Ticagrelor versus prasugrel for PCI-managed myocardial infarction: the battle of the giants continues

Abstract

Pharmacodynamic data and large phase III clinical trials have clearly established ticagrelor and prasugrel as firstline therapies in acute coronary syndrome (ACS) in preference to clopidogrel, which is unreliable as a platelet inhibitor due to interindividual variability in the efficiency of metabolising this prodrug to its active form. However, debate and controversy continue to surround the choice of ticagrelor versus prasugrel as the preferred oral P2Y12 receptor antagonist (‘P2Y12 inhibitor’) for acute management of patients with myocardial infarction (MI) who are managed with percutaneous coronary intervention (PCI). In this issue of Heart, Venetsanos and colleagues present analyses from the SWEDEHEART (Swedish Websystem for Enhancement and Development of Evidencebased care in Heart disease Evaluated According to Recommended Therapies) registry that compare the clinical outcomes associated with ticagrelor and prasugrel in 37 990 PCImanaged patients with MI. Such observational comparisons are inevitably impeded by the select nature of the prasugreltreated population who tend to be younger and at lower risk than the broader population selected for treatment with ticagrelor in view of regulatory restrictions on the use of the standard regimen of prasugrel. However, SWEDEHEART benefits from a very large population with a high usage of ticagrelor over recent years that allows for a fair adjustment of HRs according to differences between the ticagrelortreated and prasugreltreated populations, as well as the opportunity to perform propensityscore matching analysis. The findings show no difference in major adverse cardiovascular events or bleeding between patients treated with ticagrelor or prasugrel. In many ways, these results are not too surprising as the licensed ticagrelor and prasugrel regimens provide similar levels of platelet inhibition, particularly in the early highrisk phase when potent loading doses are employed that provide almost complete blockade of platelet P2Y12 receptors (table 1). 3 Hopes that ticagrelor may provide additional offtarget benefits, including cardiovascular mortality reduction, through modulation of circulating plasma adenosine levels have not been sustained by the results of phase III trials that followed the highly successful PLATO (PLATelet inhibition and patient Outcomes) study or by some pharmacodynamic studies that failed to confirm a relevant impact of ticagrelor therapy on adenosine metabolism. Ticagrelor’s reversibility of action, compared with the irreversible action of prasugrel, is less of an advantage when patients are only selected for prasugrel therapy following a decision to proceed to PCI, particularly since urgent or emergency coronary artery bypass graft surgery is only required in a tiny proportion of patients undergoing PCI. Despite conflicting studies using different platelet function methodologies, it seems reasonably clear that mean levels of platelet P2Y12 inhibition are slightly greater during longterm maintenance therapy in adherent patients taking ticagrelor compared with prasugrel. This relates to the fact that, first, a prasugrel maintenance dose of 10 mg once a day was chosen over 15 mg once a day to accommodate a lower level of platelet inhibition during maintenance therapy compared with following a 60 mg loading dose and, second, that a reduced prasugrel maintenance dose of 5 mg once a day is recommended in elderly patients regardless of body weight, predisposing to higher platelet reactivity in those with higher body weight (table 1) or less efficient metabolism to the active metabolite. In contrast, licensed regimens of ticagrelor are intended to provide similar levels of platelet inhibition during maintenance therapy as seen after a loading dose (table 1). With improvements in stent design and consequently reduced risks of stent thrombosis, it is possible that this high level of platelet inhibition may now be a disadvantage, in terms of bleeding risk, in lowrisk PCImanaged patients with MI who are also treated with aspirin; on the other hand, this consistently high level of platelet P2Y12 inhibition lends itself to subsequent deescalation to ticagrelor monotherapy. However, the analyses here of Venetsanos et al suggest that relatively subtle differences in platelet inhibition with ticagrelor and prasugrel maintenance therapy have no detectable impact on clinical outcomes in a large observational study, at least when prasugrel is used more selectively in younger patients. The SWEDEHEART results contrast with the results of the ISARREACT-5 (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment-5) trial that showed superior outcomes with a prasugrelbased strategy compared with a ticagrelor ‘pretreatment’ strategy and formed the basis for a controversial European Society of Cardiology class IIa recommendation to consider prasugrel in preference to ticagrelor following PCI for nonSTelevation ACS. 8 The limitations of the ISARREACT-5 trial are explored in detail elsewhere, but the most likely explanations for the superior outcomes in the prasugrel group are (1) worse treatment adherence in patients without diabetes in the ticagrelor group and (2) by chance, numerically fewer noncardiovascular deaths in the prasugrel group. The presumption of worse adherence is based on (1) knowledge of the reliable pharmacodynamic effects of ticagrelor; (2) the known relationship between levels of P2Y12 inhibition and the risk of stent thrombosis, which explained a considerable proportion of the excess of events in the ticagrelor group in ISARREACT-5; and (3) realworld experience of centres that have acquired extensive experience of ticagrelor therapy and its impact on stent thrombosis rates. 10 This speculation is further reinforced by the observed MI rates seen in the current SWEDEHEART analyses that showed no signal of worse rates with ticagrelor. Perhaps important messages from the available research findings are to counsel patients about the critical importance of adherence to treatment following PCI and, when using ticagrelor, to assess tolerance in view of the potential for early development of dyspnoea, meaning inhospital observation for 48 hours after dosing. Although this may be less attractive for centres that can rapidly perform invasive coronary angiograph±PCI Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK Directorate of Cardiology and Cardiothoracic Surgery, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK