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Klinische Pharmakologie der aktuellen antithrombozytären Substanzen

Clinical pharmacology of current antiplatelet drugs

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Zusammenfassung

Die duale plättchenhemmende Therapie mit niedrig dosierter Azetylsalizylsäure (ASS) in Kombination mit einem P2Y12-ADP-Rezeptor-Antagonisten ist die in den aktuellen Leilinien der Europäischen Gesellschaft für Kardiologie empfohlene Standardtherapie für Patienten mit akutem Koronarsyndrom (ACS) und Patienten, bei denen eine perkutane Koronarintervention durchgeführt wird. Neuere P2Y12-Rezeptor-Antagonisten wie Prasugrel oder Ticagrelor bewirken eine stärkere und konsistentere Inhibition des P2Y12-Rezeptors und haben in klinischen Studien gegenüber der Kombination von ASS und Clopidogrel ischämische Ereignisse bei Patienten mit ACS reduziert. Dieser therapeutische Nutzen geht mit einer Zunahme des Blutungsrisikos der Patienten einher. Alternative Therapieansätze über additive Wirkmechanismen konnten im Wesentlichen die Inzidenz ischämischer Ereignisse ebenfalls senken, ohne das Problem vermehrter Blutungen zu lösen.

Abstract

Dual antiplatelet therapy with low-dose acetylsalicylic acid (ASA) and an inhibitor of the P2Y12 adenosine diphosphate (ADP) receptor is the standard treatment for patients presenting with acute coronary syndrome (ACS) or undergoing elective coronary interventions according to the current guidelines published by the European Society of Cardiology (ESC). New generation P2Y12 inhibitors, such as prasugrel and ticagrelor exert stronger and more consistent inhibition of the P2Y12 receptor. In clinical studies enrolling patients with ACS these drugs decreased the incidence of ischemic events compared to the standard therapy with clopidogrel and ASA; however, this beneficial effect was associated with an increase in bleeding events. Alternative therapeutic approaches via addition of drugs with different modes of action showed an overall reduction of ischemic events but also failed to uncouple this beneficial effect from an increased bleeding risk.

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Literatur

  1. Lewis HD Jr, Davis JW, Archibald DG et al (1983) Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. Results of a Veterans Administration Cooperative Study. N Engl J Med 309:396–403

    Article  PubMed  Google Scholar 

  2. Cairns JA, Gent M, Singer J et al (1985) Aspirin, sulfinpyrazone, or both in unstable angina. Results of a Canadian multicenter trial. N Engl J Med 313:1369–1375

    Article  CAS  PubMed  Google Scholar 

  3. Theroux P, Ouimet H, McCans J et al (1988) Aspirin, heparin, or both to treat acute unstable angina. N Engl J Med 319:1105–1111

    Article  CAS  PubMed  Google Scholar 

  4. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group (1988) Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction. Lancet 2:349–360

  5. Maass D, Zollikofer CL, Largiader F et al (1984) Radiological follow-up of transluminally inserted vascular endoprostheses: an experimental study using expanding spirals. Radiology 152:659–663

    Article  CAS  PubMed  Google Scholar 

  6. Schatz RA, Palmaz JC, Tio FO et al (1987) Balloon-expandable intracoronary stents in the adult dog. Circulation 76:450–457

    Article  CAS  PubMed  Google Scholar 

  7. Waller BF (1983) Early and late morphologic changes in human coronary arteries after percutaneous transluminal coronary angioplasty. Clin Cardiol 6:363–372

    Article  CAS  PubMed  Google Scholar 

  8. Haude M, Erbel R, Issa H et al (1993) Subacute thrombotic complications after intracoronary implantation of Palmaz-Schatz stents. Am Heart J 126:15–22

    Article  CAS  PubMed  Google Scholar 

  9. Neumann FJ, Gawaz M, Ott I et al (1996) Prospective evaluation of hemostatic predictors of subacute stent thrombosis after coronary Palmaz-Schatz stenting. J Am Coll Cardiol 27:15–21

    Article  CAS  PubMed  Google Scholar 

  10. Gawaz M, Neumann FJ, Ott I et al (1996) Platelet function in acute myocardial infarction treated with direct angioplasty. Circulation 93:229–237

    Article  CAS  PubMed  Google Scholar 

  11. Schömig A, Neumann FJ, Kastrati A et al (1996) A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. N Engl J Med 334:1084–1089

    Article  PubMed  Google Scholar 

  12. Yusuf S, Zhao F, Mehta SR et al (2001) Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 345:494–502

    Article  CAS  PubMed  Google Scholar 

  13. Schrör K (1997) Aspirin and platelets: the antiplatelet action of aspirin and its role in thrombosis treatment and prophylaxis. Semin Thromb Hemost 23:349–356

    Article  PubMed  Google Scholar 

  14. Frelinger AL III, Furman MI, Linden MD et al (2006) Residual arachidonic acid-induced platelet activation via an adenosine diphosphate-dependent but cyclooxygenase-1- and cyclooxygenase-2-independent pathway: a 700-patient study of aspirin resistance. Circulation 113:2888–2896

    Article  CAS  PubMed  Google Scholar 

  15. Nagelschmitz J, Blunck M, Kraetzschmar J et al (2014) Pharmacokinetics and pharmacodynamics of acetylsalicylic acid after intravenous and oral administration to healthy volunteers. Clin Pharmacol 6:51–59

    CAS  PubMed Central  PubMed  Google Scholar 

  16. Catella-Lawson F, Reilly MP, Kapoor SC et al (2001) Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N Engl J Med 345:1809–1817

    Article  CAS  PubMed  Google Scholar 

  17. Hohlfeld T, Zimmermann N, Weber AA et al (2008) Pyrazolinone analgesics prevent the antiplatelet effect of aspirin and preserve human platelet thromboxane synthesis. J Thromb Haemost 6:166–173

    Article  CAS  PubMed  Google Scholar 

  18. Gachet C, Hechler B, Leon C et al (1997) Activation of ADP receptors and platelet function. Thromb Haemost 78:271–275

    CAS  PubMed  Google Scholar 

  19. Mills DC (1996) ADP receptors on platelets. Thromb Haemost 76:835–856

    CAS  PubMed  Google Scholar 

  20. Hollopeter G, Jantzen HM, Vincent D et al (2001) Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature 409:202–207

    Article  CAS  PubMed  Google Scholar 

  21. Hochholzer W, Trenk D, Bestehorn HP et al (2006) Impact of the degree of peri-interventional platelet inhibition after loading with clopidogrel on early clinical outcome of elective coronary stent placement. J Am Coll Cardiol 48:1742–1750

    Article  CAS  PubMed  Google Scholar 

  22. Bonello L, Tantry US, Marcucci R et al (2010) Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate. J Am Coll Cardiol 56:919–933

    Article  CAS  PubMed  Google Scholar 

  23. Trenk D, Hochholzer W, Fromm MF et al (2008) Cytochrome P450 2C19 681G>A polymorphism and high on-clopidogrel platelet reactivity associated with adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug-eluting or bare-metal stents. J Am Coll Cardiol 51:1925–1934

    Article  CAS  PubMed  Google Scholar 

  24. Geisler T, Schaeffeler E, Dippon J et al (2008) CYP2C19 and nongenetic factors predict poor responsiveness to clopidogrel loading dose after coronary stent implantation. Pharmacogenomics 9:1251–1259

    Article  CAS  PubMed  Google Scholar 

  25. Hochholzer W, Trenk D, Fromm MF et al (2010) Impact of cytochrome P450 2C19 loss-of-function polymorphism and of major demographic characteristics on residual platelet function after loading and maintenance treatment with clopidogrel in patients undergoing elective coronary stent placement. J Am Coll Cardiol 55:2427–2434

    Article  CAS  PubMed  Google Scholar 

  26. Price MJ, Berger PB, Teirstein PS et al (2011) Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention. JAMA 305:1097–1105

    Article  CAS  PubMed  Google Scholar 

  27. Collet JP, Cuisset T, Range G et al (2012) Bedside monitoring to adjust antiplatelet therapy for coronary stenting. N Engl J Med 367:2100–2109

    Article  CAS  PubMed  Google Scholar 

  28. Trenk D, Stone GW, Gawaz M et al (2012) A randomized trial of prasugrel versus clopidogrel in patients with high platelet reactivity on clopidogrel after elective percutaneous coronary intervention with implantation of drug-eluting stents: results of the TRIGGER-PCI (Testing Platelet Reactivity In Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel) study. J Am Coll Cardiol 59:2159–2164

    Article  CAS  PubMed  Google Scholar 

  29. Siller-Matula JM, Francesconi M, Dechant C et al (2013) Personalized antiplatelet treatment after percutaneous coronary intervention: the madonna study. Int J Cardiol 167:2018–2023

    Article  PubMed  Google Scholar 

  30. Aradi D, Tornyos A, Pintér T et al (2014) Optimizing P2Y12 receptor inhibition in patients with acute coronary syndrome on the basis of platelet function testing: impact of prasugrel and high-dose clopidogrel. J Am Coll Cardiol 63:1061–1070

    Article  CAS  PubMed  Google Scholar 

  31. Rehmel JL, Eckstein JA, Farid NA et al (2006) Interactions of two major metabolites of prasugrel, a thienopyridine antiplatelet agent, with the cytochromes P450. Drug Metab Dispos 34:600–607

    Article  CAS  PubMed  Google Scholar 

  32. Jakubowski JA, Winters KJ, Naganuma H et al (2007) Prasugrel: a novel thienopyridine antiplatelet agent. A review of preclinical and clinical studies and the mechanistic basis for its distinct antiplatelet profile. Cardiovasc Drug Rev 25:357–374

    Article  CAS  PubMed  Google Scholar 

  33. Sugidachi A, Ogawa T, Kurihara A et al (2007) 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 5:1545–1551

    Article  CAS  PubMed  Google Scholar 

  34. Wiviott SD, Braunwald E, McCabe CH et al (2007) Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 357:2001–2015

    Article  CAS  PubMed  Google Scholar 

  35. VAN Giezen JJ, Nilsson L, Berntsson P et al (2009) Ticagrelor binds to human P2Y(12) independently from ADP but antagonizes ADP-induced receptor signaling and platelet aggregation. J Thromb Haemost 7:1556–1565

    Article  Google Scholar 

  36. Angiolillo DJ, Curzen N, Gurbel P et al (2014) 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 63:1500–1509

    Article  CAS  PubMed  Google Scholar 

  37. Teng R (2012) Pharmacokinetic, pharmacodynamic and pharmacogenetic profile of the oral antiplatelet agent ticagrelor. Clin Pharmacokinet 51:305–318

    Article  CAS  PubMed  Google Scholar 

  38. Storey RF, Bliden KP, Ecob R et al (2011) Earlier recovery of platelet function after discontinuation of treatment with ticagrelor compared with clopidogrel in patients with high antiplatelet responses. J Thromb Haemost 9:1730–1737

    Article  CAS  PubMed  Google Scholar 

  39. Wallentin L, Becker RC, Budaj A et al (2009) Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 361:1045–1057

    Article  CAS  PubMed  Google Scholar 

  40. Alexopoulos D, Xanthopoulou I, Gkizas V et al (2012) Randomized assessment of ticagrelor versus prasugrel antiplatelet effects in patients with ST-segment-elevation myocardial infarction. Circ Cardiovasc Interv 5:797–804

    Article  CAS  PubMed  Google Scholar 

  41. Trenk D, Ferenc M, Schmitz R et al (2013) Delayed onset of antiplatelet effect of prasugrel and ticagrelor in patients with acute coronary syndromes. Clin Res Cardiol 102(Suppl 1):P1437

    Google Scholar 

  42. Parodi G, Valenti R, Bellandi B et al (2013) 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 61:1601–1606

    Article  CAS  PubMed  Google Scholar 

  43. Angiolillo D, Schneider D, Bhatt D et al (2012) Pharmacodynamic effects of cangrelor and clopidogrel: the platelet function substudy from the cangrelor versus standard therapy to achieve optimal management of platelet inhibition (champion) trials. J Thromb Thrombolysis 34:44–55

    Article  CAS  PubMed  Google Scholar 

  44. Bhatt DL, Stone GW, Mahaffey KW et al (2013) Effect of platelet inhibition with cangrelor during PCI on ischemic events. N Engl J Med 368:1303–1313

    Article  CAS  PubMed  Google Scholar 

  45. Angiolillo DJ, Firstenberg MS, Price MJ et al (2012) Bridging antiplatelet therapy with cangrelor in patients undergoing cardiac surgery. JAMA 307:265–274

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Steinhubl SR, Oh JJ, Oestreich JH et al (2008) Transitioning patients from cangrelor to clopidogrel: pharmacodynamic evidence of a competitive effect. Thromb Res 121:527–534

    Article  CAS  PubMed  Google Scholar 

  47. Dovlatova NL, Jakubowski JA, Sugidachi A et al (2008) 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 6:1153–1159

    Article  CAS  PubMed  Google Scholar 

  48. Ravnefjord A, Weilitz J, Emanuelsson BM et al (2012) Evaluation of ticagrelor pharmacodynamic interactions with reversibly binding or non-reversibly binding P2Y(12) antagonists in an ex-vivo canine model. Thromb Res 130:622–628

    Article  CAS  PubMed  Google Scholar 

  49. Neumann FJ, Hochholzer W, Pogatsa-Murray G et al (2001) Antiplatelet effects of abciximab, tirofiban and eptifibatide in patients undergoing coronary stenting. J Am Coll Cardiol 37:1323–1328

    Article  CAS  PubMed  Google Scholar 

  50. Thiele H, Wöhrle J, Hambrecht R et al (2012) Intracoronary versus intravenous bolus abciximab during primary percutaneous coronary intervention in patients with acute ST-elevation myocardial infarction: a randomised trial. Lancet 379:923–931

    Article  CAS  PubMed  Google Scholar 

  51. Vickers S, Theoharides AD, Arison B et al (1999) In vitro and in vivo studies on the metabolism of tirofiban. Drug Metab Dispos 27:1360–1366

    CAS  PubMed  Google Scholar 

  52. Smith BS, Gandhi PJ (2001) Pharmacokinetics and pharmacodynamics of low-molecular-weight heparins and glycoprotein IIb/IIIa receptor antagonists in renal failure. J Thromb Thrombolysis 11:39–48

    Article  CAS  PubMed  Google Scholar 

  53. Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC), Steg PG, James SK et al (2012) ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 33:2569–2619

    Article  Google Scholar 

  54. Hamm CW, Bassand JP, Agewall S et al (2011) ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 32:2999–3054

    Article  PubMed  Google Scholar 

  55. Valgimigli M, Tebaldi M, Campo G et al (2012) Prasugrel versus tirofiban bolus with or without short post-bolus infusion with or without concomitant prasugrel administration in patients with myocardial infarction undergoing coronary stenting: the fabolus pro (facilitation through aggrastat by dropping or shortening infusion line in patients with st-segment elevation myocardial infarction compared to or on top of prasugrel given at loading dose) trial. JACC Cardiovasc Interv 5:268–277

    Article  PubMed  Google Scholar 

  56. Savonitto S, D’urbano M, Caracciolo M et al (2010) Urgent surgery in patients with a recently implanted coronary drug-eluting stent: a phase II study of ‚bridging‘ antiplatelet therapy with tirofiban during temporary withdrawal of clopidogrel. Br J Anaesth 104:285–291

    Article  CAS  PubMed  Google Scholar 

  57. Merlini PA, Bauer KA, Oltrona L et al (1994) Persistent activation of coagulation mechanism in unstable angina and myocardial infarction. Circulation 90:61–68

    Article  CAS  PubMed  Google Scholar 

  58. Mega JL, Braunwald E, Wiviott SD et al (2012) Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 366:9–19

    Article  CAS  PubMed  Google Scholar 

  59. Alexander JH, Lopes RD, James S et al (2011) Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med 365:699–708

    Article  CAS  PubMed  Google Scholar 

  60. Tricoci P, Huang Z, Held C et al (2012) Thrombin-receptor antagonist vorapaxar in acute coronary syndromes. N Engl J Med 366:20–33

    Article  CAS  PubMed  Google Scholar 

  61. Morrow DA, Braunwald E, Bonaca MP et al (2012) Vorapaxar in the secondary prevention of atherothrombotic events. N Engl J Med 366:1404–1413

    Article  CAS  PubMed  Google Scholar 

  62. Storey RF (2006) Biology and pharmacology of the platelet P2Y12 receptor. Curr Pharm Des 12:1255–1259

    Article  CAS  PubMed  Google Scholar 

  63. Hochholzer W, Trenk D, Frundi D et al (2005) Time dependence of platelet inhibition after a 600-mg loading dose of clopidogrel in a large, unselected cohort of candidates for percutaneous coronary intervention. Circulation 111:2560–2564

    Article  CAS  PubMed  Google Scholar 

  64. Siller-Matula JM, Trenk D, Schrör K et al (2013) Response variability to P2Y12 receptor inhibitors: expectations and reality. JACC Cardiovasc Interv 6:1111–1128

    Article  PubMed  Google Scholar 

  65. Schrör K, Siller-Matula JM, Huber K (2011) Pharmacokinetic basis of the antiplatelet action of prasugrel. Fundam Clin Pharmacol 26:39–46

    Article  PubMed  Google Scholar 

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Einhaltung ethischer Richtlinien

Interessenkonflikt. T. Nührenberg, C. Stratz, C.M. Valina und W. Hochholzer geben an, dass kein Interessenkonflikt besteht. D. Trenk gibt an, dass er (2) Vortragshonorare von AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, MSD und Pfizer sowie Honorar für Beratungstätigkeit von AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly und Otsuka erhalten hat. Er nimmt als Mitarbeiter der Klinik an Studien folgender Sponsoren teil: AstraZeneca, Bayer, Daiichi Sankyo, GSK, Mitsubishi Pharma, REVEAL-Studienzentrale, Roche und Sanofi.

Dieser Beitrag beinhaltet keine Studien an Menschen oder Tieren.

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  1. Klinik für Kardiologie und Angiologie II, Abteilung Klinische Pharmakologie, Universitäts-Herzzentrum Freiburg – Bad Krozingen, Südring 15, 79189, Bad Krozingen, Deutschland

    D. Trenk, T. Nührenberg, C. Stratz, C.M. Valina & W. Hochholzer

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  1. D. Trenk
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  2. T. Nührenberg
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Trenk, D., Nührenberg, T., Stratz, C. et al. Klinische Pharmakologie der aktuellen antithrombozytären Substanzen. Herz 39, 790–797 (2014). https://doi.org/10.1007/s00059-014-4151-9

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