The most recent network meta‐analysis looking at the duration of DAPT [60], compared short‐term (<6 month) DAPT followed by aspirin or P2Y12 monotherapy, midterm (6 month DAPT), 12 month DAPT and extended‐term (>12 months) DAPT after PCI with DES. It included 24 RCTs with 79,073 patients, assessing the co‐primary endpoint of MI and major bleeding (net clinical benefit), by means of a frequentist network meta‐analysis with a random‐effects model. In summary, this study revealed that in comparison with 12 month DAPT, short term DAPT followed by P2Y12 inhibitor monotherapy reduced major bleeding (RR for short term DAPT 0.69, 95% CI 0.50–0.96) without a significant difference in the risks of ischemic endpoints, whereas extended‐term DAPT reduced MI (RR for extended term DAPT 0.68, 95% CI 0.54–0.87) at the expense of more bleeding events (RR 1.63, 95% CI 1.15–2.30). For the ACS sub‐group specifically, extended‐term DAPT in comparison with 12‐month DAPT was associated with a reduced risk of MI (RR for extended‐term DAPT 0.42, 95% CI 0.27–0.65) without a significant risk of major bleeding. Cardiovascular and all‐cause mortality did not differ between treatment groups. Taken together, these results suggest a personalized approach to the duration of DAPT should be considered, considering individual patient‐level relative and absolute risks of bleeding and ischemia.
Cangrelor
Cangrelor is an intravenous antagonist of the P2Y12 receptor characterized by rapid, potent, predictable and reversible platelet inhibition [61]. The plasma half‐like of cangrelor is approximately 3 to 5 mins, and platelet function is restored within 1 h after cessation of the infusion. The CHAMPION PHOENIX trial [62], in contrast to the earlier CHAMPION PCI and CHAMPION PLATFORM trials [63,64], included STEMI patients (approx. 18%) in a randomization of 11,145 patients undergoing PCI to either a bolus of cangrelor or a loading dose of clopidogrel. Cangrelor significantly reduced the rate of ischemic events (adjusted OR 0.78; 95% CI 0.66–0.93; p = 0.005) without any significant increase in severe bleeding. The Platelet Inhibition With Cangrelor and Crushed Ticagrelor in STEMI Patients Undergoing Primary Percutaneous Coronary Intervention (CANTIC) study has ruled out a significant drug‐drug interaction when cangrelor is used to “bridge the gap” in acute STEMI presentations prior to the onset of action of ticagrelor, but larger studies are needed to assess clinical endpoints [65]. Observational data from the SCAAR registry suggests similar efficacy at preventing stent thrombosis to the potent oral P2Y12 inhibitors [66].
However, a randomized trial in the UK, compared the use of ticagrelor vs cangrelor in 100 STEMI patients, and found that while platelet inhibition (as measured by platelet reactivity) at the time of initial balloon inflation was greater, this did not translate into a difference in angiographic and electrocardiographic measures of reperfusion, or a significant difference in final infarct size [67]. The FABOLUS FASTER trial [46] aimed to compare the effects of cangrelor, tirofiban, and prasugrel on early IPA in patients with STEMI undergoing primary PCI. A total of 122 P2Y12‐naïve patients were randomly allocated (1:1:1) to cangrelor, tirofiban or a 60‐mg loading dose of prasugrel, with the prasugrel group being subrandomized to chewed or integral tablets. At 30 minutes, cangrelor did not satisfy noninferiority compared with tirofiban (IPA for tirofiban 95.0 ± 8.9 vs 34.1 ± 22.5, p < 0.001). Cangrelor and tirofiban were both superior to chewed prasugrel. This study supports the use of cangrelor in a “bridge the gap” approach in acute STEMI but suggests that the antiplatelet effect of cangrelor is not a replacement for a potent GP IIb‐IIIa inhibitor, where use of the latter is deemed appropriate. Further studies are needed to assess how the results on IPA effect clinical endpoints.
Glycoprotein (GP) IIb‐IIIa inhibitors
The three historically available GP IIb‐IIIa inhibitors are abciximab, a monoclonal antibody Fab fragment that is nonspecific, with tight receptor binding and slow reversibility, tirofiban, a small non‐peptide with rapid, selective and rapidly reversible blockade of the GP IIb/IIIa receptor, and eptifibatide, a small peptide, highly specific for the GP IIb/IIIa receptor, with a relatively low‐binding affinity and rapid dissociation from its receptor [68].
Unfortunately, the decision by its manufacturer to remove abciximab from production, has had the consequent effect of meaning the GP IIb‐IIIa inhibitor with the greatest weight of evidence behind it in terms of periprocedural administration [69,70] is no longer available. It should be noted that despite abciximab featuring in the many of the significant GP IIb‐IIIa trials, there is no evidence (as established by the FINESSE trial) to suggest that routine upstream treatment with abciximab in patients with STEMI improves outcomes compared to abciximab administered immediately prior to PCI [71]. Current options for GP IIb‐IIIa inhibition include either high‐bolus tirofiban (25 μg/kg) or eptifibatide (double bolus) and importantly all trials on GP IIb/IIIa‐inhibitors have been published before the widespread use of the more potent P2Y12 inhibitors prasugrel and ticagrelor.
The Prehospital initiation of tirofiban in patients with ST‐elevation myocardial infarction undergoing primary angioplasty (On‐TIME 2) study [72], was a multicenter, double‐blind, randomized controlled trial, with clopidogrel as a second anti‐platelet, which established that high‐bolus tirofiban improved ST‐segment resolution after PCI, but was not powered to assess clinical outcomes. A subsequent pooled analysis of the open‐label and double blind phases of the study revealed that major cardiac adverse events at 30 days were significantly reduced (5.8% vs 8.6%, p = 0.043) [73]. A more recent observational study in the contemporary era did not show greater efficacy of tirofiban vs control [74], albeit in a STEMI group with larger infarcts and more complex PCI, but established safety with no difference in MACCE (death, MI, stroke) or major/minor bleeding. There is also some emerging evidence that selective injection of tirofiban through a thrombus aspiration catheter, as opposed to IV tirofiban, may improve myocardial reperfusion in the case of a large thrombus burden [75].
Similarly for eptifibatide, early studies such as the Time to Integrilin Therapy in Acute Myocardial Infarction (TITAN‐TIMI 34) trial [76], established that early administration of eptifibatide in the ED before primary PCI yielded superior TIMI myocardial perfusion (compared to initiating eptifibatide in the cath lab) without an increasing in bleeding. In terms of direct comparisons with abciximab, the Eptifibatide Versus Abciximab in Primary PCI for Acute Myocardial Infarction trial (EVA‐AMI) [77], showed that in a cohort of 427 patients with STEMI treated with primary PCI, with the adjunct of either abciximab or eptifibatide, that there was no difference in terms of ST‐segment resolution at 60 mins, and although not powered for hard clinical endpoints, showed no difference in the combined endpoint of death, nonfatal reinfarction, and target vessel revascularization at six months. A retrospective observational study of the SCAAR registry suggested that eptifibatide is noninferior to abciximab in patients undergoing primary PCI with respect to death or MI at one year [78].
On the basis of the level of evidence available for GP IIb‐IIIa inhibitors at present, ESC guidelines recommend their use for “bailout” situations (i.e. no‐reflow or a thrombotic complication) only, not routinely in all cases of STEMI [3]. AHA guidelines make a class IIb recommendation for the “upstream” administration of GP IIb‐IIIa inhibitors, as well as a class IIa recommendation for their use at the time of primary PCI [4]. It should be noted that subgroup analyses have shown differential outcomes when patients are stratified by time from symptom onset, and significantly better outcomes are seen in those treated prior to 3 h from symptom onset [79].
Antithrombotic therapy
Unfractionated heparin (UFH) is recommended as an adjunct to primary PCI,