The data presented indicate that (1) aspirin-mediated inhibition declines significantly within the first days after resuscitation. (2) Aspirin-mediated inhibition is reduced in CPR patients compared to control on day 3. (3) P2Y12-mediated platelet inhibition by ticagrelor and prasugrel is reduced in resuscitated patients. (4) The effect is transient and also most pronounced on day 3.
Previous research focussed on P2Y12-mediated platelet inhibition in resuscitated patients with therapeutic hypothermia and most studies revealed reduced or blunted effects of these drugs in this setting, indicating a potentially increased risk of acute stent thrombosis. Aspirin-mediated platelet inhibition, however, was neglected despite the fact that aspirin is the ubiquitous cornerstone of dual platelet inhibition in ACS. We therefore focussed on analysing aspirin-mediated platelet function inhibition in this prospectively recruited cohort.
Data on the prevalence of high on-aspirin platelet reactivity (HPR) are highly heterogeneous ranging from 0 to 57% . This is due to the variety of laboratory methods and cut-off values used, cohorts of different diseases analysed and the time point of analysis within the trials. We used light transmission aggregometry (LTA) the gold standard method to monitor platelet function inhibition .
Aspirin response is judged on collagen and arachidonic acid stimulation and P2Y receptor inhibition on ADP stimulation, respectively. Other frequently used platelet function tests such as PFA-100 are influenced by platelet count and circulating von Willenbrandt factor (vWF), and hypothermia itself reduces platelet count and increases vWF expression. PFA-100 values rather reflect vWF activity than platelet function  and were therefore not used for our analysis.
HPR was target in many studies ranging from healthy volunteers  to disease specific cohorts with cardiovascular  or hematologic  diseases and to large all-comers “real world” cohorts . However, there is only one recent study describing aspirin-mediated platelet inhibition in resuscitated patients and therapeutic hypothermia . This trial prospectively tested for differences between oral or intravenous administration of aspirin in CPR survivors treated with therapeutic hypothermia of 33 °C for 24 h using surface cooling. Intravenous aspirin was more likely to result in therapeutic platelet inhibition on day three compared to oral aspirin.
Four reasons might underlie the blunted inhibitory effect of aspirin. First, crushing tablets before administration via the gastric line might impair their effects. Second, gastric paresis and reduced gastric and intestinal perfusion due to reduced cardiac output and centralized circulation might reduce or delay effects. Third, hypothermia itself impacts platelet inhibition. Fourth, resuscitation with consecutive inflammation might directly affect platelet reactivity.
Although usually administered as coated tablets, the used aspirin formula (Thrombo-ASS; G.L. Pharma, Lannach, Austria) is supposed to be chewed in myocardial infarction anyway and aspirin is known to maintain platelet function inhibiting effects after being crushed. However, gastroparesis is a ubiquitous finding in resuscitated patients within the first hours and days after resuscitation and neuroprotective hypothermia in resuscitated patients also requires relaxation und most of the patients have poor hemodynamics even after successful percutaneous intervention. These general features might blunt reabsorption of any orally administrated drug, reduced absorption of orally administered drugs is common in sedated patients, and this effect is further aggravated by therapeutic hypothermia .
Only emerging evidence is available that resuscitation itself or corresponding hypoxia directly affects platelet function. Recently, it has been shown that cardiac arrest for several minutes and following resuscitation did significantly increase platelet mitochondrial bioenergetics within 4 h in a porcine model  which would improve platelet activation and coagulation. On the other hand, lactate acidosis has been shown to impair platelet function in another pig model . This finding might explain the negative correlation of lactate and SOFA score with collagen AUC, indicating stronger aspirin-mediated inhibition despite potentially reduced gastrointestinal absorption.
Impaired platelet inhibition might also be due to accelerated platelet turnover which has been described previously in states of inflammation . The latter mechanism was also considered to be the most relevant in the small cohort of the study published by Llitjos et al. .
Besides impaired aspirin effects, our study also indicates a moderate effect on platelet inhibition by P2Y12 inhibitors, which is, however, only detectable for ticagrelor and prasugrel.
The question on potentially reduced inhibitory effects of crushed oral P2Y12 inhibitors is answered in three well conducted trials for each of the drugs [20,21,22]. These trials indicate no reduction or delay in platelet inhibition after crushing tablets but rather show an accelerated and increased mode of action.
Absorption of P2Y12 inhibitors is likely to be impaired in a setting of therapeutic hypothermia and centralized circulation. This idea is supported by a recent study directly measuring clopidogrel plasma levels in previously P2Y12-inhibitor-naïve resuscitated patients with myocardial infarction treated with therapeutic hypothermia. In this study, a significantly reduced plasma concentration for clopidogrel was detected 2 and 4 h after administration .
It has already been shown that cardiogenic shock itself is associated with a high prevalence of clopidogrel resistance . Hypothermia itself reduces P450 clearance by 7–22% per degree Celsius . Hence, reduction in body core temperature by ~ 4 °C impairs this system considerably.
Besides altered metabolism hypothermia might also influence cellular drug response affecting the potency of drugs. So far, no direct data are available with respect to P2Y12 inhibitors. However, it has been shown in vitro that impaired effect was only observed for clopidogrel but not for aspirin in an in vitro hypothermia model indicating drug and not cell specific reasons for the reduced effect .
In contrast to a previous report , the present study did not show blunted effects in clopidogrel treated post-CPR patients compared to control but reduced effect in both groups if compared to treatment with either ticagrelor or prasugrel. This is in line with a recent analysis of the IABP shock trial; there was no significant interaction regarding mortality (p = 0.06) between the use of mild hypothermia and the type of P2Y12 inhibitor used if prasugrel/ticagrelor was tested versus clopidogrel” . In addition, it is important to note that platelet inhibition was weakest on day three although patients already reached normal body core temperature, supporting the hypothesis that not hypothermia but delayed or reduced absorption due to cardiogenic shock or temperature independent mechanisms underlie the reduced P2Y12-mediated platelet inhibition.
Except the described changes in P450 clearance, all these aspects would also influence aspirin-mediated platelet inhibition. Our data indicate that this aspect of platelet inhibition might be clinically even more important than the observed slight reduction in P2Y12-mediated inhibition which still remained within the therapeutic range in all patients, especially if the newer drugs (prasugrel, ticagrelor) were used.
Despite these data, retrospective analysis of larger cohorts failed to detect a significant increase in stent thrombosis in resuscitated patients treated with therapeutic hypothermia compared to regular ACS patients although percentages were increased in patients treated with hypothermia [29, 30].
In aspirin-mediated platelet inhibition, a different pattern was observed. On day 1, good and sufficient inhibition was detected in all patients. These values, however, are independent of gastrotintestinal absorption as all patients were initially treated intravenously by the emergency team or in the cath lab. All further applications were with crushed tablets via the gastric line, and reduced inhibitory effect could therefore either be due to lower maintenance dose [100 mg vs. initial dose 250 mg (150–300)] or rather malabsorption after gastric application. Therefore, prolonged intravenous application of aspirin might be recommended.