Influence of METHoxyflurane on ANtiplatelet Effect of Ticagrelor in Patients With Unstable Angina Pectoris

The purpose of this study is to evaluate differences in the pharmacokinetics and pharmacodynamics of ticagrelor and its active metabolite in patients who received ticagrelor followed with methoxyflurane versus ticagrelor followed with morphine or ticagrelor alone due to unstable angina pectoris

Results of the IMPRESSION trial published in 2015 proved that morphine use in patients with acute coronary syndromes (ACS) is associated with undesirable impact on pharmacokinetics (PK) and pharmacodynamics (PD) of ticagrelor. Despite that, morphine is still a standard analgesic treatment in ACS patients and it should not be routinely withdrawn. Based on contemporary knowledge, morphine, acting via mi-opioid receptors, was found to inhibit gastrointestinal motility or induce adverse effects such as nausea or vomiting.

We decided to design a clinical study aiming to evaluate the impact of methoxyflurane on PD of ticagrelor in patients diagnosed with unstable angina pectoris (UA). Methoxyflurane is an inhaled anesthetic, registered in Poland in emergency medicine for pain alleviation in trauma patients. The drug was widely used in 1960s to induce general anesthesia, however its clinical utility was reduced with the development of novel anesthetic agents. Taking into account its different mechanism of action, it can be presumed that, contrary to morphine, no respiratory depression should be observed as well as no attenuation or delay of antiaggregatory effect of ticagrelor should occur, as no interaction with mi-receptor in gastrointestinal tract is related to activity of methoxyflurane.

Patients will be randomized in a 1:1:1 ratio into the study arms as follows: 1) 180 mg ticagrelor (2 integral tablets of 90 mg ticagrelor) followed by 3 mg inhaled methoxyflurane, 2) 180 mg ticagrelor followed by 5 mg intravenous morphine, 3) 180 mg ticagrelor alone

Eligibility Criteria:
Inclusion Criteria:

* Provision of informed consent prior to any study specific procedures
* Diagnosis of unstable angina
* Male or non-pregnant female, aged 18-80 years
* Provision of informed consent for angiography and PCI
* GRACE score \<140 pts

Exclusion Criteria:

* Treatment with ticlopidine, clopidogrel, prasugrel or ticagrelor within 14 days before the study enrollment
* Current treatment with morphine or any opioid "mi" receptor agonist
* Hypersensitivity to ticagrelor
* Current treatment with oral anticoagulant or chronic therapy with low-molecular-weight heparin
* Active bleeding
* History of intracranial hemorrhage
* Recent gastrointestinal bleeding (within 30 days)
* History of coagulation disorders
* Platelet count less than \<100 x10\^3/mcl
* Hemoglobin concentration less than 10.0 g/dl
* History of moderate or severe hepatic impairment
* History of major surgery or severe trauma (within 3 months)
* Risk of bradycardic events as judged by the investigator
* Second- or third-degree atrioventricular block during screening for eligibility
* History of asthma or severe chronic obstructive pulmonary disease
* Kidney disease requiring dialysis
* Manifest infection or inflammatory state
* Killip class III or IV during screening for eligibility
* Respiratory failure
* History of severe chronic heart failure (NYHA class III or IV)
* Concomitant therapy with strong CYP3A inhibitors (ketoconazole, itraconazole, voriconazole, telithromycin, clarithromycin, nefazadone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir) or strong CYP3A inducers (rifampicin, phenytoin, carbamazepine, dexamethasone, phenobarbital) within 14 days and during study treatment
* Body weight below 50 kg