Download PDF
Hamostaseologie 2014; 34(01): 20-28
DOI: 10.5482/HAMO-13-08-0044
Review
Schattauer GmbH

P2Y12-receptor-inhibiting antiplatelet strategies in acute coronary syndromes

P2Y12-rezeptorblockierende Antithrombozyten-strategien beim akuten Koronarsyndrom
T. Höchtl
1   3rd Medical Department, Cardiology and Emergency Medicine, Wilhelminen Hospital, Vienna, Austria
,
K. Huber
1   3rd Medical Department, Cardiology and Emergency Medicine, Wilhelminen Hospital, Vienna, Austria
› Author Affiliations
Further Information

Publication History

received: 19 August 2013

accepted in revised form: 21 October 2013

Publication Date:
27 December 2017 (online)

Also available at
    Permissions and Reprints

Summary

Antiplatelet therapy in acute coronary syndromes is essential for preventing stent thrombosis and for reducing major adverse cardiovascular events. Treatment strategy has changed over the last years by frequent use of more active agents inhibiting the ADP mediated activation of platelets instead of clopidogrel, such as prasugrel and ticagrelor. Compared to clopidogrel these modern antiplatelet drugs showed a significant reduction of efficacy endpoints as well as an acceptable safety profile in large multicenter randomized trials (TRITON TIMI 38, PLATO). Going in with higher efficacy a generally higher bleeding risk of prasugrel could be reduced by optimizing the maintenance dose in elderly and underweight patients (TRILOGY-ACS). However even prasugrel and ticagrelor have shown a delayed onset of action in special patient populations (e.g. STEMI) suggesting that the optimal ADP inhibitor has not been found yet. Results of the CHAMPION PHOENIX trial indicate that cangrelor, an intravenous agent, might fulfill these high expectations of an ideal platelet inhibitor in the first hours of an ACS in special patient cohorts.

This review summarizes the results of most important clinical studies investigating the novel P2Y12 receptor inhibiting antiplatelet drugs.

Zusammenfassung

Die antithrombozytäre Therapie im akuten Koronarsyndrom ist essenziell um Stent-Thrombosen zu verhindern und schwere kardiovaskuläre Ereignisse zu verzögern. Die Behandlungsstrategie veränderte sich in den vergangenen Jahren durch den häufigen Gebrauch von Prasugrel oder Ticagrelor anstelle von Clopidogrel. Im Vergleich zu Clopidogrel zeigten diese modernen antithrombozytären Substanzen nicht nur eine signifikante Reduktion von Effektivitäts-Endpunkten, sondern auch ein akzeptables Sicherheitsprofil in großen Multicenter-Studien (TRITON TIMI 38, PLATO). Hand in Hand mit der höheren Effektivität geht jedoch ein erhöhtes Blutungsrisiko, das unter Prasugrel durch Optimierung der Erhaltungsdosis bei älteren und untergewichtigen Patienten reduziert werden konnte. Jedoch zeigten sowohl Prasugrel als auch Ticagrelor eine verzögerte Wirksamkeit bei speziellen Patientenpopulationen gezeigt (z. B. STEMI-Patienten), was vermuten lässt, dass der optimale ADP-Rezeptorblocker noch nicht gefunden ist. Ergebnisse aus der CHAMPION PHOENIX-Studie lassen hoffen, dass Camgrelor, eine intravenöse Substanz, die hohen Erwartungen an einen idealen Thrombozyten-Hemmstoff in bestimmten Patienten-Kohorten erfüllen könnte.

Diese Arbeit fasst die Ergebnisse der wichtigsten klinischen Studien zu den neuen P2Y12-Rezeptor-Inhibitoren zusammen.

Keywords

Antiplatelet agents - ticagrelor - prasugrel - cangrelor - acute coronary syndrome

Schlüsselwörter

Thrombozytenaggregationshemmer - Ticagrelor - Prasugrel - Cangrelor - akutes Koronar -syndrom
 

  • References

  • 1 Trip MD, Cats VM, van Capelle FJ, Vreeken J. Platelet hyperreactivity and prognosis in survivors of myocardial infarction. N Engl J Med 1990; 322: 1549-1554.
    CrossrefPubMedGoogle Scholar
  • 2 Wijns W, Kolh P, Danchin N. et al. Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). EurHeart J 2010; 31: 2501-2555.
    PubMedGoogle Scholar
  • 3 Grossmann R, Sokolova O, Schnurr A. et al. Variable extent of clopidogrel responsiveness in patients after coronary stenting. Thromb Haemost 2004; 92: 1201-1206.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 4 Gurbel PA, Tantry US. Drug insight: Clopidogrel nonresponsiveness. Nat Clin Pract Cardiovasc Med 2006; 03: 387-395.
    CrossrefPubMedGoogle Scholar
  • 5 Muller I, Besta F, Schulz C. et al. Prevalence of clopidogrel non-responders among patients with stable angina pectoris scheduled for elective coronary stent placement. Thromb Haemost 2003; 89: 783-787.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 Serebruany VL, Steinhubl SR, Berger PB. et al. Variability in platelet responsiveness to clopidogrel among 544 individuals. J Am Coll Cardiol 2005; 45: 246-251.
    CrossrefPubMedGoogle Scholar
  • 7 Siller-Matula J, Schrör K, Wojta J, Huber K. Thienopyridines in cardiovascular disease: focus on clopidogrel resistance. Thromb Haemost 2007; 97: 385-393.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 8 Collet JP, Hulot JS, Pena A. et al. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet 2009; 373: 309-317.
    CrossrefPubMedGoogle Scholar
  • 9 Mega JL, Close SL, Wiviott SD. et al. Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON-TIMI 38 trial: a pharmacogenetic analysis. Lancet 2010; 376: 1312-1319.
    CrossrefPubMedGoogle Scholar
  • 10 Simon T, Verstuyft C, Mary-Krause M. et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009; 360: 363-375.
    CrossrefPubMedGoogle Scholar
  • 11 Yukhanyan L, Freynhofer MK, Siller-Matula J. et al. Genetic variability in response to clopidogrel therapy and its clinical implications. Thromb Haemost 2011; 105: S55-S59.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 12 Tentzeris I, Siller-Matula J, Farhan S. et al. Platelet function variability and non-genetic causes. Thromb Haemost 2011; 105: S60-S66.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 13 Mega JL, Hochholzer W, Frelinger 3rd AL. et al. Dosing clopidogrel based on CYP2C19 genotype and the effect on platelet reactivity in patients with stable cardiovascular disease. JAMA 2011; 306: 2221-2228.
    PubMedGoogle Scholar
  • 14 Bonello L, Camoin-Jau L, Armero S. et al. Tailored clopidogrel loading dose according to platelet reactivity monitoring to prevent acute and subacute stent thrombosis. Am J Cardiol 2009; 103: 5-10.
    CrossrefPubMedGoogle Scholar
  • 15 Bonello L, Camoin-Jau L, Arques S. et al. Adjusted clopidogrel loading doses according to vasodilator-stimulated phosphoprotein phosphorylation index decrease rate of major adverse cardiovascular events in patients with clopidogrel resistance: a multicenter randomized prospective study. J Am Coll Cardiol 2008; 51: 1404-1411.
    CrossrefPubMedGoogle Scholar
  • 16 Mehta SR, Tanguay JF, Eikelboom JW. et al. Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial. Lancet 2010; 376: 1233-1243.
    CrossrefPubMedGoogle Scholar
  • 17 Montalescot G, Sideris G, Meuleman C. et al. A randomized comparison of high clopidogrel loading doses in patients with non-ST-segment elevation acute coronary syndromes: the ALBION (Assessment of the Best Loading Dose of Clopidogrel to Blunt Platelet Activation, Inflammation and Ongoing Necrosis) trial. J Am Coll Cardiol 2006; 48: 931-938.
    CrossrefPubMedGoogle Scholar
  • 18 Wallentin L, James S, Storey RF. et al. Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial. Lancet 2010; 376: 1320-1328.
    CrossrefPubMedGoogle Scholar
  • 19 Wiviott SD, Braunwald E, McCabe CH. et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357: 2001-2015.
    CrossrefPubMedGoogle Scholar
  • 20 Montalescot G, Wiviott SD, Braunwald E. et al. Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITONTIMI 38): double-blind, randomised controlled trial. Lancet 2009; 373: 723-731.
    CrossrefPubMedGoogle Scholar
  • 21 Wiviott SD, Braunwald E, Angiolillo DJ. et al. Greater clinical benefit of more intensive oral antiplatelet therapy with prasugrel in patients with diabetes mellitus in the trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel-Thrombolysis in Myocardial Infarction 38. Circulation 2008; 118: 1626-1636.
    CrossrefPubMedGoogle Scholar
  • 22 Murphy SA, Antman EM, Wiviott SD. et al. Reduction in recurrent cardiovascular events with prasugrel compared with clopidogrel in patients with acute coronary syndromes from the TRITONTIMI 38 trial. Eur Heart J 2008; 29: 2473-2479.
    CrossrefPubMedGoogle Scholar
  • 23 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; 34: 600-607.
    CrossrefPubMedGoogle Scholar
  • 24 Smith PK, Goodnough LT, Levy JH. et al. Mortality benefit with prasugrel in the TRITON-TIMI 38 coronary artery bypass grafting cohort: risk-adjusted retrospective data analysis. J Am Coll Cardiol 2012; 60: 388-396.
    CrossrefPubMedGoogle Scholar
  • 25 Roe MT, Armstrong PW, Fox KA. et al. Prasugrel versus clopidogrel for acute coronary syndromes without revascularization. N Engl J Med 2012; 367: 1297-1309.
    CrossrefPubMedGoogle Scholar
  • 26 Roe MT, Goodman SG, Ohman EM. et al. Elderly patients with acute coronary syndromes managed without revascularization insights into the safety of long-term dual antiplatelet therapy with reduced-dose prasugrel vs. standard-dose clopidogrel. Circulation 2013; 128: 823-833.
    CrossrefPubMedGoogle Scholar
  • 27 Gurbel PA, Erlinge D, Ohman EM. et al. Platelet Function During Extended Prasugrel and Clopidogrel Therapy for Patients With ACS Treated Without Revascularization: The TRILOGY ACS Platelet Function Substudy. JAMA 2012; 308: 1-10.
    PubMedGoogle Scholar
  • 28 Wallentin L, Becker RC, Budaj A. et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361: 1045-1057.
    CrossrefPubMedGoogle Scholar
  • 29 Storey RF, Bliden KP, Patil SB. et al. Incidence of dyspnea and assessment of cardiac and pulmonary function in patients with stable coronary artery disease receiving ticagrelor, clopidogrel, or placebo in the ONSET/OFFSET study. J Am Coll Cardiol 2010; 56: 185-193.
    CrossrefPubMedGoogle Scholar
  • 30 Van Giezen JJ, Sidaway J, Glaves P. et al. Ticagrelor inhibits adenosine uptake in vitro and enhances adenosine-mediated hyperemia responses in a canine model. J Cardiovasc Pharmacol Ther 2011; 17: 164-172.
    PubMedGoogle Scholar
  • 31 Steg PG, James S, Harrington RA. et al. Ticagrelor versus clopidogrel in patients with ST-elevation acute coronary syndromes intended for reperfusion with primary percutaneous coronary intervention: A Platelet Inhibition and Patient Outcomes (PLATO) trial subgroup analysis. Circulation 2010; 122: 2131-2141.
    CrossrefPubMedGoogle Scholar
  • 32 James S, Angiolillo DJ, Cornel JH. et al. Ticagrelor vs. clopidogrel in patients with acute coronary syndromes and diabetes: a substudy from the PLATelet inhibition and patient Outcomes (PLATO) trial. Eur Heart J 2010; 31: 3006-3016.
    CrossrefPubMedGoogle Scholar
  • 33 Held C, Asenblad N, Bassand JP. et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes undergoing coronary artery bypass surgery: results from the PLATO (Platelet Inhibition and Patient Outcomes) Trial. J Am Coll Cardiol 2011; 31: 3006-16.
    PubMedGoogle Scholar
  • 34 James S, Budaj A, Aylward P. et al. Ticagrelor versus clopidogrel in acute coronary syndromes in relation to renal function: results from the Platelet Inhibition and Patient Outcomes (PLATO) trial. Circulation 2010; 122: 1056-1067.
    CrossrefPubMedGoogle Scholar
  • 35 Husted S, James S, Becker RC. et al. Ticagrelor versus clopidogrel in elderly patients with acute coronary syndromes: a substudy from the prospective randomized PLATelet inhibition and patient Outcomes (PLATO) trial. Circ Cardiovasc Qual Outcomes 2012; 05: 680-688.
    CrossrefPubMedGoogle Scholar
  • 36 James SK, Roe MT, Cannon CP. et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes intended for non-invasive management: substudy from prospective randomised PLATelet inhibition and patient Outcomes (PLATO) trial. BMJ 2011; 342: d3527.
    CrossrefPubMedGoogle Scholar
  • 37 Steg PG, James SK, Atar D. et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 2012; 33: 2569-2619.
    CrossrefPubMedGoogle Scholar
  • 38 Hamm CW, Bassand JP, Agewall S. et al. 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 2011; 32: 2999-3054.
    CrossrefPubMedGoogle Scholar
  • 39 Small DS, Wrishko RE, Ernest CS. et al. Prasugrel pharmacokinetics and pharmacodynamics in subjects with moderate renal impairment and endstage renal disease. J Clin Pharm Ther 2009; 34: 585-594.
    CrossrefPubMedGoogle Scholar
  • 40 Bellemain-Appaix A, O’Connor SA, Silvain J. et al. Association of clopidogrel pretreatment with mortality, cardiovascular events, and major bleeding among patients undergoing percutaneous coronary intervention: a systematic review and metaanalysis. JAMA 2012; 308: 2507-2516.
    CrossrefPubMedGoogle Scholar
  • 41 Montalescot G, Bolognese L, Dudek D. et al. Pretreatment with prasugrel in non-ST-segment elevation acute coronary syndromes. N Engl J Med 2013; 369: 999-1010.
    CrossrefPubMedGoogle Scholar
  • 42 Montalescot G, Lassen JF, Hamm CW. et al. Ambulance or in-catheterization laboratory administration of ticagrelor for primary percutaneous coronary intervention for ST-segment elevation myocardial infarction: rationale and design of the randomized, double-blind Administration of Ticagrelor in the cath Lab or in the Ambulance for New ST elevation myocardial Infarction to open the Coronary artery (ATLANTIC) study. Am Heart J 2013; 165: 515-522.
    CrossrefPubMedGoogle Scholar
  • 43 Höchtl T, Tentzeris I, Schrör K, Huber K. Antiplatelet function variability in clopidogrel-treated patients: need for new antiplatelet agents. Fundamental Clin Pharm 2012; 26: 2-10.
    PubMedGoogle Scholar
  • 44 Husted S, Emanuelsson H, Heptinstall S. et al. Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin. Eur Heart J 2006; 27: 1038-1047.
    CrossrefPubMedGoogle Scholar
  • 45 Schrör K, Siller-Matula JM, Huber K. Pharmacokinetic basis of the antiplatelet action of prasugrel. Fundamental Clin Pharm 2012; 26: 39-46.
    PubMedGoogle Scholar
  • 46 Wiviott SD, Trenk D, Frelinger AL et al.. Prasugrel compared with high loading- and maintenancedose clopidogrel in patients with planned percutaneous coronary intervention: the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 trial. Circulation 2007; 116: 2923-2932.
    CrossrefPubMedGoogle Scholar
  • 47 Parodi G, Valenti R, Bellandi B. et al. Comparison of prasugrel and ticagrelor loading doses in STsegment elevation myocardial infarction patients: RAPID (Rapid Activity of Platelet Inhibitor Drugs) primary PCI study. J Am Coll Cardiol 2013; 61: 1601-1606.
    CrossrefPubMedGoogle Scholar
  • 48 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; 05: 797-804.
    CrossrefPubMedGoogle Scholar
  • 49 Valgimigli M, Tebaldi M, Campo G. et al. Prasugrel versus tirofiban bolus with or without short postbolus 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 2012; 05: 268-277.
    CrossrefPubMedGoogle Scholar
  • 50 Bhatt DL, Stone GW, Mahaffey KW. et al. Effect of platelet inhibition with cangrelor during PCI on ischemic events. N Engl J Med 2013; 368: 1303-1313.
    CrossrefPubMedGoogle Scholar