Influence of Morphine on Pharmacokinetics and Pharmacodynamics of Ticagrelor in Patients With Acute Myocardial Infarction - IMPRESSION

Description:

The goal of the trial was to assess the pharmacokinetics and pharmacodynamics of a loading dose of ticagrelor and its active metabolite (AR-C124910XX) among invasively treated patients with acute myocardial infarction (AMI) who also received intravenous morphine.

Contribution to the literature: The IMPRESSION trial showed that intravenous morphine has an adverse effect on the pharmacokinetics and pharmacodynamics of ticagrelor loading dose in patients undergoing percutaneous coronary intervention (PCI) for AMI.

Study Design

Patients were randomized in a 1:1 fashion to either intravenous morphine 5 mg (n = 35) or matching placebo (n = 35).

  • Total number of enrollees: 70
  • Duration of follow-up: In-hospital
  • Mean patient age: 62 years
  • Percentage female: 27%

Inclusion criteria:

  • Ages 18-80 years
  • Diagnosis of ST-segment elevation MI (STEMI) or non-STEMI
  • Plan for angiography with or without PCI
  • Admission between 6 a.m. and 6 p.m.

Exclusion criteria:

  • Chest pain described by the patient as unbearable
  • Patient’s request for analgesics
  • Prior morphine administration during the current AMI
  • Treatment with any P2Y12 receptor inhibitor within 14 days prior to study enrollment
  • Ongoing treatment with oral anticoagulant or chronic therapy with low molecular weight heparin
  • Active bleeding or history of coagulation disorders
  • Killip class III or IV, respiratory failure

Other salient features/characteristics:

  • STEMI: 65%
  • Glycoprotein inhibitor use: 22%
  • Anti-emetic administration: 2%

Principal Findings:

Pharmacokinetic data:

  • Area under the curve (AUC) for ticagrelor at 12 hours for morphine vs. placebo: 6307 vs. 9791 ng h/ml; difference, 36%; p = 0.003
  • AUC for AR-C124910XX at 12 hours for morphine vs. placebo: 1503 vs. 2388 ng h/ml; difference, 37%; p = 0.008

Pharmacodynamic data:

  • Prevalence of high platelet reactivity for morphine vs. placebo higher at all time points studied other than baseline (vasodilator-stimulated phosphoprotein [VASP] assay): 30 minutes: 91% vs. 71%, p = 0.06; 1 hour: 66% vs. 37%, p = 0.03; 2 hours: 57% vs. 29%, p = 0.03; 4 hours: 37% vs. 17%, p = 0.1

Secondary outcomes:

  • Stent thrombosis: 1 vs. 0, p > 0.05

Interpretation:

The results of this small, but intriguing trial indicate that co-administration of ticagrelor and intravenous morphine results in diminished pharmacokinetics and pharmacodynamics for ticagrelor and its active metabolite in AMI patients undergoing PCI. These results confirm earlier observational data on this topic.

The advantages of ticagrelor over clopidogrel include faster onset of action and more potent antiplatelet effect. This trial suggests that there may be substantial loss of these benefits with co-administration of morphine, and thus, should be avoided in patients receiving ticagrelor, particularly for the first time as a loading dose. This effect is believed to be due to impaired absorption of ticagrelor due to activation of opioid receptors in the myenteric plexus and in the intestines. It is unclear if this effect would be observed with all opioid analgesics or is specific to morphine alone, and should be investigated further.

References:

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 2015;Oct 21:[Epub ahead of print].

Clinical Topics: Acute Coronary Syndromes, Invasive Cardiovascular Angiography and Intervention, Interventions and ACS, Interventions and Imaging, Angiography, Nuclear Imaging

Keywords: Acute Coronary Syndrome, Analgesics, Opioid, Angiography, Microfilament Proteins, Morphine, Myocardial Infarction, Percutaneous Coronary Intervention, Pharmacokinetics, Phosphoproteins, Purinergic P2Y Receptor Antagonists, Receptors, Opioid, Stents, Thrombosis, Ticlopidine


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