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

From the Franz-Volhard Cardiovascular Clinic, Berlin, Germany.

Address correspondence and reprint requests to PD Dr. Thomas H. Müller, Franz-Volhard Cardiovascular Clinic, Max-Delbrück-Centre for Molecular Medicine, Charité, Faculty of Medicine, Humboldt University, Wiltbergstrasse 50, Berlin D 13 125, Germany.

Effects of low-dose acetylsalicylic acid (ASA, 50 mg/day), dipyridamole (sustained-release preparation 400 mg/day), and their combination were investigated in a model of human platelet–vessel wall interaction. In a randomized, double-blind clinical pharmacology trial in 96 healthy subjects, the inhibition 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, dipyridamole, ASA combined with dipyridamole, or placebo. Both the size and the number of platelet thrombi adherent to a thrombogenic matrix after a 15-minute 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 of all thrombi. The combination of both agents had an additive effect. Formation of the subpopulation of very large thrombi was reduced by ASA and dipyridamole to a similar extent, with their combination producing an effect at least twice as strong as that witnessed in a single treatment. These results suggest that ASA and dipyridamole affect platelet thrombus growth by different mechanisms of action.

These findings provide the pharmacologic rationale for the combination of ASA (suppressing the synthesis of prothrombotic thromboxane A₂) and dipyridamole (by feedback inhibition of platelet activation via local accumulation of adenosine) as a highly effective and safe combination for secondary prevention of stroke. They are consistent with the clinical findings of the Second European Stroke Prevention Study (ESPS-2). In this large trial, the addition of dipyridamole (400 mg/day in a sustained-release preparation) to aspirin (50 mg/day) doubled the efficacy of aspirin in the secondary prevention of stroke without increasing the risk for bleeding.

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