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Thromb Haemost 2016; 116(01): 96-102
DOI: 10.1160/TH16-02-0102
Cellular Haemostasis and Platelets
Schattauer GmbH

Morphine delays the onset of action of prasugrel in patients with prior history of ST-elevation myocardial infarction

Mark R. Thomas
1   Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK
,
Allison C. Morton
1   Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK
2   Academic Directorate of Cardiology and Cardiothoracic Surgery, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
,
Rashed Hossain
1   Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK
,
Beining Chen
3   Chemistry Department, University of Sheffield, Sheffield, UK
,
Lei Luo
3   Chemistry Department, University of Sheffield, Sheffield, UK
,
Nur Nazihah B. Md. Shahari
3   Chemistry Department, University of Sheffield, Sheffield, UK
,
Peng Hua
3   Chemistry Department, University of Sheffield, Sheffield, UK
,
Richard G. Beniston
4   Biological Mass Spectrometry Facility, University of Sheffield, Sheffield, UK
,
Heather M. Judge
1   Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK
,
Robert F. Storey
1   Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK
2   Academic Directorate of Cardiology and Cardiothoracic Surgery, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
› Author Affiliations Financial support: This study was funded by University of Sheffield and was supported by National Institute for Health Research award to the Sheffield NIHR Clinical Research Facility.
Further Information

Publication History

Received: 08 February 2016

Accepted after minor revision: 26 March 2016

Publication Date:
27 November 2017 (online)

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Summary

Delays in the onset of action of prasugrel during primary percutaneous coronary intervention (PPCI) have been reported and could be related to the effects of morphine on gastric emptying and subsequent intestinal absorption. The study objective was to determine whether morphine delays the onset of action of prasugrel in patients with a prior history of ST-elevation myocardial infarction (STEMI) treated with PPCI. This was a crossover study of 11 aspirin-treated patients with prior history of STEMI treated with PPCI, for which prasugrel and morphine had been previously administered. Patients were randomised to receive either morphine (5 mg) or saline intravenously followed by 60 mg prasugrel. Blood samples were collected before randomised treatment and over 24 hours after prasugrel administration. The inhibitory effects of prasugrel on platelets were determined using the VerifyNow P2Y12 assay and light transmission aggregometry. Plasma levels of prasugrel and prasugrel active metabolite were measured. Platelet reactivity determined by VerifyNow PRU, VerifyNow % Inhibition and LTA was significantly higher at 30–120 minutes (min) when morphine had been co-administered compared to when saline had been co-administered. Morphine, compared to saline, significantly delayed adequate platelet inhibition after prasugrel administration (158 vs 68 min; p = 0.006). Patients with delayed onset of platelet inhibition also had evidence of delayed absorption of prasugrel. In conclusion, prior administration of intravenous morphine significantly delays the onset of action of prasugrel. Intravenous drugs may be necessary to reduce the risk of acute stent thrombosis in morphine-treated STEMI patients undergoing PPCI.

Keywords

Prasugrel - P2Y12 inhibitors - antiplatelet medications - morphine - platelet reactivity
 

  • References

  • 1 O’Gara PT, Kushner FG, Ascheim DD. et al. 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013; 61: e78-e140.
    PubMedGoogle Scholar
  • 2 Bellemain-Appaix A, Brieger D, Beygui F. et al. New P2Y12 Inhibitors Versus Clopidogrel in Percutaneous Coronary Intervention:A Meta-Analysis. J Am Coll Cardiol 2010; 56: 1542-1551.
    CrossrefPubMedGoogle Scholar
  • 3 Frelinger AL, Bhatt DL, Lee RD. et al. Clopidogrel pharmacokinetics and pharmacodynamics vary widely despite exclusion or control of polymorphisms (CYP2C19, ABCB1, PON1), noncompliance, diet, smoking, co-medications (including proton pump inhibitors), and pre-existent variability in platelet function. J Am Coll Cardiol 2013; 61: 872-879.
    CrossrefPubMedGoogle Scholar
  • 4 Payne CD, Li YG, Small DS. et al. Increased active metabolite formation explains the greater platelet inhibition with prasugrel compared to high-dose clopidogrel. J Cardiovasc Pharmacol 2007; 50: 555-562.
    CrossrefPubMedGoogle Scholar
  • 5 Brandt JT, Payne CD, Wiviott SD. et al. A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation. Am Heart J 2007; 153: e9-16.
    CrossrefPubMedGoogle Scholar
  • 6 Michelson AD, Frelinger AL, Braunwald E. et al. Pharmacodynamic assessment of platelet inhibition by prasugrel vs. clopidogrel in the TRITON-TIMI 38 trial. Eur Heart J 2009; 30: 1753-1763.
    CrossrefPubMedGoogle Scholar
  • 7 Udell JA, Braunwald E, Antman EM. et al. Prasugrel Versus Clopidogrel in Patients With ST-Segment Elevation Myocardial Infarction According to Timing of Percutaneous Coronary Intervention: A TRITON-TIMI 38 Subgroup Analysis (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis In Myocardial Infarction 38). JACC: Cardiovascular Interventions 2014; 07: 604-612.
    CrossrefPubMedGoogle Scholar
  • 8 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
  • 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: 1601-1606.
    CrossrefPubMedGoogle Scholar
  • 10 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 2014; 08: e0015933.
    PubMedGoogle Scholar
  • 11 Nimmo WS, Heading RC, Wilson J. et al. Inhibition of gastric emptying and drug absorption by narcotic analgesics. Br J Clin Pharmacol Blackwell Publishing Ltd 1975; 02: 509-513.
    PubMedGoogle Scholar
  • 12 Angiolillo DJ, Suryadevara S, Capranzano P. et al. Prasugrel: a novel platelet ADP P2Y 12receptor antagonist. A review on its mechanism of action and clinical development. Expert Opin Pharmacother 2008; 09: 2893-2900.
    CrossrefPubMedGoogle Scholar
  • 13 Aradi D, Storey RF, Komócsi A. et al. Expert position paper on the role of platelet function testing in patients undergoing percutaneous coronary intervention. Eur Heart J 2013; 35: 209-215.
    PubMedGoogle Scholar
  • 14 Aradi D, Kirtane A, Bonello L. et al. Bleeding and stent thrombosis on P2Y12-inhibitors: collaborative analysis on the role of platelet reactivity for risk stratification after percutaneous coronary intervention. Eur Heart J 2015; 36: 1762-1771.
    CrossrefPubMedGoogle Scholar
  • 15 Alexopoulos D, Xanthopoulou I, Gkizas V. et al. Randomised assessment of ticagrelor versus prasugrel antiplatelet effects in patients with ST-segment-elevation myocardial infarction. Circulation Cardiovasc Interv 2012; 05: 797-804.
    PubMedGoogle Scholar
  • 16 Hobl E-L, Stimpfl T, Ebner J. et al. Morphine decreases clopidogrel concentrations and effects: a randomised , double-blind, placebo-controlled trial. J Am Coll Cardiol 2014; 63: 630-635.
    CrossrefPubMedGoogle Scholar
  • 17 Franchi F, Rollini F, Cho JR. et al. Impact of Escalating Loading Dose Regimens of Ticagrelor in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention: Results of a Prospective Randomised Pharmacokinetic and Pharmacodynamic Investigation. JACC Cardiovasc Interv 2015; 08: 1457-1467.
    CrossrefPubMedGoogle Scholar
  • 18 Montalescot G, van ’t Hof AW, Lapostolle F. et al. Prehospital ticagrelor in STsegment elevation myocardial infarction. N Engl J Med 2014; 371: 1016-1027.
    CrossrefPubMedGoogle Scholar
  • 19 Silvain J, Silvain J, Storey R. et al. Impact of morphine administration on ticagrelor-induced platelet inhibition in ST-elevation myocardial infarction patients treated by primary PCI: results from the PRIVATE-ATLANTIC study. J Am Coll Cardiol 2015; 65: 10.
    PubMedGoogle Scholar
  • 20 Kubica J, Adamski P, Ostrowska M. et al. Morphine delays and attenuates ticagrelor exposure and action in patients with myocardial infarction: the randomised, double-blind, placebo-controlled IMPRESSION trial. Eur Heart J 2015; ehv547.
    PubMedGoogle Scholar
  • 21 Meine TJ, Roe MT, Chen AY. et al. Association of intravenous morphine use and outcomes in acute coronary syndromes: Results from the CRUSADE Quality Improvement Initiative. Am Heart J 2005; 149: 1043-1049.
    CrossrefPubMedGoogle Scholar