NSAIDs interfere with aspirin-induced platelet inhibition in vitro: notable differences between individual compounds

Prof. Dr. Hohlfeld, Thomas , Prof. Dr. Schrör, Karsten , Dr. Hafner, Dieter. Heinrich-Heine-Universität Duesseldorf Institut fuer Pharmakologie und Klinische Pharmakologie, Moorenstrasse 5, 40225 Duesseldorf, Germany.

Background and purpose: clinical studies suggested that ibuprofen and naproxen interfere with platelet inhibition by aspirin. It is unknown, however, whether this applies to all nonsteroidal antiinflammatory drugs (NSAIDs). The purpose of this study was to examine drug interference with aspirin of a large series of chemically distinct NSAIDs. Experimental approach: platelet-rich plasma of healthy donors was pretreated in vitro with one of 14 clinically important NSAIDs over a wide range of concentrations. Aspirin (30 µmol/L) was added thereafter. Subsequently, arachidonic acid-induced aggregation and thromboxane (TX) synthesis were determined. Platelet inhibition by NSAIDs alone (without aspirin) was also determined. Moreover, a computerized model was established to characterize the aspirin/NSAID interaction. Key results: aspirin alone completely inhibited aggregation (<5% of control). This inhibition was significantly (p<0.05) impaired or prevented in the presence of ibuprofen (51±13%), piroxicam (83±10%), flufenamate (99±4%), mefenamate (89±8%), dipyrone (66±10%), propyphenazone (81±12%), sulindac (63±11%) and naproxen (28±14%). The interactions occurred at low NSAID concentrations (3-10µmol/L). In contrast, acetaminophen, diclofenac, flurbiprofen, indomethacin and ketoprofen did not alter the inhibition by aspirin at all. TX synthesis showed comparable results. The differences between NSAIDs probably reflect different binding modes to the substrate channel of platelet COX-1. Mathematical simulation confirmed that reversible COX inhibitors may partially prevent the irreversible inhibition by aspirin already at low concentrations. Conclusions and implications: many NSAIDs, including propionates, fenamates, oxicams and pyrazoles, interfere with aspirin at clinically relevant concentrations. However, remarkable differences exist between the individual compounds.