PLATO trial demonstrated superiority of ticagrelor over clopidogrel in ACS. Which unique pharmacodynamic property distinguishes ticagrelor from clopidogrel?

• A Ticagrelor irreversibly blocks P2Y12 receptor; clopidogrel is reversible
• B Ticagrelor directly and reversibly blocks P2Y12 without requiring hepatic activation; clopidogrel is a prodrug requiring CYP2C19 ✓
• C Ticagrelor inhibits COX-1 in addition to P2Y12 blockade
• D Ticagrelor has a longer half-life (5 days) compared to clopidogrel (8 hours)

Explanation

Ticagrelor is a direct-acting, reversible P2Y12 ADP receptor antagonist that does not require hepatic bioactivation, unlike clopidogrel which is a prodrug requiring CYP2C19-mediated conversion to its active thiol metabolite. This explains why CYP2C19 loss-of-function polymorphisms (poor metabolizers) significantly reduce clopidogrel efficacy but have no effect on ticagrelor. The PLATO trial showed ticagrelor reduced the primary composite endpoint by 16% relative risk reduction vs. clopidogrel in ACS with a modest increase in non-CABG bleeding.

Reference: Harrison's Principles of Internal Medicine, 21st ed.

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