Inhibition of thrombus formation by low-dose acetylsalicylic acid, dipyridamole, and their combination in a model of platelet-vessel wall interaction

Effects of low-dose acetylsalicylic acid (ASA, 50 mg/day), dipyridamole (su stained-release preparation 400 mg/day), and their combination were investi gated in a model of human platelet-vessel wall interaction. In a randomized , double-blind clinical pharmacology trial in 96 healthy subjects, the inhi bition of mural platelet thrombus was measured ex vivo using blood samples collected both before and 2 hours after a 3.5-day treatment with ASA, dipyr idamole, ASA combined with dipyridamole, or placebo. Both the size and the number of platelet thrombi adherent to a thrombogenic matrix after a 15-min ute flow experiment were identified by automated fluorescence microscopy. ASA treatment alone reduced the mean size of all thrombi by about 45%, and dipyridamole alone achieved an approximate 17% reduction in the mean size o f all thrombi. The combination of both agents had an additive effect. Forma tion of the subpopulation of very large thrombi was reduced by ASA and dipy ridamole to a similar extent, with their combination producing an effect at least twice as strong as that witnessed in a single treatment. These resul ts suggest that ASA and dipyridamole affect platelet thrombus growth by dif ferent mechanisms of action. These findings provide the pharmacologic rationale for the combination of A SA (suppressing the synthesis of prothrombotic thromboxane A(2)) and dipyri damole (by feedback inhibition of platelet activation via local accumulatio n of adenosine) as a highly effective and safe combination for secondary pr evention of stroke. They are consistent with the clinical findings of the S econd European Stroke Prevention Study (ESPS-2). In this large trial, the a ddition of dipyridamole (400 mg/day in a sustained-release preparation) to aspirin (50 mg/day) doubled the efficacy of aspirin in the secondary preven tion of stroke without increasing the risk for bleeding.