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It is common practice to coadminister proton pump inhibitors with aspirin to diminish the risk of upper gastrointestinal bleeding. This is the first study that investigated the potential impact of a proton pump inhibitor on aspirin effects on platelet aggregation. Twenty-four hypertensive subjects eligible for treatment with low-dose enteric-coated aspirin (LDECA) for primary prevention of cardiovascular disease were randomized to receive 100 mg LDECA or 100 mg LDECA plus 30 mg lansoprazole for 4 weeks. Then, participants were crossed over to the alternative regimen for another 4 weeks. Salicylic, gastrin, and pepsinogen I blood level counting were used to ensure adherence to treatment. Platelet aggregation was evaluated by light transmittance aggregometry and PFA100. The LDECA administration reduced arachidonic acid (P < 0.001), collagen (P < 0.01), and epinephrine (P < 0.001) tests. These changes paralleled an increase in collagen/epinephrine duration (P < 0.001) but not in collagen/adenosine diphosphate duration and platelet count. No significant difference was found in any of these platelets' function tests with LDECA alone versus LDECA plus lansoprazole. A significant increase in salicylic levels was observed in patients on LDECA as well as in those on LDECA plus lansoprazole, whereas gastrin and pepsinogen I levels were increased only when lansoprazole was added. These data suggest that the concomitant use of the lansoprazole at 30-mg daily does not influence the long-term effect of LDECA on platelet aggregation. Furthermore, they might imply that an interaction of LDECA with other proton pump inhibitors on platelet aggregation is unlikely.