P2Y₁₂ receptor inhibition and effect of morphine in patients undergoing primary PCI for ST-segment elevation myocardial infarction

Summary

PRIVATE-ATLANTIC (P2Y₁₂ Receptor Inhibition with VASP Testing using Elisa kit during the ATLANTIC study) is a pre-specified substudy of the randomised, double-blind ATLANTIC trial in patients with ST-segment elevation myocardial infarction, designed to help interpret the main trial results. The primary objective of ATLANTIC was to assess coronary reperfusion prior to percutaneous coronary intervention (PCI) with pre- vs in-hospital ticagrelor 180 mg loading dose (LD). PRIVATE-ATLANTIC assessed platelet inhibition in 37 patients by measurement of vasodilator-associated stimulated phosphoprotein (VASP) platelet reactivity index (PRI) and VerifyNow platelet reactivity units (PRU) before angiogram (T1), immediately after PCI (T2), 1 (T3), and 6 (T4) hours (h) after PCI, and before next study drug administration (T5). The median time difference between the two ticagrelor LD was 41 minutes. Platelet reactivity was unaffected at T1 when measured by VASP-PRI (89.8 vs 93.9% for pre- and in-hospital ticagrelor, respectively; p = 0.18) or PRU (239 vs 241; p = 0.82). Numerical differences were apparent at T2 and maximal at T3. Morphine administration significantly delayed onset of platelet inhibition at T3 (VASP-PRI 78.2 vs 23.4% without morphine; p = 0.0116) and T4 (33.1 vs 11.0%; p = 0.0057). In conclusion, platelet inhibition in ATLANTIC was unaffected by pre-hospital ticagrelor administration at the time of initial angiogram due to the short transfer delay. The maximum difference in platelet inhibition was detected 1 h after PCI (T3). Morphine administration was associated with delayed onset of action of ticagrelor and appeared more important than timing of ticagrelor administration.

Keywords

Ticagrelor - platelet reactivity - morphine - STEMI - PCI

^* “PRIVATE-ATLANTIC” = P2Y12 Receptor Inhibition with VASP Testing using Elisa kit during the Administration of Ticagrelor in the Cath Lab or in the Ambulance for New ST elevation Myocardial Infarction to open the Coronary Artery

• References

• 1 Montalescot G, van 't Hof AW, Lapostolle F. et al. Prehospital ticagrelor in ST-segment elevation myocardial infarction. N Engl J Med 2014; 371: 1016-1027.
• 2 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.
• 3 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; 61: 1601-1606.
• 4 Valgimigli M, Tebaldi M, Campo G. et al. 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 2012; 5: 268-277.
• 5 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; 5: 797-804.
• 6 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.
• 7 Barragan P, Paganelli F, Camoin-Jau L. et al. Validation of a novel ELISA-based VASP whole blood assay to measure P2Y12-ADP receptor activity. Thromb Haemost 2010; 104: 410-411.
• 8 Abtan J, Silvain J, Kerneis M. et al. Identification of poor response to P2Y12 inhibitors in ACS patients with a new ELISA-based vasodilator-associated stimulated phosphoprotein (VASP) phosphorylation assay. Thromb Haemost 2013; 110: 1055-1064.
• 9 Collet JP, Cuisset T, Range G. et al. Bedside monitoring to adjust antiplatelet therapy for coronary stenting. N Engl J Med 2012; 367: 2100-2109.
• 10 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; 66: 487-496.
• 11 Storey RF, Angiolillo DJ, Patil SB. et al. Inhibitory effects of ticagrelor compared with clopidogrel on platelet function in patients with acute coronary syndromes: the PLATO (PLATelet inhibition and patient Outcomes) PLATELET substudy. J Am Coll Cardiol 2010; 56: 1456-1462.
• 12 Storey RF, Husted S, Harrington RA. et al. Inhibition of platelet aggregation by AZD6140, a reversible oral P2Y12 receptor antagonist, compared with clopidogrel in patients with acute coronary syndromes. J Am Coll Cardiol 2007; 50: 1852-1856.
• 13 Montalescot G, Borentain M, Payot L. et al. Early vs late administration of glycoprotein IIb/IIIa inhibitors in primary percutaneous coronary intervention of acute ST-segment elevation myocardial infarction: a meta-analysis. J Am Med Assoc 2004; 292: 362-366.
• 14 van 't Hof AW, ten Berg J, Heestermans T. et al. Prehospital initiation of tirofiban in patients with ST-elevation myocardial infarction undergoing primary angioplasty (On-TIME 2): a multicentre, double-blind, randomised controlled trial. Lancet 2008; 372: 537-546.
• 15 ten Berg JM, van 't Hof AW, Dill T. et al. Effect of early, pre-hospital initiation of high bolus dose tirofiban in patients with ST-segment elevation myocardial infarction on short- and long-term clinical outcome. J Am Coll Cardiol 2010; 55: 2446-2455.
• 16 Hermanides RS, van Werkum JW, Ottervanger JP. et al. The effect of pre-hospital glycoprotein IIb-IIIa inhibitors on angiographic outcome in STEMI patients who are candidates for primary PCI.. Catheter Cardiovasc Interv 2012; 79: 956-964.
• 17 Postma S, Dambrink JH, Ottervanger JP. et al. Early ambulance initiation versus in-hospital initiation of high dose clopidogrel in ST-segment elevation myocardial infarction. Thromb Haemost 2014; 112: 606-613.
• 18 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; 63: 630-635.
• 19 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; 8: ii e001593.
• 20 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; 37: 245-252.
• 21 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; 46: 7-14.
• 22 Hobl EL, Reiter B, Schoergenhofer C. et al. Morphine interaction with prasugrel: a double-blind, cross-over trial in healthy volunteers. Clin Res Cardiol. 2015 Epub ahead of print.