Antiplatelet therapy – ticagrelor

Summary

Ticagrelor, a cyclopentyltriazolopyrimidine (CPTP), is the representative of a new chemical class of P2Y₁₂ receptor inhibitors that differ from thienopyridines (ticlopidin, clopidogrel, prasugrel) as ticagrelor is not a prodrug requiring active biotransformation by cytochromes in the liver and thus is characterized by a more rapid, more effective and more consistent platelet inhibition than ticlopidin or clopidogrel. An extensive study program for dose finding and safety for AZD6140 (DISPERSE studies) and a large-scaled phase III trial (PLATO) were undertaken on more than 18 000 patients for validation of efficacy and safety. In the PLATO trial, patients presenting with the broad spectrum of ACS, i.e. unstable angina, non-STEMI or STEMI, were randomized to ticagrelor (Brilique, Brilinta) or clopidogrel within 24 hours after onset of symptoms, regardless whether they were allocated to a planned invasive or conservative treatment. Compared to clopidogrel, ticagrelor reduced rates of the primary endpoint consisting of cardiovascular death, non-fatal MI, or stroke, without an excess of the primary safety endpoint that was PLATO-defined major bleedings. Results from the pre-specified confirmatory subgroup of patients undergoing planned invasive treatment was consistent with PLATO main trial. In addition, the primary endpoint, as well as CV death and all cause death were consistently reduced with ticagrelor in numerous exploratory subgroups including STEMI patients, those planned for non-invasive treatment, patients undergoing CABG, patients with renal failure, and those with diabetes mellitus, although patients were pretreated before coronary angiography and patients with clopidogrel pretreatment were not excluded. Conclusions: The pharmacological properties and convincing study results of the PLATO trial have stimulated a paradigm change for dual antiplatelet therapy. The new ESC guidelines on the management of ACS without ST segment elevation recommend the use of clopidogrel only when a new antiplatelet drug, e. g. ticagrelor or prasugrel is not available or contraindicated.

Zusammenfassung

Ticagrelor ist ein neuer direkter, reversibler Thrombozytenaggregationshemmer aus der neuen chemischen Klasse der Cyclopentyltria-zolopyrimidine (CPTP). Ticagrelor führt nach oraler Einnahme zu einem schnelleren Wir-kungseintritt, einer besseren und konsistenteren Hemmung des P2Y₁₂-Rezeptors als Clopidogrel. Die optimale Dosis und Sicherheit von Ticagrelor (AZD6140, Brilique, Brilinta) wurde in einem ausführlichen Studienprogramm getestet (DISPERSE-Studien) und abschließend in einer Phase-3-Studie an über 18 000 Patienten hinsichtlich Effektivität und Sicherheit validiert. In der PLATO Studie wurden Patienten, die innerhalb von 24 Stunden mit einem akuten Koronarsyndrom aufgenommen wurden, unabhängig von einer Vorbehandlung mit Clopidogrel und unabhängig von einem primär invasiven oder konservativem Therapieansatz, zu Ticagrelor oder Clopidogrel randomisiert. Ticagrelor zeigte eine signifikante Senkung des primären Effektivitätsendpunkts, bestehend aus kardiovaskulärem Tod, nichttödlichem Myokardinfarkt oder Schlaganfall, ohne eine Erhöhung des primären Sicherheitsendpunkts, definiert als Majorblutung nach der PLATO Blutungsdefinition. Ticagrelor reduzierte die Rate kardiovaskulärer Todesfälle sowie die Rate an Todesfällen jeglicher Ursache. Die Ergebnisse der PLATO-Hauptstudie bestätigten sich konsistent an der prä-spezifizierten konfirmatorischen Subgruppe der primär invasiv behandelten Patienten. Zahlreiche weitere explorative Subgruppenanalysen an Patienten mit STEMI, Patienten mit Diabetes mellitus, Patienten mit schwerer Niereninsuffizienz, oder primär konservativ behandelten Patienten zeigten eine konsistente Überlegenheit von Ticagrelor gegenüber Clopidogrel, obwohl in der PLATO Studie die Vorbehandlung und der Einsatz einer höheren 600-mg-Aufsättigungsdosis erlaubt war. Schlussfolgerungen: Die pharmakologischen Vorteile und überzeugenden Studienergebnisse haben zu m Paradigmenwechsel in der Behandlung des akuten Koronarsyndroms geführt. In den aktuellen ESC-Leitlinien wird der Einsatz der neuen Plättchenhemmer favorisiert, während Clopidogrel dann indiziert ist, wenn die neuen Substanzen nicht gegeben werden können.

Keywords

DISPERSE - PLATO - Ticagrelor - acute coronary syndrome

Schlüsselwörter

DISPERSE - PLATO - Ticagrelor - akutes Koronar syndrom

• References

• 1 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 doubleblind comparison to clopidogrel with aspirin. Eur Heart J 2006; 27: 1038-1047.
• 2 Husted S, van Giezen JJ. Ticagrelor: the first reversibly binding oral P2Y12 receptor antagonist. Cardiovasc Ther 2009; 27: 259-274.
• 3 Van Giezen JJJ, Humphries RG. Preclinical and clinical studies with selective reversible direct P2Y12 antagonists. Semin Thromb Hemost 2005; 31: 195-204.
• 4 Van Giezen JJJ, Zachrisson H, Björkman JA. Reduced bleeding time prolongation for the reversible P2Y12 antagonist AZD6140 compared with clopidogrel and AZ11703072, a chemical compound indistinguishable from prasugrel, in both a rat and a dog model of combined thrombosis and hemostasis. Arterioscler Thromb Vasc Biol 2008; 28 e-140. Abstract P585.
• 5 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; 121: 1188-1199.
• 6 Teng R, Oliver S, Hayes MA, Butler K. Absorption, distribution, metabolism, and excretion of ticagrelor in healthy subjects. Drug Metab Dispos 2010; 38: 1514-1521.
• 7 Gurbel PA, Bliden KP, Butler K. et al. Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study. Circulation 2009; 120: 2577-2585.
• 8 Brilique EU label. 2010
• 9 Brilinta label in USA: http://www1.astrazeneca-us.com/pi/brilinta.pdf
• 10 Cannon CP, Husted S, Harrington RA. et al. for the DISPERSE-2 Investigators. Safety, tolerability, and initial efficacy of AZD6140, the first reversible oral adenosine diphosphate receptor antagonist, compared with clopidogrel, in patients with non-STsegment elevation acute coronary syndrome: Primary results of the DISPERSE-2 trial. J Am Coll Cardiol 2007; 50: 1844-1851.
• 11 Wallentin L, Becker RC, Budaj A. et al. PLATO Investigators, Freij A, Thorsén M. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361: 1045-1057.
• 12 Cannon CP, Harrington RA, James S. et al. PLATelet inhibition and patient Outcomes Investigators. Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO): a randomised doubleblind study. Lancet 2010; 375: 283-293.
• 13 James SK, Roe MT, Cannon CP. et al. PLATO Study Group. Ticagrelor versus clopidogrel in patients with acute coronary syndromes intended for noninvasive management: substudy from prospective randomised PLATelet inhibition and patient Outcomes (PLATO) trial. BMJ 2011; 342: d3527.
• 14 Steg PG, James S, Harrington RA. et al. PLATO Study Group. 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.
• 15 James S, Angiolillo DJ, Cornel JH. et al. PLATO Study Group. 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.
• 16 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.
• 17 Wallentin L, James S, Storey RF. et al. PLATO investigators. 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.
• 18 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; 57: 672-684.
• 19 Hamm CW, Bassand JP, Agewall S, et al. ESC Committee for Practice Guidelines. Bax JJ, Auricchio A, Baumgartner H. et al ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J 2011; 32: 2999-3054.
• 20 Mahaffey KW, Wojdyla DM, Carroll K. et al. PLATO Investigators. Ticagrelor compared with clopidogrel by geographic region in the Platelet Inhibition and Patient Outcomes (PLATO) trial. Circulation 2011; 124: 544-554.
• 21 Storey RF, Becker RC, Harrington RA. et al. Characterization of dyspnoea in PLATO study patients treated with ticagrelor or clopidogrel and its association with clinical outcomes. Eur Heart J 2011; 32: 2945-2953.
• 22 Burki NK, Dale WJ, Lee L-Y. Intravenous adenosine and dyspnea in humans. J Appl Physiol 2005; 98: 180-185.
• 23 Storey RF, Becker RC, Harrington RA. et al. Pulmonary function in patients with acute coronary syndrome treated with ticagrelor or clopidogrel (from the Platelet Inhibition and Patient Outcomes [PLATO] pulmonary function substudy). Am J Cardiol 2011; 108: 1542-1546.
• 24 Scirica BM, Cannon CP, Emanuelsson H. et al. PLATO Investigators. The incidence of bradyarrhythmias and clinical bradyarrhythmic events in patients with acute coronary syndromes treated with ticagrelor or clopidogrel in the PLATO(Platelet Inhibition and Patient Outcomes) trial: results of the continuous electrocardiographic assessment substudy. J Am Coll Cardiol 2011; 57: 1908-1916.
• 25 Task Force on Myocardial Revascularization of the European Society of Cardiology(ESC) and the European Association for Cardio-Thoracic Surgery (EACTS); European Association for Percutaneous Cardiovascular Interventions (EAPCI). Wijns W, Kolh P, Danchin N. et al. Guidelines on myocardial revascularization. Eur Heart J 2010; 31: 2501-2555.