Magnitude and time course of platelet inhibition with Aggrenox® and Aspirin in patients after ischemic stroke: The AGgrenox versus Aspirin Therapy Evaluation (AGATE) trial

The European Stroke Prevention Study showed greater stroke prevention for Aggrenox® than either for aspirin or dipyridamole alone. To test whether Aggrenox® has superior antiplatelet properties to aspirin alone we conducted the AGgrenox versus Aspirin Therapy Evaluation (AGATE) trial. Forty patients with prior ischemic stroke not taking aspirin for at least 30 days were randomized to Aggrenox® (2 pills/daily) or aspirin (81 mg plus matching placebo/daily) for 30 days. Platelet function was assessed at baseline, 24 h, and days 3, 7, 15, and 30 by aggregometry, flow cytometry and cartridge-based analyzers. Both Aggrenox® and aspirin provided fast and sustained platelet inhibition. Aggrenox®, however, especially after 15 days, showed significant prolongation of the closure time (P=0.04), diminished expression of platelet/endothelial cell adhesion molecule-1 (PECAM-1) (P=0.01), glycoprotein IIb (GPIIb) antigen (P=0.02), and GPIIb/IIIa activity (P=0.01) by PAC-1 C antibody, CD63 (P=0.03), as well as inhibition of Protease Activated Receptors (PAR-1) associated with intact (SPAN12, P=0.01) and cleaved (WEDE15, P=0.01) thrombin receptors as compared with aspirin. Surprisingly, GPIb expression increased, especially after aspirin. In the randomized trial of small sample size, aspirin and Aggrenox® produced fast and sustained platelet inhibition. In 25 of 90 direct comparisons, Aggrenox® was superior to aspirin, whereas in 4 of 90, aspirin was superior to Aggrenox®. In 61 of 90 direct comparisons, aspirin and Aggrenox® were equivalent. Aggrenox® was associated with a profound reduction of PAR-1 receptors, an observation that may be related to the greater clinical benefit of Aggrenox® compared with Aspirin in preventing recurrent stroke.