When undergoing an early invasive strategy for myocardial infarction, the guidelines and trials typically support dual platelet inhibition. Most commonly, this regimen consists of aspirin and clopidogrel. However, the P2Y12 receptor antagonists ticagrelor and prasugrel have been promoted as options due to incremental increased platelet inhibition over clopidogrel. The theoretical benefits of early dual platelet inhibition include spontaneous lysis and prevention of re-thrombosis, as well as decreased early in-stent thrombosis. Unfortunately, the ACCOAST trial demonstrated early prasugrel was associated only with increased bleeding and no associated cardiovascular endpoint benefits.
Now we have ATLANTIC, with a similar treatment strategy, utilizing ticagrelor.
Which is also negative.
Negative for the “co-primary” endpoints of ST-segment resolution or pre-PCI TIMI flow grade, at least. The authors, however, focus on two other endpoints: bleeding, and in-stent thrombosis. These authors note, contrary to ACCOAST, there was no detectable difference in bleeding between the pre-hospital and in-hospital groups. They also note, as expected but not witnessed in ACCOAST, there was a reduction in short-term “definite” in-stent thrombosis. Therefore, the authors – by which I mean AstraZeneca and their ghostwriters – clearly present this secondary outcome (Figure 2) and conclude pre-hospital ticagrelor is safe.
Interestingly, there was a 1% absolute difference favoring pre-hospital ticagrelor in “definite” in-stent thrombosis at 30 days – but a 0.2% absolute difference favoring in-hospital ticagrelor in “definite or probable” in-stent thrombosis. For their definition, “probable” in-stent thrombosis included any death at 30 days for a patient receiving a stent. I’m not sure the expanded definition accurately reflects underlying stent thrombosis, but it is a fair combined endpoint to report for completeness.
There are a few differences between this trial and ACCOAST, however. In ACCOAST, patients were diagnosed with NSTEMI based on elevated troponin levels, and all were scheduled for coronary angiography 2 to 48 hours later. In ATLANTIC, patients were diagnosed prehospital with STEMI – and required to undergo PCI within 120 minutes. This reduced time of exposure to multiple anticoagulants may explain discrepancy in bleeding events between the trials. The in-stent thrombosis rate was also much higher in the peri-PCI antiplatelet group in ATLANTIC compared with ACCOAST, leading to the possibility of detecting a difference in in-stent thrombosis.
Details aside, however – it’s simply not clear there’s any advantage to utilizing these agents outside the peri-PCI environment. Regardless, I expect we will see more resources devoted to similar trials in slightly different populations, attempting to ferret out some subgroup and primary outcome definition capable of demonstrating a statistically significant benefit.
“Prehospital Ticagrelor in ST-Segment Elevation Myocardial Infarction”
http://www.nejm.org/doi/full/10.1056/NEJMoa1407024