Platelet Inhibition After Pre-hospital Ticagrelor Using Fentanyl Compared to Morphine in Patients With ST-segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention

Study Overview
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Brief Summary
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Prospective, randomized, open-label, single-center, investigator-initiated trial, including patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI) within 12 hours of the symptom's onset. The study aims to compare platelet inhibition (pharmacodynamics and pharmacokinetics) of pre-hospital Ticagrelor in patients with STEMI according to two different analgesia protocols using Fentanyl or Morphine.

Detailed Description
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Consecutive patients with acute STEMI within 12 hours of the symptoms' onset and candidates for PPCI will be screened for inclusion in the study. Eligible patients who require analgesia for the relief of acute chest pain, defined as Visual Analogue Scale ≥3, will be randomized in a 1:1 ratio into one of the two treatment arms to receive analgesia with either Morphine or Fentanyl following administration of a pre-hospital loading dose of Ticagrelor. Randomized patients will undergo primary PCI and managed according to the current guidelines of the European Society of Cardiology. Blood samples (10 ml) will be collected at 0, 1, 2, 4, 6, 12 and 24 hours after the loading dose of Ticagrelor to assess platelet inhibition using the VerifyNow P2Y12 function and the Vasodilator-Stimulated-phosphoprotein Phosphorylation (VASP) assays, plasma concentration of Ticagrelor and its active metabolite (AR-C124910XX) using a validated liquid chromatography/mass spectrometry detection method and the procoagulant action of platelets.

Official Title
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Comparison of Analgesia With Fentanyl and Morphine on Platelet Inhibition After Pre-hospital Ticagrelor Administration in Patients With ST-segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention

Conditions
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Acute Myocardial Infarction

Intervention / Treatment
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* Drug: Fentanyl
* Drug: Morphine
* Drug: Ticagrelor
* Drug: Aspirin
* Drug: Unfractioned Heparin
* Procedure: Primary PCI


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >18-year-old STEMI within 12 hours of symptoms' onset eligible for primary PCI with stent implantation. Patient able to give written informed consent. Exclusion Criteria: Contraindication, intolerance or hypersensitivity to Ticagrelor, or any excipients Contraindication, intolerance or hypersensitivity to Morphine, Fentanyl, or any excipients Active bleeding or bleeding diathesis History of intracranial haemorrhage Chronic oral anticoagulation treatment Previous antiplatelet treatment Contraindications to antiplatelet therapy Severe renal insufficiency (creatinine clearance <30 mL/min) Severe hepatic dysfunction Severe chronic obstructive pulmonary disease Periprocedural glycoprotein IIb/IIIa inhibitors administration Relevant haematological disease Patient who is currently, plans, or has been enrolled in another clinical study involving use of an investigational drug or device within the prior 30 days. If female, patient pregnant or breastfeeding.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Morphine<br>Pre-hospital Ticagrelor 180 mg loading dose orally. Morphine, initial dose: 4-8 mg, additional doses of 2 mg every 5-15 minutes to achieve adequate sedation, if required. Aspirin 500 mg loading dose orally (or intravenously). Unfractioned heparin 5'000 IU loading dose intravenously, additional doses to achieve an ACT >250 sec during PCI are allowed. Primary PCI. | Drug: Morphine<br>* Analgesia protocol using Morphine (initial dose: 4-8 mg, additional doses of 2 mg every 5-15 minutes to achieve adequate sedation, if required).<br>Drug: Ticagrelor<br>* Pre-hospital Ticagrelor loading dose of 180 mg administered orally, followed by 90 mg bid<br>* Other names: Brilique;Drug: Aspirin<br>* 500 mg loading dose orally (or intravenously), followed by 100 mg od<br>Drug: Unfractioned Heparin<br>* 5'000 IU loading dose intravenously, additional doses to achieve an ACT >250 sec during PCI are allowed.<br>Procedure: Primary PCI<br>* Primary PCI with stent implantation according to the guidelines of the European Society of Cardiology.<br>|
| Experimental: Fentanyl<br>Pre-hospital Ticagrelor 180 mg loading dose orally. Fentanyl, initial dose: 50-100 mcg, additional doses of 25 mcg every 2-5 minutes to achieve adequate sedation, if required. Aspirin 500 mg loading dose orally (or intravenously). Unfractioned heparin 5'000 IU loading dose intravenously, additional doses to achieve an ACT >250 sec during PCI are allowed. Primary PCI. | Drug: Fentanyl<br>* Analgesia protocol using Fentanyl (initial dose: 50-100 mcg, additional doses of 25 mcg every 2-5 minutes to achieve adequate sedation, if required).<br>Drug: Ticagrelor<br>* Pre-hospital Ticagrelor loading dose of 180 mg administered orally, followed by 90 mg bid<br>* Other names: Brilique;Drug: Aspirin<br>* 500 mg loading dose orally (or intravenously), followed by 100 mg od<br>Drug: Unfractioned Heparin<br>* 5'000 IU loading dose intravenously, additional doses to achieve an ACT >250 sec during PCI are allowed.<br>Procedure: Primary PCI<br>* Primary PCI with stent implantation according to the guidelines of the European Society of Cardiology.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Residual platelet reactivity (PR) by Platelet Reactivity Units (PRU) |  | 2 hours after loading dose of Ticagrelor | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Residual PR by PRU |  | 0, 1, 4, 6, 12 and 24 hours after the loading dose of Ticagrelor | 
| High on Treatment Platelet Reactivity (HTPR) rates |  | 0, 1, 2, 4, 6, 12 and 24 hours after the loading dose of Ticagrelor | 
| Peak plasma concentration (Cmax) of Ticagrelor and AR-C124910XX |  | at 1, 2, 4, 6 and 12 hours | 
| Time to peak plasma concentration (tmax) of Ticagrelor and AR-C124910XX |  | at 1, 2, 4, 6 and 12 hours | 
| Area under the plasma concentration-time curve of Ticagrelor |  | at 1, 2, 4, 6 and 12 hours | 
| Proportion of patients with 70% or greater resolution of the ST-segment elevation before PCI |  | at 2 hours | 
| Proportion of patients without Thrombolysis in Myocardial Infarction flow grade 3 in the infarct-related artery at initial angiography |  | at 2 hours |