No direct randomized comparison between prasugrel and ticagrelor has been performed to date with clinical outcome. Data from network meta-analyses suggested similar safety and efficacy of the two drugs, but indicated better protection from stent thrombosis with prasugrel at the expense of a higher rate of bleeding [56, 57]. However, differences between TRITON-TIMI 38 and PLATO designs and the context of the two trials limit comparability of these findings. The ongoing ISAR-REACT (iNtracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment)-5 clinical outcome trial will elucidate this issue [58]. So far, in a direct, randomized, pharmacodynamic comparison of prasugrel vs ticagrelor in ACS patients post stenting with HPR while on-clopidogrel, ticagrelor reduced platelet reactivity by VerifyNow more than prasugrel (32.9 PRU, 95 % CI 18.7–47.2 vs 101.3 PRU, 95 % CI 86.8–115.7, respectively, p < 0.001), Fig. 18.1 [59]. Similar results have been obtained in diabetic patients [60]. The clinical relevance of this pharmacodynamic difference is unclear. In an observational study of bleeding events following 1-month maintenance treatment with either ticagrelor or prasugrel and following propensity matching, BARC type 1 bleeding rate was marginally higher in ticagrelor vs prasugrel treated patients (35.7 % vs 27.1 %, p = 0.05), though BARC type ≥2 events did not differ between groups [61]. As ticagrelor appears to have fewer contraindications/ special warnings for precaution than prasugrel, it has been suggested that a STEMI protocol using ticagrelor allows a higher proportion of patients to receive a novel P2Y12 inhibitor compared to a protocol based on prasugrel and a higher adhesion to the protocol by emergency practitioners [52, 62].

In STEMI patients undergoing primary PCI, direct, randomized, pharmacodynamic comparisons between ticagrelor and prasugrel did not reveal any significant difference between them regarding platelet reactivity during the first 24 h [12, 63]. However, a delay in the onset of antiplatelet action from what expected from stable or ACS patients data was observed for the first 2 h for both agents, likely due to a delayed absorption.

The issue of pre-treatment with prasugrel or ticagrelor has been addressed by two recent trials. In the ACCOAST (Comparison of Prasugrel at the Time of Percutaneous Coronary Intervention (PCI) or as Pretreatment at the Time of Diagnosis in Patients with Non-ST Elevation Myocardial Infarction) trial 4033 patients with NSTE ACS and a positive troponin level were randomized to pre-treatment with prasugrel 30 mg (and additional 30 mg at the time of PCI) vs placebo and 60 mg of prasugrel at the time of PCI. The rate of the primary efficacy end point did not differ between arms, while the rate of the key safety end point of all Thrombolysis in Myocardial Infarction (TIMI) major bleeding episodes through day 7 was increased with pre-treatment [hazard ratio (95 % CI) 1.90 (1.19–3.02), p = 0.006] [10]. Following these results, prasugrel received a class III recommendation in the recent ESC guidelines for revascularization [4]. In the ATLANTIC (Administration of Ticagrelor in the Cath Lab or in the Ambulance for New ST Elevation Myocardial Infarction to Open the Coronary Artery) study in 1862 patients with on-going STEMI, pre-hospital administration of ticagrelor loading dose (180 mg) was not associated with any difference in ST resolution before PCI or TIMI flow at initial angiography compared to in-hospital administration [11]. A lower stent thrombosis rate was observed with the pre-hospital administration, a finding that however should be considered as exploratory. Major bleeding events did not differ between groups. Pre-hospital administration of ticagrelor appears therefore safe and supports its administration at first medical contact in patients with STEMI.

Finally, the unusual event of HPR while on prasugrel leading to stent thrombosis can be successfully managed by ticagrelor [64].

Cangrelor is an intravenous, reversible P2Y12 inhibitor with rapid (within minutes) onset and offset of action which is currently undergoing regulatory review for approval in the US and Europe. In the Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition (CHAMPION PHOENIX) trial, 10,942 P2Y12 inhibitor naïve patients with stable CAD or ACS undergoing PCI were randomized to receive clopidogrel 300 or 600 mg LD or cangrelor 30 mcg/kg bolus + 4 mcg/kg/min for 2–4 h, initiated just before the PCI. Cangrelor reduced the 48-h primary endpoint (a composite of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis) from 5.4 to 4.1 % [odds ratio (95 % CI) 0.75 (0.63–0.90), p = 0.002]. Diagnosis at presentation (stable angina, nonSTE-ACS, STEMI) did not affect this outcome (p for interaction = 0.98). There was no increase in the incidence of severe bleeding with cangrelor, although moderate bleeding was increased [13]. Cangrelor may therefore appear as an attractive alternative to clopidogrel particularly suitable for patients not pre-treated, heavily sedated, vomiting or intubated patients, or those treated with therapeutic hypothermia after cardiac arrest. Cangrelor’s role in the early hours of STEMI in comparison with potent agents deserves further elucidation.

One of the ‘hottest’ areas of interest is DAPT in the context of triple antithrombotic treatment. Long-term oral anticoagulation is required in approximately 7 % of PCI patients and triple antithrombotic treatment carries undoubtedly a several-fold increased bleeding risk. Apart from the duration, the ideal type of DAPT is unclear. The safety and efficacy of clopidogrel alone compared with clopidogrel plus aspirin was investigated in the WOEST randomised trial involving 573 patients on oral anticoagulants and undergoing PCI. The primary outcome of any bleeding episode within 1 year of PCI occurred less frequently in the double compared to triple therapy group [HR (95 % CI) 0.36 (0.26–0.50) p < 0.0001] without concomitant increase in the rate of thrombotic events [64]. The ISAR-TRIPLE trial randomized 614 patients to receive aspirin and a vitamin-K antagonist plus 6 weeks or 6 months of clopidogrel [65]. Following 9-months, no difference in the primary endpoint (death, myocardial infarction, stent thrombosis, stroke or TIMI major bleeding) was observed between groups. WOEST and ISAR-TRIPLE therefore, suggested a strategy of omitting aspirin or clopidogrel beyond the 6th week, respectively. Prasugrel-instead of clopidogrel- has been studied as a part of triple therapy in an observational registry, with an unacceptably high rate of bleeding events, and should not be given in this setting [66].

There are several controversial and unresolved issues remaining when prescribing DAPT following stenting.