Effect of prasugrel in patients with asthma : results of PRINA, a randomized, double-blind, placebo-controlled, cross-over study

BACKGROUND: Although experimental studies demonstrated that platelets are pro-inflammatory cells, no randomized studies tested the anti-inflammatory effect of antiplatelet agents in humans. The platelet P2Y12 receptors mediated bronchial inflammation in a mouse model of asthma, suggesting that P2Y12 represents a pharmacological target for asthma. OBJECTIVES: In this proof-of concept, placebo-controlled, randomized, cross-over study we tested the effects of the P2Y12 antagonist prasugrel on bronchial hyper-reactivity of asthmatic patients. PATIENTS/METHODS: Twenty-six asthmatic patients were randomly and blindly allocated to prasugrel (10mg o.d.) or placebo for 15 days. After ≥15-day wash-out, patients were crossed-over to the alternative treatment. Before and after each treatment, patients underwent bronchial provocation test with mannitol and measurement of fractional exhaled nitric oxide (FeNO). Inhibition of P2Y12- dependent platelet reactivity (PRI) was measured by the VASP phosphorylation assay. RESULTS: The provocative dose of mannitol causing a 15%-drop in FEV1 tended to increase from 142 mg (95%CI 82-202) to 187 mg (113-262) after prasugrel (p=0.09) and did not change after placebo (136 mg; 76-196 and 144 mg; 84-204, p=0.65). FeNO did not change after either treatment. PRI decreased from 80%(77-83) to 23%(7-29) after prasugrel (p<0.001) and remained unchanged after placebo. CONCLUSIONS: Our proof-of-concept, randomized, controlled study is the first one to test in vivo the anti-inflammatory effects of platelet inhibition in human patients. Its results suggest that pharmacological inhibition of P2Y12 receptors may slightly reduce the bronchial inflammatory burden and lays the groundwork for further studies, with clinical end-points. This article is protected by copyright. All rights reserved.