 2007;2007(1):172–178.
  • Levi M, Eerenberg E, Kamphuisen PW. Bleeding risk and reversal strategies for old and new anticoagulants and antiplatelet agents. J Thromb Haemost. 2011 Sep;9(9):1705–1712.
  • Jaben EA, Mulay SB, Stubbs JR. Reversing the effects of antiplatelet agents in the setting of intracranial hemorrhage: a look at the literature. J Intensive Care Med. 2015 Jan;30(1):3–7.
  • Zisman E, Erport A, Kohanovsky E, et al. Platelet function recovery after cessation of aspirin: preliminary study of volunteers and surgical patients. Eur J Anaesthesiol. 2010 Jul;27(7):617–623.
  • Kruger P, Chan N, Eikelboom JW. Platelet transfusion for ticagrelor reversal. Circ Cardiovasc Interv. 2017 Aug;10(8). DOI:10.1161/CIRCINTERVENTIONS.117.005579.
  • Reiter RA, Mayr F, Blazicek H, et al. Desmopressin antagonizes the in vitro platelet dysfunction induced by GPIIb/IIIa inhibitors and aspirin. Blood. 2003 Dec 15;102(13):4594–4599.
  • Colucci G, Stutz M, Rochat S, et al. The effect of desmopressin on platelet function: a selective enhancement of procoagulant COAT platelets in patients with primary platelet function defects. Blood. 2014 Mar 20;123(12):1905–1916.
  • O’Connor SA, Amour J, Mercadier A, et al. Efficacy of ex vivo autologous and in vivo platelet transfusion in the reversal of P2Y12 inhibition by clopidogrel, prasugrel, and ticagrelor: the APTITUDE study. Circ Cardiovasc Interv. 2015 Nov;8(11):e002786.
  • Teng R, Mitchell PD, Butler K. The effect of desmopressin on bleeding time and platelet aggregation in healthy volunteers administered ticagrelor. J Clin Pharm Ther. 2014 Apr;39(2):186–191.
  • Hobl EL, Derhaschnig U, Firbas C, et al. Reversal strategy in antagonizing the P2Y12 -inhibitor ticagrelor. Eur J Clin Invest. 2013 Dec;43(12):1258–1261.
  • Angheloiu GO, Gugiu GB, Ruse C, et al. Ticagrelor removal from human blood. JACC Basic Transl Sci. 2017 Apr;2(2):135–145.
  • Schoener L, Jellinghaus S, Richter B, et al. Reversal of the platelet inhibitory effect of the P2Y12 inhibitors clopidogrel, prasugrel, and ticagrelor in vitro: a new approach to an old issue. Clin Res Cardiol. 2017 Nov;106(11):868–874.
  • Buchanan A, Newton P, Pehrsson S, et al. Structural and functional characterization of a specific antidote for ticagrelor. Blood. 2015 May 28;125(22):3484–3490.
  • Bhatt DL, Pollack CV, Weitz JI, et al. Antibody-based ticagrelor reversal agent in healthy volunteers. N Engl J Med. 2019 May 9;380(19):1825–1833.
  • Bhatt DL, Pollack CV, Mazer CD, et al., for the REVERSE-IT Investigators. Bentracimab for ticagrelor reversal in patients Undergoing urgent surgery. NEJM Evidence. 2021.
  • Tcheng JE. Clinical challenges of platelet glycoprotein IIb/IIIa receptor inhibitor therapy: bleeding, reversal, thrombocytopenia, and retreatment. Am Heart J. 2000 Feb;139(2 Pt 2):S38–45.
  • Reiter RA, Knobl P, Varadi K, et al. Changes in von Willebrand factor-cleaving protease (ADAMTS13) activity after infusion of desmopressin. Blood. 2003 Feb 1;101(3):946–948.
  • Mascelli MA, Lance ET, Damaraju L, et al. Pharmacodynamic profile of short-term Abciximab treatment demonstrates prolonged platelet inhibition with gradual recovery from GP IIb/IIIa receptor blockade. Circulation. 1998 May 5;97(17):1680–1688.
  • Cai TQ, Wickham LA, Sitko G, et al. Platelet transfusion reverses bleeding evoked by triple anti-platelet therapy including vorapaxar, a novel platelet thrombin receptor antagonist. Eur J Pharmacol. 2015 Jul 5;758:107–114.
  • Gorog DA, Price S, Sibbing D, et al. Antithrombotic therapy in patients with acute coronary syndrome complicated by cardiogenic shock or out-of-hospital cardiac arrest: a joint position paper from the European society of cardiology (ESC) working group on thrombosis, in association with the acute cardiovascular care association (ACCA) and European association of percutaneous cardiovascular interventions (EAPCI). Eur Heart J Cardiovasc Pharmacother. 2021 Mar 15;7(2):125–140.
  • Gelbenegger G, Grafeneder J, Gager GM, et al. Advanced pharmacodynamics of cangrelor in healthy volunteers: a dose-finding, open-label, pilot trial. Thromb J. 2022 Apr 14;20(1):19.
  • Gargiulo G, Esposito G, Avvedimento M, et al. Cangrelor, tirofiban, and chewed or standard prasugrel regimens in patients with ST-segment-elevation myocardial infarction: primary results of the FABOLUS-FASTER trial. Circulation. 2020 Aug 4;142(5):441–454.
  • Tavenier AH, Hermanides RS, Fabris E, et al. Bridging the gap: current and future insights for improving suboptimal platelet inhibition in STEMI. Int J Cardiol. 2021 Apr 1;328:40–45.
  • McFadyen JD, Schaff M, Peter K. Current and future antiplatelet therapies: emphasis on preserving haemostasis. Nat Rev Cardiol. 2018 Mar;15(3):181–191.

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