Deciding about prolonged ticagrelor therapy in coronary clot formers: an ongoing dilemma

This editorial refers to ‘Ischaemic risk and efficacy of ticagrelor in relation to time from P2Y12 inhibitor withdrawal in patients with prior myocardial infarction: insights from PEGASUS-TIMI 54’†, by M.P. Bonaca et al., on page 1133. Platelet reactivity to ADP and thromboxane A2, two key secondary agonists, plays a pivotal role in the occurrence of arterial thrombotic events. This foundation positions the platelet as a ‘nidus of evil’ and is the major rationale for dual signalling pathway blockade with a COX-1 and a P2Y12 receptor inhibitor in high-risk patients.1,2 There is good evidence that the potent P2Y12 receptor inhibitors prasugrel and ticagrelor are more efficient in reducing thrombotic events when administered at the time of an acute coronary syndrome (ACS) and continued for 1 year compared with clopidogrel, but also carry a bleeding risk.3,4 Lingering questions remain about the net utility of more prolonged dual antiplatelet therapy (DAPT). In the DAPT study, 11 648 patients who were treated with aspirin and a thienopyridine for 12 months after successful coronary stenting were then randomly assigned to placebo vs. continuation on DAPT for another 18 months. Thirty-one per cent of patients enrolled were stented for acute myocardial infarction (MI). Prolonged DAPT was associated with a significant reduction in major adverse cardiovascular and cerebrovascular events (MACCE) in those with and without MI, but the treatment effect was more pronounced in the ‘clot formers’, i.e. those with MI (Pinteraction = 0.03). Bleeding was also more pronounced in the group treated with prolonged DAPT, but, perhaps not surprisingly, the absolute occurrences and relative risk of bleeding were numerically lower in the clot formers, suggesting that they have an inherent prothrombotic state.5 Prasugrel therapy (n = 1745, 35%) was associated with 48% reduction in the occurrence of the primary endpoint compared with a 20% reduction with clopidogrel (n = 3725, 65%) in drug-eluting stent (DES)-treated patients. The latter observation lends further support for the ‘platelet hypothesis’—superior platelet inhibition results in a more favourable reduction in ischaemic outcomes.6 Moreover, there was an increased risk of MI (both stent-related and non-stent-related) and stent thrombosis during the first 3 months after discontinuation of P2Y12 inhibitor therapy. The latter observation suggests that heightening of platelet reactivity to ADP plays an important role in these cessation-related ischaemic event occurrences even at 33 months post-stenting for the index event.6