Platelet reactivity during mild therapeutic hypothermia in patients with acute myocardial infarction treated with ticagrelor: study protocol of a single-centre study

Abstract

In summary, the available data on the antiplatelet efficacy of P2Y12 receptor inhibitors suggest their less potent and/or delayed effect in patients undergoing mild therapeutic hypothermia (MTH). However, previous studies do not explain the mechanisms of the impact of MTH on platelet function. Moreover, there is a lack of evidence of any relationship between the increased prevalence of thrombotic complications in MTH patients and the anti-platelet effect of P2Y12 receptor inhibitors.We hypothesise that MTH may interfere with the absorption of ticagrelor and consequently results in significant changes in the pharmacokinetic and pharmacodynamic profile of this P2Y12 receptor inhibitor.It cannot be ruled out that the high initial level of platelet activation in MTH patients may additionally modify the pharmacodynamics of ticagrelor. Malabsorption may slow down the desired antiplatelet effect, while high levels of platelet activation may reduce the antiplatelet effect of ticagrelor.The aim of this study is to verify whether the use of MTH after resuscitation in out-of-hospital cardiac arrest (OHCA) patients with STEMI (ST-segment elevation myocardial infarction) treated with primary percutaneous coronary intervention (pPCI), affects the anti-platelet effect of ticagrelor. Moreover, we attempt to elucidate the mechanisms of impaired effect of ticagrelor in MTH patients based on pharmacodynamic and pharmacokinetic measurements.To achieve the aim of the study, we planned the following: 1) comparison of the pharmacokinetic and pharmacodynamic results obtained from the study population (MTH + pPCI + ticagrelor) with results obtained from a demographically and clinically comparable population of patients with STEMI treated with primary PCI and receiving ticagrelor (pPCI + ticagrelor); and 2) analysis of the pharmacodynamic results in relation to the pharmacokinetic measurements in the target population.Understanding the mechanisms standing behind the impact of MTH on the efficacy of platelet inhibition with P2Y12 inhibitors is pivotal in reducing the risk of thrombotic complications. The study is expected to provide information leading to improvement of the safety of MTH in STEMI patients with OHCA treated with pPCI and receiving ticagrelor.

Impact of mild therapeutic hypothermia on bioavailability of ticagrelor in patients with acute myocardial infarction after out-of-hospital cardiac arrest

“…The maximal plasma concentration of ticagrelor was lower in MTH group vs. no-MTH group (C max for ticagrelor: 475 ± 353 vs. 1568 ± 784 ng/mL, p = 0.0002), whereas there were no differences in maximal concentration of the metabolite between the groups (C max for AR-C124910XX: 203 ± 121 vs. 337 ± 186 ng/mL; p = 0.1). Time to achieve maximal plasma concentrations was delayed for both ticagrelor and AR-C124910XX in MTH group vs. no-MTH group (t max for ticagrelor: 12 [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] vs. 4 [2][3][4][5][6][7][8][9][10][11][12] h, p = 0.01; t max for AR-C124910XX: 18 [12][13][14][15][16][17][18][19][20][21][22][23][24] vs. 4 [4][5][6]…”

“…The study was designed and performed as a phase IV, single-center, investigator-initiated, prospective, observational trial aimed to compare pharmacokinetics of ticagrelor between MI patients after OHCA treated with primary PCI and MTH (MTH group) and MI patients without OHCA treated with primary PCI (no-MTH group). The inclusion as well as exclusion criteria for both groups have been previously published [21].…”

“…In order to reach the target temperature and maintain it over subsequent 24 h, intravascular cooling supported by cold saline (4°C) infusion and external cooling at the induction phase of MTH were used. The MTH procedure applied in this study has also been previously described [21].…”

“…This effect is even more pronounced with concomitant morphine administration [13][14][15][16][17][18][19]. In survivors of OHCA due to MI additional factors including mild therapeutic hypothermia (MTH) may further impede ticagrelor's bioavailability [20][21][22]. The decreased antiplatelet effect of ticagrelor caused by hindered pharmacokinetics might be responsible for an increased risk of stent thrombosis in resuscitated patients undergoing MTH despite DAPT [23,24].…”

“…Thus, the present study was designed [21] and performed using a prospective observational approach to assess pharmacokinetics of ticagrelor in MI patients after OHCA treated with primary PCI and MTH.…”