year (HR 1.00; 95% CI 0.68–1.47; p = 0.99 for the STEMI cohort).
In terms of the timing of prasugrel administration, particularly in contrast to recently published data for patients presenting without persistent ST‐segment elevation, it should be noted that there exists no clear evidence with regard to whether early upstream administration of prasugrel for STEMI patients leads to better outcomes compared to on table administration. One study, however, involving 328 consecutive patients presenting with STEMI, 46% of whom were administered prasugrel, assessed pre‐ and post‐PCI TIMI flow grade stratified by time of P2Y12 inhibitor administration prior to intervention [45]. Those that had a P2Y12 inhibitor administered >60 mins prior to PCI appeared to have better TIMI flow pre‐ and post‐PCI, and better resolution of ST segment elevation. However, this study was not powered to assess hard clinical endpoints.
In terms of the mode of administration, it has been shown that crushed prasugrel is better absorbed than integral prasugrel, but this has not been shown to correlate with better clinical outcomes. In the FABOLUS FASTER trial [46], chewed prasugrel, despite yielding higher active metabolite concentration, did not provide higher inhibition of platelet activity (IPA) over integral prasugrel. In the COMPARE CRUSH trial [47], 727 STEMI patients were assigned to a loading dose of either crushed or integral prasugrel. Results revealed a significantly decreased proportion of patients with high platelet reactivity at the beginning of primary PCI with crushed tablets, but this did not translate into significant differences in TIMI 3 flow in the IRA at initial angiography (OR 0.92, 95% CI 0.65–1.30; p = 0.64 for the crushed group), or the proportion of patients with complete ST‐segment resolution one hour post primary PCI (OR 1.11, 95% CI 0.78–1.58; p = 0.55) [48].
Ticagrelor
The PLATO randomized trial compared ticagrelor to clopidogrel for the prevention of cardiovascular events in patients admitted to hospital with acute coronary syndrome [49]. Just under 38% of the total population enrolled in the study presented with STEMI, and in a subgroup analysis, the hazard ratio for a primary endpoint of CV death/MI or stroke was 0.87 (95% CI 0.75–1.01; p = 0.07). This arises from an 18% relative reduction in the composite of MI and cardiovascular mortality but an increase in the rate of (non‐hemorrhagic) stroke. There was no significant increase in major bleeding overall.
In contrast to prasugrel, there have been several studies looking at the optimal timing of administration of ticagrelor. The Administration of Ticagrelor in the Cath Lab or in the Ambulance for New ST Elevation Myocardial Infarction to Open the Coronary Artery (ATLANTIC) study looked at a cohort of 1862 patients who were either administered prehospital (in the ambulance) versus in‐hospital (in the cath lab) ticagrelor, with a median time difference between the two treatment strategies of only 31 minutes [50]. There was no significant difference between the degree of ST‐segment element resolution or proportion of patients with TIMI III flow in the IRA. There was, however, a close to significant reduction in acute, definite stent thrombosis (0 vs 8 cases, p = 0.055). Rates of major bleeding were virtually identical in both groups. A study assessing 7433 patients, through the SWEDEHEART registry, who presented with acute STEMI and were either pretreated with ticagrelor, or given it only in the catherization lab, revealed no difference in a composite endpoint of mortality, MI or stent thrombosis [51].
Prasugrel vs Ticagrelor
In terms of direct head‐to‐head comparisons between prasugrel and ticagrelor, the initial STEMI data was provided by the PRAGUE‐18 study [52], which randomized a total of 1230 patients with AMI being treated with primary PCI to either prasugrel or ticagrelor. This study was terminated early for futility, with no significant difference being seen in any of the components of the primary end point (death, reinfarction, urgent target vessel revascularization, stroke or serious bleeding at seven days). However, this trial is underpowered and medication was switched to clopidogrel after hospital discharge in many patients for reimbursement issues in the Czech Republic, thus limiting the results.
However, in the ISAR‐REACT 5 trial [53], a multicenter, randomized, open‐label trial which randomly assigned patients who presented with ACS and for whom invasive evaluation was planned to either receive ticagrelor or prasugrel, the hazard ratio for the primary endpoint of death, myocardial infarction or stroke at one year was 1.36 (95% CI 1.09–1.70; p = 0.006) for ticagrelor as compared to prasugrel. This result is for the ACS population in general, however, is made up of approx. 40% STEMI presentations.
Duration of DAPT
In terms of the long term duration of DAPT, both current ESC and ACC/AHA guidelines recommend a duration of 12 months post PCI, unless there are contraindications such as an excessive risk of bleeding [3,4]. In this case, the ESC guidelines recommend consideration of stopping DAPT after six months, while the AHA guidelines do not make a specific recommendation. The AHA focused update on duration of DAPT in patients with CAD updates this with a Class IIb recommendation in the case of an excessive bleeding risk (discontinuation of the second antiplatelet may be considered after six months) [54].
The SMART‐DATE trial was a randomized, open‐label, non‐inferiority trial, randomizing 2712 patients in 31 centers in South Korea post ACS to either six months DAPT or 12 months DAPT, with predominantly clopidogrel the P2Y12 receptor of choice in approx. 80% of cases across both groups [55]. This showed that six months DAPT was non‐inferior to 12 months, albeit with a p‐value for non‐inferiority of 0.03 with a pre‐defined non‐inferiority margin of 2.0%, and a finding that MI occurred more frequently in the 6‐month group (HR 2.41; 95% CI 1.15 – 5.05; p = 0.02).
The DAPT‐STEMI trial [56], randomizing 870 patients to either 6 or 12 months of DAPT, had the advantage that it specifically looked at the STEMI population; 58% of patients were treated with prasugrel or ticagrelor, the remainder with clopidogrel. The primary outcome was a composite of all‐cause mortality, MI, revascularization, stroke, and TIMI major bleeding at 18 months. The hazard ratio for the primary endpoint was 0.73; 95% CI 0.41–1.27; p = 0.2, meeting the pre‐specified conditions for non‐inferiority. Neither statistically significant nor meaningful numerical differences were noted for the components of the composite endpoint. Note that only patients who were event free at six months were randomized.
The results of the REDUCE trial were suggestive of the acceptability of an even shorter duration of DAPT when absolutely necessary, with the randomization of 1496 patients with ACS treated with the COMBO stent to either 3 or 12 months of DAPT, showing that 3 months was non‐inferior in terms of a primary endpoint of all‐cause mortality, MI, stent thrombosis, stroke, target vessel revascularization and bleeding at 12 months (8.2% vs 8.4%, p value for non‐inferiority <0.001) [57]. In this study, the hazard ratio for MI in the three month arm crossed the midline (HR 1.18; 95% CI 0.67–2.08; p value for superiority 0.577). Of note, in contrast to the SMART‐DATE trial, approx. 60% of patients in both arms were treated with either prasugrel or ticagrelor rather than clopidogrel.
The trial of Ticagrelor Monotherapy After 3 Months in the Patients Treated with New Generation Sirolimus‐eluting stent for Acute Coronary Syndrome (TICO) [58], assessed an alternative approach. Patients with ACS, approximately one third of whom underwent primary PCI for STEMI, were randomized to receive ticagrelor monotherapy after three months DAPT, or ticagrelor based 12 month DAPT. Overall, 3056 patients in 38 centers in South Korea were randomized. The primary outcome was defined as a composite of major bleeding and adverse cardiovascular and cerebrovascular events (death, MI, stent thrombosis, stroke, or target‐vessel revascularization). The hazard ratio for the primary outcome in the ticagrelor monotherapy group was 0.66 (95% CI, 0.48–0.92; p = 0.01), driven by an increased risk of bleeding events in the DAPT group (HR 0.56, 95% CI 0.34–0.91; p = 0.02), without a significant difference in the incidence of major cardiovascular and cerebrovascular events, suggesting that this approach may be considered in those patients in whom DAPT poses an unacceptably high bleeding risk.
The Ticagrelor with Aspirin or Alone in High‐Risk Patients after Coronary Intervention (TWILIGHT) trial [59], addressed a similar question in a predominantly North American and European population of 9006 patients, however looked at an ACS population in general, rather than a STEMI population. Patients who were