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

BackgroundAlthough experimental studies have demonstrated that platelets are proinflammatory cells, no randomized studies have tested the anti-inflammatory effect of antiplatelet agents in humans. The platelet P2Y(12) receptors mediated bronchial inflammation in a mouse model of asthma, suggesting that P2Y(12) represents a pharmacologic target for asthma. ObjectivesIn this proof-of concept, placebo-controlled, randomized, cross-over study, we tested the effects of the P2Y(12) antagonist prasugrel on bronchial hyperreactivity of asthmatic patients. Patients/MethodsTwenty-six asthmatic patients were randomly and blindly allocated to prasugrel (10mg once daily) or placebo for 15days. After a 15-day wash-out, patients were crossed over to the alternative treatment. Before and after each treatment, patients underwent a bronchial provocation test with mannitol and measurement of fractional exhaled nitric oxide (FeNO). Inhibition of P2Y(12)-dependent platelet reactivity (platelet reactivity index [PRI]) was measured with the vasodilator-stimulated phosphoprotein phosphorylation assay. ResultsThe provocative dose of mannitol causing a 15% drop in forced expiratory volume in 1s increased from 142mg (95% confidence interval [CI]82-202) to 187mg (95%CI113-262) after prasugrel treatment (P=0.09), and did not change after placebo treatment (136mg [95%CI76-196] and 144mg [95%CI84-204], P=0.65). FeNO did not change after either treatment. The PRI decreased from 80% (95%CI77-83) to 23% (95%CI7-29) after prasugrel treatment (P<0.001) and remained unchanged after placebo. ConclusionsOur proof-of-concept, randomized, controlled study is the first one to test invivo the anti-inflammatory effects of platelet inhibition in human patients. The results suggest that pharmacologic inhibition of P2Y(12) receptors may slightly reduce the bronchial inflammatory burden, and lay the groundwork for further studies, with clinical endpoints.