Aspirin and Clopidogrel Resistance: A Study on 96 Healthy Volunteers and Role of the P2Y12 H1/H2 Gene Polymorphism

Abstract number: P0356

Fontana P, Nolli S, Reber G, de Moerloose P

Aspirin resistance (AR) and clopidogrel resistance (CR) have been correlated to clinical outcome. However, AR is poorly defined because some assays are not specific of thromboxane (Tx) A2 production. Whether aspirin resistant subjects are clopidogrel resistant is not known. Genetic variations may be part of the underlying mechanisms of AR and CR. We studied 96 healthy subjects receiving in a randomized manner a one-week course of aspirin 100 mg/day followed by a one-week course of clopidogrel (300 mg and 75 mg/day), or vice-versa, separated by a two-week wash-out period. Drug efficacy was evaluated by platelet aggregation, PFA-100™, RPFA-ASA™ and serum TxB2. Only one subject showed AR, as defined by a serum TxB2 > 80 pg/µl after the aspirin course (real aspirin resistance, RAR), that was confirmed by RPFA-ASA™. Moreover, platelets isolated from this subject and incubated with 100 µM aspirin still displayed irreversible arachidonic acid-induced platelet aggregation. PFA-100™ was within the normal range in 30% of the subjects after aspirin intake despite abolition of TxB2 production (defined as pseudo aspirin resistance, PAR). Clopidogrel response was evaluated by ADP-induced platelet aggregation and divided into quartiles, quartile 4 being defined as CR. We found no association between PAR and CR. However, the RAR subject was clopidogrel resistant. The P2Y12 H1/H2 polymorphism was associated neither with PAR nor with clopidogrel response. In conclusion, RAR is rare in healthy subjects (1%). However, RAR subjects could be clopidogrel resistant. PAR is more frequent (30%) but aspirin may not be sufficient in these subjects to inhibit platelet function, suggesting a prominent role for platelet amplification pathways that are not targeted by aspirin. Since there is no association between PAR and CR, clopidogrel could be an alternative for most PAR patients, and aspirin for most CR patients. Finally, heterozygosity for the H1/H2 polymorphism was not associated with CR.