Phase 4 N=30 Randomized Double-blind Treatment

Effect of Methylnaltrexone on the PK/PD Profiles of Ticagrelor in Patients Treated With Morphine

Coronary Artery Disease

Bottom Line

View on ClinicalTrials.gov: NCT02403830 ↗

Enrolled (actual)

Serious AEs

0.0%

Results posted

Apr 2017

Primary outcome: Primary: Platelet Reactivity Measured by VerifyNow P2Y12 — 130; 97 PRU — p=0.261

Study Design & Population

Study type: Interventional
Phase: Phase 4
Interventions: Methylnaltrexone (Drug); Placebo (Other); Morphine (Drug); Ticagrelor (Drug)
Age: Adult, Older Adult · 18+ yrs
Sex: All
Sponsor: University of Florida
Primary completion: May 2016

Outcome Measures

Outcome	Result	p-value
PRIMARY Platelet Reactivity Measured by VerifyNow P2Y12	130; 97	0.261
SECONDARY Platelet Reactivity Measured by VASP	47; 40	—
SECONDARY AUC of Ticagrelor Plasma Levels	2952; 2276	—

Summary

Ticagrelor is associated with more prompt and potent antiplatelet effects compared with clopidogrel, leading to better clinical outcomes, including reduced cardiovascular mortality, across the spectrum of patients with acute coronary syndrome, including those with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). However, in this latter setting a delay in the onset of its antiplatelet effects has been shown. Morphine has been identified as a cause of delayed P2Y12 inhibition in patients with STEMI. Methylnaltrexone is a parenteral peripheral opioid receptor antagonist which has the potential to prevent or reverse opioid-induced peripherally mediated side effects without affecting analgesia. However, whether the use of intravenous methylnaltrexone may overcome the effects of morphine administration on the pharmacokinetic (PK) and pharmacodynamics (PD) profiles of ticagrelor has not been investigated yet. The proposed investigation will include patients with coronary artery disease and will have a prospective, randomized, cross-over design.

Eligibility Criteria

Inclusion criteria

Patients with angiographically documented CAD.
On treatment with low-dose aspirin (81 mg) for at least 30 days, as per standard of care.
Age between 18 and 80 years old.

Exclusion criteria

History of prior intracranial bleeding.
On treatment with a P2Y12 receptor antagonist (ticlopidine, clopidogrel, prasugrel, ticagrelor) or with vorapaxar in past 30 days.
Known allergies to ticagrelor.
On treatment with any oral anticoagulant (vitamin K antagonists, dabigatran, rivaroxaban, apixaban).
Treatment with glycoprotein IIb/IIIa inhibitors in past 7 days.
Known blood dyscrasia or bleeding diathesis.
Platelet count <80x106/mL.
Hemoglobin <10 g/dL.
Active bleeding.
Hemodynamic instability.
Creatinine clearance <30 mL/minute (as estimated by Cockcroft-Gault formula).
Severe hepatic dysfunction.
Acute or severe bronchial asthma or upper airway obstruction.
Known or suspected mechanical gastrointestinal obstruction.
Patients with sick sinus syndrome (SSS) or high degree AV block without pacemaker protection.
Current treatment with any drug interfering with morphine: central nervous system depressants (other narcotic analgesics, general anesthetics, phenothiazines, tricyclic antidepressants, tranquilizers, sedatives, hypnotics, antiemetics, and alcohol), muscle relaxants, mixed agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol), cimetidine, monoamine oxidase inhibitors (MAOIs), anticholinergics.
Current treatment with drugs interfering with CYP3A4 metabolism (to avoid interaction with ticagrelor): Ketoconazole, itraconazole, voriconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir, and telithromizycin.
Pregnant females*. *Women of childbearing age must use reliable birth control (i.e. oral contraceptives) while participating in the study.

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Data sourced from ClinicalTrials.gov (NCT02403830). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.