Pre-treatment with a P2Y12 antagonist before PCI in STEMI: why should we wait?

This editorial refers to ‘Pretreatment with P2Y12 receptor antagonists in ST-elevation myocardial infarction: a report from the Swedish Coronary Angiography and Angioplasty Registry’†, by B. Redfors et al., on page 1202. Over the last decade, the timing of administration of a P2Y12 antagonist relative to percutaneous coronary intervention (PCI) has been debated.1–5 In ST-segment elevation myocardial infarction (STEMI) patients triaged to PCI, the guidelines recommend early administration of oral antiplatelet agents, which seems to have little downside and has theoretical benefits related to the need for absorption, and, for some, metabolism, of a prodrug in order to achieve effective platelet inhibition. The only randomized trial in this context was the ATLANTIC trial6 which compared pre-hospital vs. in-catheterization laboratory administration of ticagrelor and found no difference in either of its two co-primary endpoints of TIMI flow in the infarct-related artery and ST-segment resolution on the ECG. Of note, the ATLANTIC trial did find a, statistically significant, large relative reduction in the secondary endpoint of stent thrombosis, a dreaded complication of urgent PCI. There was no apparent downside from early administration and, therefore, both European and American guidelines recommend pre-treatment among STEMI patients prior to primary PCI.7 , 8 In the present issue of the European Heart Journal, Redfors et al. present an analysis of a large observational cohort from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR), a nationwide multicentre prospective registry, among patients referred for primary PCI in the setting of STEMI between 2005 and 2016.9 Patients who received pre-hospital treatment with oral P2Y12 receptor antagonists at the time of first medical contact were compared with those who did not and only received it at the time of PCI. In their analysis, the overwhelming majority of the 44 804 patients (85%) received a pre-hospital loading dose of various P2Y12 receptor antagonists such as clopidogrel (58%), ticagrelor (35%), or prasugrel (5.3%). The authors, using propensity score adjustment, did not find a statistically significant association between pre-hospital treatment and lower in-hospital mortality, improved infarct artery patency, lower stent thrombosis, or higher bleeding rates. The observational data provided by this analysis are therefore more neutral than the conclusions of the ATLANTIC randomized controlled trial. The strength of such an analysis pertains mainly to the size of the cohort with multiple, precise data collection and a low rate of missing data with respect to ‘hard’ outcomes such as mortality. The credit goes to the Swedish system of comprehensive population-based registries, among which the SCAAR has already provided high quality data10 , 11 and is able to address issues that would otherwise require prohibitive resources. However, the interpretation of this observational analysis should be cautious. First of all, the fact that the overwhelming majority of patients received antiplatelet therapy at the time of first medical contact suggests that the subset who did not are a ‘special’ group, very different from most routine patients. While the authors attempted to minimize confounding by using propensity score adjustment, they cannot rule out residual confounding. Secondly, pre-treatment studies are comparing a given drug with itself, with only a slightly different timing. Therefore, the differences in outcome are expected to be modest, and the impact on mortality minimal. In the present analysis, outcomes are provided with confidence intervals ranging from very real benefit to harm, and cannot rule out a genuine benefit of pre-treatment (absence of significant evidence of a difference is not proof of absence of a difference). The time difference in antiplatelet therapy administration between the groups (which is of critical importance since it presumably reflects the hypothesis tested) is missing. In the ATLANTIC trial,6 in the setting of a closely controlled study testing only ticagrelor, the median time difference was only 31 min and some have pointed out10 that such a small difference in delay, when compared with time required for optimal drug absorption, may have skewed the results towards the null. This is a particular concern given that a large proportion of the patients received clopidogrel, a drug with a very slow onset of action, particularly when absorption or metabolism is slowed by the acute setting and by the frequent use of morphine,11 , 12 and given that doses of clopidogrel used for loading are not provided. Overall, the analysis performed by Redfors et al. does not allow definitive conclusions regarding the optimal timing of P2Y12 blockade in the setting of primary PCI. The potential for a reduced rate of stent thrombosis with early administration (suggested in the ATLANTIC trial) remains to be confirmed.6 Given the catastrophic outcome of stent thrombosis, this is of critical interest.13 , 14 Patients with a substantial delay between first medical contact and PCI are likely to be those in which there might be benefit of an early loading dose. Fundamentally, the question of providing rapid antiplatelet therapy at the time of stent implantation in acute coronary syndrome (ACS) remains unanswered. Given our current knowledge regarding the pharmacokinetic and pathophysiological relationships in this setting for clopidogrel, prasugrel, and ticagrelor,15 optimal platelet inhibition at the time of stent implantation in primary PCI for STEMI may require more than early administration of oral agents (Take home figure). Apart from earlier administration, this could be achieved by improving absorption using measures such as crushing ticagrelor16 or by using intravenous agents providing immediate efficacy such as glycoprotein IIb/IIIa inhibitors17 (but with a substantial increase in the risk of bleeding) or cangrelor, which provides immediate and reversible P2Y12 blockade. A trial is ongoing (the CANTIC trial, NCT03247738) comparing ‘crushed’ ticagrelor with intravenous cangrelor in this setting. Overview of the critical aspects of pre-treatment before PCI according to the different antiplatelet drugs. The CHAMPION trial, using cangrelor, found clinical benefit in a broad spectrum of patients undergoing PCI,18 with a reduction in the composite outcome of death, myocardial infarction, ischaemia-driven revascularization, or stent thrombosis, and without an increase in risk of severe GUSTO bleeding. Of note, both in CHAMPION PHOENIX and in a meta-analysis of all cangrelor trials in PCI,19 clinical benefit was consistent in both ACS and non-ACS patients,20 and specifically in STEMI patients. However, the use of cangrelor is still piecemeal, varying from country to country, and is influenced by cost and availability of the drug. Finally, given the strong pharmacokinetic and pathophysiological rationale, the lack of a downside of oral early treatment with P2Y12 antagonists with no added cost (the same drug used for early vs. in-catheterization laboratory loading) and no safety concern, in an era of dominant radial arterial access and in a patient subset in which the risk of emergency surgery is extremely low, the fundamental question may be ‘why should we wait?’ Conflict of interest: J.