Since the
P2Y12 receptor antagonists were first introduced, they have been extensively tested in patients with
acute coronary syndrome and are now standard of care. These
antiplatelet drugs are very effective in reducing subsequent cardiovascular events,
stent thromboses, and mortality in patients with acute
myocardial infarction undergoing reperfusion
therapy. Although the prevailing view is that their benefit derives from their antithrombotic properties, other unrelated pleiotropic effects appear to be equally beneficial. Accumulating clinical and animal evidence indicates that, if present at the time of reperfusion, these drugs have a direct anti-
infarct effect similar to that of
ischemic postconditioning. Four oral antagonists have been developed in rapid succession:
ticlopidine,
clopidogrel,
prasugrel, and
ticagrelor. Each agent had a more consistent and rapid onset of action than the previous one, and this has correlated with improved clinical outcomes when given early in treatment. Unfortunately, gut absorption causes an appreciable delay in the onset of effect, especially when
morphine is used, and the constant push to minimize the door-to-balloon time has made it difficult to achieve adequate platelet inhibition at the time of
percutaneous coronary intervention with an oral agent. An intravenous P2Y12 antagonist such as
cangrelor may optimize treatment because it produces nearly maximal inhibition of platelet aggregation within minutes. If
antiplatelet agents do protect through postconditioning's mechanism, then they would render any other intervention that protects through that mechanism redundant. Indeed, animals treated with
cangrelor cannot be further protected by pre- or postconditioning. However, interventions that use a different mechanism such as mild
hypothermia or
cariporide, a Na(+)-H(+) exchange blocker, do add to
cangrelor's protection. Future research should be directed toward identifying interventions that can augment the protection from antiplatelet
therapy and finding a way to optimize P2Y12 inhibition at reperfusion in all patients.