The PLATO trial compared ticagrelor vs clopidogrel in ACS patients. The significant survival benefit of ticagrelor was partly attributed to an off-target mechanism. Which of the following correctly identifies this off-target effect?
- A COX-1 inhibition causing permanent platelet inhibition
- B ENT1 (equilibrative nucleoside transporter-1) inhibition elevating adenosine levels, causing pleiotropic effects ✓
- C GPIb receptor blockade preventing von Willebrand factor-mediated platelet adhesion
- D Thrombin receptor (PAR-1) antagonism
Explanation
Ticagrelor reversibly inhibits the P2Y12 ADP receptor but also blocks ENT1, the primary adenosine re-uptake transporter. This elevates local adenosine concentrations, which may provide cardioprotective effects (vasodilation, anti-inflammatory, ischaemic preconditioning-like effects) and is thought to contribute to the mortality benefit beyond platelet inhibition alone. This mechanism also explains the unique side effect of dyspnoea with ticagrelor (adenosine-mediated). COX-1 inhibition is aspirin's mechanism. GPIb blockade is not a mechanism of any approved antiplatelet. PAR-1 antagonism is vorapaxar's mechanism.
Reference: Harrison's Principles of Internal Medicine, 21st ed.
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