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

Phase 4

Completed

Conditions: ST-segment Elevation Myocardial Infarction
Non-ST-segment Elevation Myocardial Infarction
VA Drug Interactions

Interventions: Drug: Placebo
Drug: Morphine
Drug: Ticagrelor

Registration Number: NCT02217878

Lead Sponsor: Collegium Medicum w Bydgoszczy

Brief Summary: 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.

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 74

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	sodium chloride 0,9% 5 mg IV followed by 180 mg loading dose of ticagrelor
Morphine	Morphine	morphine sulfate 5 mg IV followed by 180 mg loading dose of ticagrelor
Morphine	Ticagrelor	morphine sulfate 5 mg IV followed by 180 mg loading dose of ticagrelor
Placebo	Ticagrelor	sodium chloride 0,9% 5 mg IV followed by 180 mg loading dose of ticagrelor

Primary Outcome Measures

Name	Time	Method
Area Under the Plasma Concentration-time Curve for Ticagrelor (AUC 0-12h)	prior to the initial dose and 30min, 1h, 2h, 3h, 4h, 6h, 12h post dose	Exposure to ticagrelor during the first 12 hours after ticagrelor loading dose

Secondary Outcome Measures

Name	Time	Method
Time to Maximum Concentration for AR-C124910XX	12 hours	Time to maximum concentration (Tmax) for AR-C124910XX
Percentage of Patients With High Platelet Reactivity After the Loading Dose of Ticagrelor Assessed With MEA	2 hours	Percentage of Patients With High Platelet Reactivity (HPR) After the Loading Dose of Ticagrelor Assessed With MEA
Time to Reach Platelet Reactivity Below the Cut-off Value for High Platelet Reactivity Evaluated With VASP	12 hours	Time to Reach Platelet Reactivity Below the Cut-off Value for High Platelet Reactivity (HPR) Evaluated With VASP
Time to Reach Platelet Reactivity Below the Cut-off Value for High Platelet Reactivity Evaluated With MEA	12 hours	Time to Reach Platelet Reactivity Below the Cut-off Value for High Platelet Reactivity (HPR) Evaluated With MEA
Maximum Concentration of Ticagrelor	12 hours	Maximum concentration (Cmax) of ticagrelor
Area Under the Plasma Concentration-time Curve for AR-C124910XX (AUC 0-12h)	prior to the initial dose and 30min, 1h, 2h, 3h, 4h, 6h, 12h post dose	Exposure to ticagrelor metabolite during the first 12 hours after ticagrelor loading dose
Maximum Concentration of AR-C124910XX	12 hours	Maximum concentration (Cmax) of AR-C124910XX
Time to Maximum Concentration for Ticagrelor	12 hours	Time to maximum concentration (Tmax) for ticagrelor
Platelet Reactivity Index Assessed by VASP Assay	12 hours post ticagrelor dose	Platelet Reactivity Index (PRI) evaluated by VASP assay (cut-off value for high platelet reactivity: PRI \>50%)
P2Y12 Reaction Units Assessed by VerifyNow	12 hours post ticagrelor dose	P2Y12 Reaction Units (PRU) Assessed by VerifyNow (cut-off value for high platelet reactivity: PRU \>208)
Area Under the Plasma Concentration-time Curve for Ticagrelor (AUC 0-6h)	prior to the initial dose and 30min, 1h, 2h, 3h, 4h, 6h post dose	Exposure to ticagrelor during the first 6 hours after ticagrelor loading dose
Area Under the Plasma Concentration-time Curve for AR-C124910XX (AUC 0-6)	prior to the initial dose and 30min, 1h, 2h, 3h, 4h, 6h post dose	Exposure to ticagrelor metabolite during the first 6 hours after ticagrelor loading dose
Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry	12 hours post ticagrelor dose	Platelet reactivity assessed by Multiple Electrode Aggregometry (cut-off value for high platelet reactivity: AUC \>46 Platelet Arbitrary Aggregation Units)
Percentage of Patients With High Platelet Reactivity After the Loading Dose of Ticagrelor Assessed With VASP	2 hours	Percentage of Patients With High Platelet Reactivity (HPR) After the Loading Dose of Ticagrelor Assessed With VASP
Percentage of Patients With High Platelet Reactivity After the Loading Dose of Ticagrelor Assessed With VerifyNow	2 hours	Percentage of Patients With High Platelet Reactivity (HPR) After the Loading Dose of Ticagrelor Assessed With VerifyNow
Time to Reach Platelet Reactivity Below the Cut-off Value for High Platelet Reactivity Evaluated With VerifyNow	12 hours	Time to Reach Platelet Reactivity Below the Cut-off Value for High Platelet Reactivity (HPR) Evaluated With VerifyNow