METoclopramide Administration as a Strategy to Overcome MORPHine-ticagrelOr Interaction in PatientS with Unstable Angina PectorIS—The METAMORPHOSIS Trial

Joanna Sikora; Piotr Niezgoda; Malwina Barańska; Katarzyna Buszko; Natalia Skibińska; Wiktor Sroka; Krzysztof Pstrągowski; Jolanta Siller-Matula; Jilma Bernd; Diana Gorog; Eliano Pio Navarese; Michał Piotr Marszałł; Jacek Kubica

doi:10.1055/s-0038-1675605

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2018; 118(12): 2126-2133
DOI: 10.1055/s-0038-1675605

Cellular Haemostasis and Platelets

Georg Thieme Verlag KG Stuttgart · New York

METoclopramide Administration as a Strategy to Overcome MORPHine-ticagrelOr Interaction in PatientS with Unstable Angina PectorIS—The METAMORPHOSIS Trial

Joanna Sikora^*

¹Laboratory for Experimental Biotechnology, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland

,

Piotr Niezgoda^*

²Department of Cardiology and Internal Medicine, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland

,

Malwina Barańska

²Department of Cardiology and Internal Medicine, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland

,

Katarzyna Buszko

³Department of Theoretical Foundations of Biomedical Science and Medical Informatics, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland

,

Natalia Skibińska

²Department of Cardiology and Internal Medicine, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland

,

Wiktor Sroka

⁴Department of Medicinal Chemistry, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland

,

Krzysztof Pstrągowski

²Department of Cardiology and Internal Medicine, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland

,

Jolanta Siller-Matula

⁵Department of Cardiology, Medical University of Vienna, Vienna, Austria

,

Jilma Bernd

⁶Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria

,

Diana Gorog

⁷National Heart and Lung Institute, Imperial College London, London, United Kingdom

,

Eliano Pio Navarese

¹Laboratory for Experimental Biotechnology, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland

⁸Inova Center for Thrombosis Research and Drug Development, Inova Heart and Vascular Institute, Fairfax, Virginia, United States

⁹SIRIO MEDICINE Research Network, Inova Center for Thrombosis Research and Drug Development, Inova Heart and Vascular Institute, Fairfax, Virginia, United States

,

Michał Piotr Marszałł

⁴Department of Medicinal Chemistry, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland

,

Jacek Kubica

²Department of Cardiology and Internal Medicine, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland

› Author Affiliations

Abstract

Extensive search for methods of overcoming morphine-related delay of the absorption and onset of action of oral P2Y₁₂ inhibitors in patients presenting with acute coronary syndrome is on-going. The aim of the trial was to investigate whether metoclopramide co-administration could reduce this delay and improve the pharmacokinetics (PKs) and pharmacodynamics (PDs) of ticagrelor and its active metabolite AR-C124900XX. Plasma concentration of both compounds and platelet reactivity were evaluated in nine pre-defined time points within 6 hours after administration of ticagrelor loading dose. The results of our study show that mean platelet activity within the first hour was noticeably higher in metoclopramide-naive patients. Moreover, ticagrelor mean plasma concentration was significantly higher within the initial four time points (15, 30, 45, 60 minutes) in patients receiving metoclopramide (p = 0.039; p = 0.009; p = 0.005; p = 0.008, respectively). To conclude, the co-administration of metoclopramide in patients presenting with unstable angina and treated with morphine, has a beneficial effect on the PK/PD profile of ticagrelor and its metabolite; however, its impact on ST-elevation myocardial infarction patients requires further investigation.

Keywords

anti-platelet agents - morphine - metoclopramide

Full Text

References

References
1 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 (25) 2577-2585
2 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 double-blind study. Lancet 2010; 375 (9711): 283-293
3 Hamm CW, Bassand JP, Agewall S. , et al; ESC Committee for Practice Guidelines. 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 (23) 2999-3054
4 Steg PG, James SK, Atar D. , et al; Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC). ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 2012; 33 (20) 2569-2619
5 Jneid H, Anderson JL, Wright RS. , et al. 2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2012; 60 (07) 645-681
6 O'Gara PT, Kushner FG, Ascheim DD. , et al; American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines; American College of Emergency Physicians; Society for Cardiovascular Angiography and Interventions. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the American College of Emergency Physicians and Society for Cardiovascular Angiography and Interventions. Catheter Cardiovasc Interv 2013; 82 (01) E1-E27
7 Kubica J, Kubica A, Jilma B. , et al. Impact of morphine on antiplatelet effects of oral P2Y12 receptor inhibitors. Int J Cardiol 2016; 215: 201-208
8 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 (03) 245-252
9 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 (15) 1601-1606
10 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 (06) 797-804
11 Silvain J, Storey RF, Cayla G. , et al. P2Y12 receptor inhibition and effect of morphine in patients undergoing primary PCI for ST-segment elevation myocardial infarction. The PRIVATE-ATLANTIC study. Thromb Haemost 2016; 116 (02) 369-378
12 Albibi R, McCallum RW. Metoclopramide: pharmacology and clinical application. Ann Intern Med 1983; 98 (01) 86-95
13 Pinder RM, Brogden RN, Sawyer PR, Speight TM, Avery GS. Metoclopramide: a review of its pharmacological properties and clinical use. Drugs 1976; 12 (02) 81-131
14 Sikora J, Niegoda P, Barańska M. , et al. The influence of metoclopramide on pharmacokinetics and pharmacodynamics of ticagrelor in patients with unstable angina pectoris receiving concomitant treatment with morphine — a protocol of a randomized trial. Med Res J 2016; 1: 68-71
15 Niezgoda P, Sikora J, Barańska M. , et al. Crushed sublingual versus oral ticagrelor administration strategies in patients with unstable angina. A pharmacokinetic/pharmacodynamic study. Thromb Haemost 2017; 117 (04) 718-726
16 Tilemann LM, Stiepak J, Zelniker T. , et al. Efficacy of enteral ticagrelor in hypothermic patients after out-of-hospital cardiac arrest. Clin Res Cardiol 2016; 105 (04) 332-340
17 Parodi G, Xanthopoulou I, Bellandi B. , et al. Ticagrelor crushed tablets administration in STEMI patients: the MOJITO study. J Am Coll Cardiol 2015; 65 (05) 511-512
18 Zafar MU, Farkouh ME, Fuster V, Chesebro JH. Crushed clopidogrel administered via nasogastric tube has faster and greater absorption than oral whole tablets. J Interv Cardiol 2009; 22 (04) 385-389
19 Rollini F, Franchi F, Hu J. , et al. Crushed prasugrel tablets in patients with STEMI undergoing primary percutaneous coronary intervention: the CRUSH study. J Am Coll Cardiol 2016; 67 (17) 1994-2004
20 Asher E, Frydman S, Katz M. , et al; For The PLATIS (Platelets and Thrombosis in Sheba) Study Group. Chewing versus swallowing ticagrelor to accelerate platelet inhibition in acute coronary syndrome - the CHEERS study. Thromb Haemost 2017; 117 (04) 727-733
21 Venetsanos D, Sederholm Lawesson S, Swahn E, Alfredsson J. Chewed ticagrelor tablets provide faster platelet inhibition compared to integral tablets: the inhibition of platelet aggregation after administration of three different ticagrelor formulations (IPAAD-Tica) study, a randomised controlled trial. Thromb Res 2017; 149: 88-94
22 Sumaya W, Parker WAE, Fretwell R. , et al. Pharmacodynamic effects of a 6-hour regimen of enoxaparin in patients undergoing primary percutaneous coronary intervention (PENNY PCI Study). Thromb Haemost 2018; 118 (07) 1250-1256
23 Flierl U, Zauner F, Sieweke J-T. , et al. Efficacy of prasugrel administration immediately after percutaneous coronary intervention in ST-elevation myocardial infarction. Thromb Haemost 2017; 117 (01) 99-104