Impact of Mild Therapeutic Hypothermia on Platelet Inhibition in Acute Coronary Syndrome

Background: Mild therapeutic hypothermia (MTH) improves outcome for patients with acute coronary syndrome (ACS) after cardiac arrest (CA). Previous data point to an interaction between hypothermia and drug metabolism, thus potentially impacting on platelet function under antiplatelet therapy. Purpose: The aim of the study is to determine clopidogrel metabolism and platelet function in clopidogrel naïve ACS patients treated with mild hypothermia (33°C, n=12) compared with ACS patients (troponin positive) with normal body temperature (n=14). Methods: Platelet function was measured by light transmittance aggregometry (LTA), multiple electrode platelet aggregometry (MEA) and VASP phosphorylation analysis before, 2h, 4h and 24h after administration of a 600 mg clopidogrel loading dose. Furthermore, plasma concentrations of clopidogrel, the active thiol metabolite and the inactive carboxyl metabolite were determined. All patients were screened for CYP2C19*2 polymorphism and scheduled for PCI. Mild hypothermia was carried out according to current guidelines for 24 hours at a target temperature of 33°C. Results: Plasma concentration of clopidogrel and metabolites were lower in the MTH group after 2h and 4h, respectively (all p<0.005). All platelet function tests showed an attenuated response to clopidogrel with respect to baseline platelet activity in the MTH group. This was significant for VASP analysis and LTA (p<0.05). Moreover, there was no difference in genotype and platelet function determined ex vivo with 33°C and 37°C, respectively. Conclusion: Inhibition of platelet function is decreased under MTH, presumably due to a diminished clopidogrel absorption and metabolization. Thus, these patients might have a higher risk for cardiovascular events despite antiplatelet therapy.