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

NCT ID: NCT02217878

Last Updated: 2017-09-12

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 74 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-08-31
• Study Completion Date: 2015-06-30

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.

Conditions

ST-segment Elevation Myocardial Infarction; Non-ST-segment Elevation Myocardial Infarction; VA Drug Interactions

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Morphine

morphine sulfate 5 mg IV followed by 180 mg loading dose of ticagrelor

Group Type: ACTIVE_COMPARATOR

Morphine

Intervention Type: DRUG

IV bolus injection

Ticagrelor

Intervention Type: DRUG

180 mg loading dose

Placebo

sodium chloride 0,9% 5 mg IV followed by 180 mg loading dose of ticagrelor

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

IV bolus injection

Ticagrelor

Intervention Type: DRUG

180 mg loading dose

Interventions

Morphine

IV bolus injection

Intervention Type: DRUG

Placebo

IV bolus injection

Intervention Type: DRUG

Ticagrelor

180 mg loading dose

Intervention Type: DRUG

Other Intervention Names

Morphine sulfate; Sodium chloride 0,9%; Brilique

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Collegium Medicum w Bydgoszczy

OTHER

Sponsor Role: lead

Responsible Party

Jacek Kubica

Prof. dr hab.

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Prof. Jacek Kubica, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Collegium Medicum im. Ludwika Rydygiera w Bydgoszczy, Uniwersytet Mikołaja Kopernika w Toruniu

Locations

Cardiology Department, Dr. A. Jurasz University Hospital

Bydgoszcz, Kuyavian-Pomeranian Voivodeship, Poland

Countries

Poland

References

Kubica J, Adamski P, Ostrowska M, Sikora J, Kubica JM, Sroka WD, Stankowska K, Buszko K, Navarese EP, Jilma B, Siller-Matula JM, Marszall MP, Rosc D, Kozinski M. Morphine delays and attenuates ticagrelor exposure and action in patients with myocardial infarction: the randomized, double-blind, placebo-controlled IMPRESSION trial. Eur Heart J. 2016 Jan 14;37(3):245-52. doi: 10.1093/eurheartj/ehv547. Epub 2015 Oct 21.

Reference Type: DERIVED

PMID: 26491112 (View on PubMed)

Kubica J, Adamski P, Ostrowska M, Kozinski M, Obonska K, Laskowska E, Obonska E, Grzesk G, Winiarski P, Paciorek P. Influence of Morphine on Pharmacokinetics and Pharmacodynamics of Ticagrelor in Patients with Acute Myocardial Infarction (IMPRESSION): study protocol for a randomized controlled trial. Trials. 2015 Apr 29;16:198. doi: 10.1186/s13063-015-0724-z.

Reference Type: DERIVED

PMID: 25925591 (View on PubMed)

Other Identifiers

CMUMK202

Identifier Type: -

Identifier Source: org_study_id