Drug: morphine chlorhydrate Drug: saline solution. Phase 3. Study Type :. Interventional Clinical Trial. Actual Enrollment :. Study Start Date :. Actual Primary Completion Date :. Actual Study Completion Date :. Experimental: Morphine chlorhydrate Intracoronary injection of morphine chlorhydrate during reperfusion. Drug: morphine chlorhydrate 1mg of morphine chlorhydrate dilute in 3ml of saline solution, intracoronary injection, just before reperfusion Other Name: Morphine Chlorhydrate Lavoisier.
Placebo Comparator: Saline solution Intracoronary injection of saline solution during reperfusion. Drug: saline solution 3 ml of saline solution , intracoronary injection during reperfusion. Unfortunately, these adverse effects are unsubstantiated by prospective, randomized outcomes trials.
Although further research is needed, study design will be difficult to structure because of ethical limitations associated with placebo-controlled randomization. The study authors summarized alternatives to morphine, including acetaminophen for pain measuring less than 7 on a visual analogue scale; alfentanil, which has some limitations; and drugs in the naloxone, naloxagol, and methylnaltrexone family.
The researchers concluded that morphine remains a valuable agent when nitrates, beta-blockers, and expedited reperfusion fail to relieve pain. Benefits of Morphine for Myocardial Infarction Treatment. June 23, Cardiovascular pharmacology: a look back and a glimpse into the future. Eur Heart J Cardiovasc Pharmacother ; 1 : 7 — 9. Hammer A. Ein Fall von thrombotischem Verschluss einer der Kranzarterien des Herzens. Wiener Med Wochenschr 28 : Atar D.
Should oxygen be given in myocardial infarction? BMJ ; : c Oxygen therapy in acute coronary syndrome: are the benefits worth the risk? Eur Heart J ; 34 : — Shuvy M Lotan C. Oxygen therapy in myocardial infarction? Still waiting for an answer. Cardiology ; : 68 — N Engl J Med ; : — Morphine decreases clopidogrel concentrations and effects: a randomized, double-blind, placebo-controlled trial.
J Am Coll Cardiol ; 63 : — Morphine is associated with a delayed activity of oral antiplatelet agents in patients with ST-elevation acute myocardial infarction undergoing primary percutaneous coronary intervention. Circ Cardiovasc Interv ; 81 : e Emerg Med J ; 25 : — Use of intravenous morphine for acute decompensated heart failure in patients with and without acute coronary syndromes. Acute Card Care ; 13 : 76 — Parodi G.
Importantly, both the safety and efficacy of morphine have never been tested in randomized trials in the ACS setting, while a large, retrospective analysis of the CRUSADE registry suggests that morphine administration may be associated with increased mortality in patients with non-ST-segment elevation ACS [ 8 ]. Some of the previously listed side effects of morphine could affect the intestinal absorption and thus the pharmacokinetics PK and pharmacodynamics PD of orally administered drugs which are concomitantly used with morphine.
Note that currently all commercially available P2Y12 blockers are oral agents. In concordance with those facts, it was observed that morphine lags clopidogrel absorption, decreases plasma levels of clopidogrel and its active metabolite, and delays and diminishes antiplatelet effects of this thienopyridine, although this was observed in a group of healthy volunteers [ 9 ]. Moreover, Parodi et al.
However, a definitive evidence of a possible interaction between morphine and the novel P2Y12 receptor antagonists may be obtained only in randomized studies. The secondary objective of this study is to determine whether intravenous administration of morphine prior to ticagrelor administration in AMI patients attenuates the antiplatelet effects of ticagrelor.
Additionally, a predefined subanalysis has been planned to investigate which of the platelet reactivity assessment methods utilized in the study best reflects concentration of ticagrelor and its active metabolite. After admission to the study center Cardiology Clinic, Dr.
The inclusion and exclusion criteria are as listed in Table 1. Eligible patients will be randomly assigned in a ratio to one of two study arms. The patients in the intervention arm will receive 5 mg of morphine intravenously IV followed by a mg loading dose of ticagrelor, whereas patients in the control arm will obtain 5 mg of a placebo IV followed by a mg loading dose of ticagrelor Figure 1.
Subsequently all patients will undergo a coronary angiography followed by percutaneous coronary intervention PCI , if necessary.
Blood samples for PK and PD assessment will be drawn at eight predefined time points during the first 12 hours after randomization, according to the blood sampling schedule as presented in Figure 2. Each patient will provide a written informed consent to participate in the study. Blood plasma concentrations of ticagrelor and AR-CXX will be evaluated using liquid chromatography mass spectrometry in samples obtained in eight predefined time points Figure 2.
A platelet vasodilator-stimulated phosphoprotein VASP assay will be applied to all study participants at all predefined time points Figure 2. Details regarding methods to be used for the assessment of platelet reactivity were previously described [ 11 - 14 ]. During their participation in the study, all patients will be treated according to the current ESC guidelines.
Interventional cardiologists will be encouraged to use manual thrombectomy in case of visible thrombus. The choice of the access of the coronary invasive procedure radial or femoral and the type of implanted stent drug-eluting stent [DES] or bare metal stent [BMS] will be at the discretion of the operator, although high rates of radial access and DES implantation are expected to occur.
From the loading dose of ticagrelor until completion of the study, all patients will receive maintenance doses of ticagrelor 90 mg twice daily. In addition, standard therapy will include aspirin 75 to mg daily , beta blockers, statins, and angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, if not contraindicated.
The primary endpoint of this trial is the area under the plasma concentration-time curve AUC 0—12 for ticagrelor for the first 12 hours after the loading dose of ticagrelor. Since there is no reference study examining the PK of ticagrelor in patients presenting with STEMI or NSTEMI, we decided to perform an internal pilot study of approximately 30 patients 15 patients for each arm to estimate the final sample size.
Based on these results and assuming a two-sided alpha value of 0. Proportions will be compared by the Fisher exact test or chi-square test when appropriate. Pharmacokinetic calculations will be performed using a dedicated software. Furthermore, the study could specify the suspected connection between alterations in ticagrelor absorption and modification of its antiplatelet activity.
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