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

Abstract

Background: Out-of-hospital cardiac arrest (OHCA) frequently occurs in the early phase of acute myocardial infarction (MI). Survivors require percutaneous coronary intervention (PCI) with concomitant dual antiplatelet therapy. Target temperature management, including mild therapeutic hypothermia (MTH), should be applied in comatose patients after resuscitation. However, an increased risk of stent thrombosis in patients undergoing hypothermia is observed. The aim of this study was to assess the impact of MTH on pharmacokinetics of ticagrelor in cardiac arrest survivors with MI treated with MTH and PCI. Methods: In a prospective, observational, single-center study pharmacokinetics of ticagrelor were evaluated in 41 MI patients, including 11 patients after OHCA undergoing MTH (MTH group) and 30 MI patients without OHCA and MTH (no-MTH group). Blood samples were drawn before administration of a 180 mg ticagrelor loading dose, and 30 min, 1, 2, 4, 6, 12, and 24 h after the loading dose. Results: In patients treated with MTH total exposure to ticagrelor during the first 12 h after the loading dose and maximal plasma concentration of ticagrelor were significantly lower than in the no-MTH group : 3403 ± 2879 vs. 8746 ± 5596 ng·h/mL, difference: 61%, p = 0.01; C max : 475 ± 353 vs. 1568 ± 784 ng/mL, p = 0.0002). Time to achieve maximal ticagrelor plasma concentration was also delayed in the MTH group (t max for ticagrelor: 12 [6-24] vs. 4 [2-12] h, p = 0.01). Conclusions: Bioavailability of ticagrelor was substantially decreased and delayed in MI patients treated with MTH after OHCA. Trial registration: ClinicalTrials.gov Identifier: NCT02611934 (Cardiol J XXXX; XX, X: xx-xx)

Does morphine remain a standard of care in acute myocardial infarction?

“…Additionally, increased sympathetic activation and selective perfusion of vital organs results in delayed stomach emptying, slower intestinal transit, and deferred drug absorption. Interestingly, impaired gastrointestinal absorption is probably also responsible for the delayed antiplatelet effect of potent P2Y 12 inhibitors observed within the first hours of treatment in MI patients managed with mild therapeutic hypothermia, as well as in critically ill patients [16,17].…”

Stratified Approaches to Antiplatelet Therapies Based on Platelet Reactivity Testing

“…Furthermore, the presence of STEMI and diabetes mellitus were found to be associated with impaired metabolism of ticagrelor within first 6 h post ticagrelor loading dose in ACS patients (67). It has been recently published, that bioavailability of ticagrelor in MI patients managed with mild therapeutic hypothermia after out-of-hospital cardiac arrest is significantly decreased, thus increasing the risk of stent thrombosis, a possibly lethal complication, which is not uncommon in this specific subset of patients (68, 69). The main reasons of insufficient antiplatelet effect of the P2Y 12 inhibitors in out-of-hospital cardiac arrest survivors treated with mild therapeutic hypothermia are probably impaired gastrointestinal absorption and altered cytochrome activity causing a delay in drug metabolism (69–71).…”

“…It has been recently published, that bioavailability of ticagrelor in MI patients managed with mild therapeutic hypothermia after out-of-hospital cardiac arrest is significantly decreased, thus increasing the risk of stent thrombosis, a possibly lethal complication, which is not uncommon in this specific subset of patients (68, 69). The main reasons of insufficient antiplatelet effect of the P2Y 12 inhibitors in out-of-hospital cardiac arrest survivors treated with mild therapeutic hypothermia are probably impaired gastrointestinal absorption and altered cytochrome activity causing a delay in drug metabolism (69–71). The temporary use of cangrelor may be a solution to overcome HTPR while oral antiplatelet agents start to work in resuscitated patients undergoing mild therapeutic hypothermia (72).…”

High Platelet Reactivity after Transition from Cangrelor to Ticagrelor in Hypothermic Cardiac Arrest Survivors with ST-Segment Elevation Myocardial Infarction

“…Hypothermia, morphine treatment and hemodynamic compromise, however, may impair oral P2Y12 inhibitor uptake and metabolism, resulting in delayed and insufficient platelet inhibition after coronary stenting [4][5][6][7]. Both cardiac arrest and absence of P2Y12 inhibition are independent risk factors for acute stent thrombosis, a potentially fatal complication following successful PCI [8,9].…”