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

Collegium Medicum w Bydgoszczy74 enrolled

Overview

The purpose of the IMPRESSION study is to determine whether intravenous administration of morphine prior to ticagrelor administration in ST-segment elevation myocardial infarction (STEMI) patients and in non-ST-segment elevation myocardial infarction (NSTEMI) patients alters the plasma concentrations of ticagrelor and its active metabolite and whether it is associated with any negative impact on the antiplatelet effect of ticagrelor.

The European Society of Cardiology and American Heart Association guidelines recommend use of morphine as a treatment of choice for pain relief in STEMI patients. However, this recommendation, although strong, is only based on expert consensus (class of recommendation I, level of evidence C). Morphine, apart from its analgesic effects, also alleviates the work of breathing and reduces anxiety. On the other hand, despite its favorable analgesic and sedative actions, morphine also exerts adverse effects, which include hypotension, bradycardia, respiratory depression, vomiting and reduction of gastrointestinal motility. Some of the previously listed morphine's side effects could affect the intestinal absorption and thus pharmacokinetics and pharmacodynamics of orally administered drugs which are concomitantly used with morphine. At present, no pharmacokinetic and pharmacodynamic data regarding the concurrent use of morphine and P2Y12 blockers in the STEMI or NSTEMI setting are available. Therefore, evidence-based verification of morphine's influence on pharmacokinetics and pharmacodynamics of ticagrelor and its active metabolite (AR-C124910XX) could provide a valuable insight in the knowledge regarding modern acute myocardial infarction management. Predefined subanalysis: aimed to investigate which one of platelet reactivity assessment methods utilized in the study (VASP assay, MEA, LTA, VerifyNow) best reflects concentration of ticagrelor and its active metabolite (AR-C124910XX). Since there is no reference study examining pharmacokinetics of ticagrelor in STEMI or NSTEMI patients, we decided to perform an internal pilot study of approximately 30 patients (15 patients for each arm) for estimating the final sample size.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Eligibility

Sex: ALLMin age: 18 YearsMax age: 80 Years

Medical Language ↔ Plain English

Inclusion Criteria: * provision of informed consent prior to any study specific procedures * diagnosis of acute ST-segment elevation myocardial infarction or acute non-ST-segment elevation myocardial infarction * male or non-pregnant female, aged 18-80 years old * provision of informed consent for angiography and PCI Exclusion Criteria: * chest pain described by the patient as unbearable or patient's request for analgesics * prior morphine administration during the current STEMI or NSTEMI * treatment with ticlopidine, clopidogrel, prasugrel or ticagrelor within 14 days before the study enrollment * 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) * patients considered by the investigator to be at risk of bradycardic events * second or third degree atrioventricular block during screening for eligibility * history of asthma or severe chronic obstructive pulmonary disease * patient required 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

Outcomes

Primary Outcomes

Area Under the Plasma Concentration-time Curve for Ticagrelor (AUC 0-12h)

Exposure to ticagrelor during the first 12 hours after ticagrelor loading dose

Time frame: prior to the initial dose and 30min, 1h, 2h, 3h, 4h, 6h, 12h post dose

Secondary Outcomes

Area Under the Plasma Concentration-time Curve for AR-C124910XX (AUC 0-12h)

Exposure to ticagrelor metabolite during the first 12 hours after ticagrelor loading dose

Time frame: prior to the initial dose and 30min, 1h, 2h, 3h, 4h, 6h, 12h post dose

Maximum Concentration of Ticagrelor

Maximum concentration (Cmax) of ticagrelor

Time frame: 12 hours

Maximum Concentration of AR-C124910XX

Maximum concentration (Cmax) of AR-C124910XX

Time frame: 12 hours

Time to Maximum Concentration for Ticagrelor

Time to maximum concentration (Tmax) for ticagrelor

Time frame: 12 hours

Time to Maximum Concentration for AR-C124910XX

Time to maximum concentration (Tmax) for AR-C124910XX

Time frame: 12 hours

Area Under the Plasma Concentration-time Curve for Ticagrelor (AUC 0-6h)

Exposure to ticagrelor during the first 6 hours after ticagrelor loading dose

Time frame: prior to the initial dose and 30min, 1h, 2h, 3h, 4h, 6h post dose

Area Under the Plasma Concentration-time Curve for AR-C124910XX (AUC 0-6)

Exposure to ticagrelor metabolite during the first 6 hours after ticagrelor loading dose

Time frame: prior to the initial dose and 30min, 1h, 2h, 3h, 4h, 6h post dose

Platelet Reactivity Index Assessed by VASP Assay

Platelet Reactivity Index (PRI) evaluated by VASP assay (cut-off value for high platelet reactivity: PRI \>50%)

Time frame: prior to the initial ticagrelor dose

Platelet Reactivity Index Assessed by VASP Assay

Platelet Reactivity Index (PRI) evaluated by VASP assay (cut-off value for high platelet reactivity: PRI \>50%)

Time frame: 30 minutes post ticagrelor dose

Platelet Reactivity Index Assessed by VASP Assay

Platelet Reactivity Index (PRI) evaluated by VASP assay (cut-off value for high platelet reactivity: PRI \>50%)

Time frame: 1 hour post ticagrelor dose

Platelet Reactivity Index Assessed by VASP Assay

Platelet Reactivity Index (PRI) evaluated by VASP assay (cut-off value for high platelet reactivity: PRI \>50%)

Time frame: 2 hours post ticagrelor dose

Platelet Reactivity Index Assessed by VASP Assay

Platelet Reactivity Index (PRI) evaluated by VASP assay (cut-off value for high platelet reactivity: PRI \>50%)

Time frame: 3 hours post ticagrelor dose

Platelet Reactivity Index Assessed by VASP Assay

Platelet Reactivity Index (PRI) evaluated by VASP assay (cut-off value for high platelet reactivity: PRI \>50%)

Time frame: 4 hours post ticagrelor dose

Platelet Reactivity Index Assessed by VASP Assay

Platelet Reactivity Index (PRI) evaluated by VASP assay (cut-off value for high platelet reactivity: PRI \>50%)

Time frame: 6 hours post ticagrelor dose

Platelet Reactivity Index Assessed by VASP Assay

Platelet Reactivity Index (PRI) evaluated by VASP assay (cut-off value for high platelet reactivity: PRI \>50%)

Time frame: 12 hours post ticagrelor dose

Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry