When the literature behind ticagrelor hit, there seemed to be a short-lived cheer. Where prasugrel (Effient) fell short, this drug excelled – superior (composite endpoint of vascular death, MI and stroke) to clopidogrel (Plavix) with no excess bleeding. What followed was a resounding thud since 10% of the population in PLATO, who were from North America, did not see this benefit. But the confusion didn’t end there. Especially for pharmacists…
In a mysterious turn of events, patients who received > 100mg of aspirin seemed to have no benefit (composite endpoint of vascular death, MI or stroke) with ticagrelor and more bleeding. The mechanism of this interaction as theorized by the PLATO authors is that by administering aspirin at doses greater than 80 mg /day, the inhibition of prostacyclin production at these concentrations will offset the potent P2Y12 inhibition and additional prostacyclin release caused by ticagrelor (circa 1983).
Although this makes sense, it’s not the whole story. We know that prostacyclin (specifically PGI2) inhibits platelet aggregation and causes vasodilation. Its production by COX-1 is readily inhibited by aspirin, however, its production by COX-2 is still maintained at normal daily aspirin doses. But at the end of the day, the suppression of PGI2 from higher doses of aspirin isn’t enough to overcome the inhibitory effects of TXA2 to initiate or predispose a patient to thrombosis (unlike COX-2 inhibitors)
Moreover, if P2Y12 inhibition mediated prostacycline release was blunted in a clinically significant manner by aspirin, we should see this effect with clopidogrel and prasugrel – which we don’t. There is a difference between showing no difference in clinical outcomes based on the dose of aspirin you use with clopidogrel (CURRENT-OASIS 7) and saying higher dose aspirin causes worse outcomes.
Or perhaps in everyone got aspirin 325mg daily in the region where ticagrelor did terribly (N. America) and virtually nobody received that dose elsewhere.
In the words of one of the ED pharmacists I work with, “I smell a fart with this one.” The FDA advisory panel regarding ticagrelor seems to agree.