Efficiency in clinical research: assessment in vitro of potential anti-thrombotic drug interactions

To determine whether testing in vitro of combinations of anti-thrombotic agents can identify potentially important interactions, we evaluated the combination of rNAPc2 with antagonists of platelet GP IIb-IIIa to identify potentially altered anticoagulant properties, antiplatelet effects, or both.

Blood was obtained from healthy subjects who were taking aspirin (325 mg/day). Selected concentrations of rNAPc2, enoxaparin, and GP IIb-IIIa inhibitors were added in vitro. Platelet function was assessed with the use of flow cytometry.

No effect on clotting or platelet inhibition was apparent when abciximab was added to the combination of aspirin, enoxaparin, and rNAPc2 at concentrations up to 250 ng/ml. A modest (less than 10%, P <0.02) effect on the time to clot assessed with the activated clotting time was demonstrated when either eptifibatide or tirofiban was combined with aspirin and enoxaparin plus rNAPc2. rNAPc2 did not alter antiplatelet effects of eptifibatide. By contrast, a modest, approximately 10%, increase in the inhibition of fibrinogen binding (P <0.01) was seen when rNAPc2 was added to the combination of aspirin, enoxaparin, and tirofiban.

The lack of an exaggerated effect on clotting and platelet function when GP IIb-IIIa inhibitors were combined with rNAPc2, aspirin, and enoxaparin suggests that no substantial increment in the incidence of bleeding would be observed when concentrations of rNAPc2 up to 250 ng/ml were to be used in clinical studies. More extensive use of testing in vitro in advance of large-scale clinical trials of anti-thrombotic agents and regimens is likely to enhance their design and implementation.