Discussion
In this prespecified analysis from the EUROMAX trial, we observed that use of the newer oral P2Y12 inhibitors, prasugrel or ticagrelor, was not associated with a lower rate of acute stent thrombosis or 30-day ischaemic outcomes as compared with the use of clopidogrel.
Rapid and potent platelet inhibition is key in order to reduce the risk of ischaemic complications in patients with STEMI. As a consequence, current guidelines recommend the early use of P2Y12 inhibitors.16 17 However, whereas the European Society of Cardiology guidelines16 recommend using prasugrel or ticagrelor over clopidogrel, the American College of Cardiology/American Heart Association guidelines17 stipulate the same level of recommendation for all three.
The absence of a difference in the rate of acute stent thrombosis according to the oral P2Y12 inhibitor used for the loading dose in our analysis is consistent with the existing literature. In the PLATO trial, the rate of acute stent thrombosis was not significantly different in patients on ticagrelor versus those on clopidogrel.5 In the ATLANTIC trial, prehospital administration of ticagrelor did not improve pre-PCI coronary reperfusion. However, the rates of definite stent thrombosis were lower in the prehospital group, which can be interpreted as indicating that earlier administration may counteract a delayed onset of action of this agent in patients with STEMI18 as the action of P2Y12 inhibitors is delayed due to a slower gastrointestinal absorption compared with that in healthy controls.7–10 This delay may be due to several factors, including the action of morphine or morphine derivatives, which are frequently used prehospital or intrahospital to relieve pain in patients with STEMI10 18 19 and haemodynamic dysfunction in patients with shock or preshock.20
The lack of a difference in 30-day outcomes according to the P2Y12 inhibitor used as maintenance treatment in our study appears somewhat at variance with the results of the TRITON and PLATO trials, both of which demonstrated a significant reduction in the rate of ischaemic events in the overall population as well as in the group with STEMI.1 2 However, the present analysis is underpowered since EUROMAX was much a smaller trial than TRITON or PLATO, and we analysed 30 day rather than 1-year outcomes.
As detailed in figure 1, a substantial proportion of patients had a switch of P2Y12 inhibitor between loading and maintenance doses. This is probably because the loading dose was administered in a prehospital setting for most patients, while the maintenance dose was given in hospital. Hospital and prehospital antiplatelet protocols might differ as they are usually managed by different teams. This might be a confounding factor when analysing 30-day outcomes.
The use of bivalirudin for pPCI has been associated with an increase in the risk of acute stent thrombosis.11 12 In the HEAT-PPCI trial, despite the fact that newer oral P2Y12 inhibitors were used in >90% of cases, an increase in both early stent thrombosis and other ischaemic events was observed.21 Those results are consistent with our observations. The mechanism of bivalirudin-associated acute stent thrombosis is probably associated with a rapid clearance of the drug after discontinuation of the drug, resulting in an insufficient thrombin inhibition in the first hours following stent implantation and prior to the effectiveness of oral antiplatelet agents. Therefore, there is a ‘gap’ in antithrombotic protection.8 9 22 Whether this risk could be addressed by an intravenous antiplatelet agent with faster onset of action, for example, cangrelor, remains to be demonstrated.23–25 In contrast, several analyses tend to demonstrate that potent post-PCI thrombin inhibition decreases the risk of acute stent thrombosis. In the BRIGHT trial,26 in a subgroup analysis from EUROMAX27 and in an exploratory analysis of the MATRIX trial,28patients who received a prolonged infusion of bivalirudin at the full dose of 1.75 mg/kg/hour after PCI had no excess risk of acute stent thrombosis.
Limitations
These data were derived from a prespecified analysis of postrandomisation data. Thus, the decision to use clopidogrel or one of the newer P2Y12 inhibitors was left to the discretion of the investigators and confounding cannot be excluded. In addition, there were major differences in the geographical distribution and the baseline clinical characteristics as a function of the agent used, some of which can affect the risk of ischaemic or bleeding complications. Even if we performed multivariable adjustments, our results may be partially due to residual confounding. The low number of events and the large CI observed in the comparison of stent thrombosis between the two groups makes a statistical type 2 error possible. This result should therefore be interpreted with caution. The fact that most patients received pretreatment with P2Y12 inhibitors might have attenuated differences in platelet inhibition between the two groups. However, precise information on the timing of the administration of the loading dose is not available. The relatively low numbers of patients receiving each of the two newer P2Y12 agents and low number of stent thromboses prevent a sound comparison between prasugrel and ticagrelor. This comparison is currently being done in a randomised trial (ISAR-REACT 5 trial NCT01944800). Finally, EUROMAX was an open-label trial. However, a central adjudication committee blinded to treatment allocation reviewed all events.