A trial of type 12 purinergic (P2Y12) receptor inhibition with prasugrel identifies a potentially distinct endotype of patients with aspirin-exacerbated respiratory disease

Publication date: January 2019

Source: Journal of Allergy and Clinical Immunology, Volume 143, Issue 1

Author(s): Tanya M. Laidlaw, Katherine N. Cahill, Juan Carlos Cardet, Katherine Murphy, Jing Cui, Brittney Dioneda, Parul Kothari, Benjamin A. Raby, Elliot Israel, Joshua A. Boyce

Background

Aspirin-exacerbated respiratory disease (AERD) is characterized by asthma, recurrent nasal polyposis, and respiratory reactions on ingestion of COX-1 inhibitors. Increased numbers of platelet-leukocyte aggregates are present in the sinus tissue and blood of patients with AERD compared with that of aspirin-tolerant patients, and platelet activation can contribute to aspirin-induced reactions.

Objective

We sought to determine whether treatment with prasugrel, which inhibits platelet activation by blocking the type 12 purinergic (P2Y₁₂) receptor, would attenuate the severity of sinonasal and respiratory symptoms induced during aspirin challenge in patients with AERD.

Methods

Forty patients with AERD completed a 10-week, double-blind, placebo-controlled crossover trial of prasugrel. All patients underwent oral aspirin challenges after 4 weeks of prasugrel and after 4 weeks of placebo. The primary outcome was a change in the provocative dose of aspirin that would elicit an increase in Total Nasal Symptom Score (TNSS) of 2 points. Changes in lung function, urinary eicosanoids, plasma tryptase, platelet-leukocyte aggregates, and platelet activation were also recorded.

Results

Prasugrel did not significantly change the mean increase in TNSS of 2 points (79 ± 15 for patients receiving placebo and 139 ± 32 for patients receiving prasugrel, P = .10), platelet-leukocyte aggregates, or increases in urinary leukotriene E₄ and prostaglandin D₂ metabolite levels during aspirin-induced reactions in the study population as a whole. Five subjects (responders) reacted to aspirin while receiving placebo but did not have any reaction to aspirin challenge after the prasugrel arm. In contrast to prasugrel nonresponders (35 subjects), the prasugrel responders had smaller reaction-induced increases in TNSS; did not have significant aspirin-induced increases in urinary leukotriene E₄, prostaglandin D₂ metabolite, or thromboxane B₂ levels; and did not display increases in serum tryptase levels during aspirin reactions on the placebo arm, all of which were observed in the nonresponders.

Conclusion

In the overall study population, prasugrel did not attenuate aspirin-induced symptoms, possibly because it failed to decrease the frequencies of platelet-adherent leukocytes or to diminish aspirin-induced mast cell activation. In a small subset of patients with AERD who had greater baseline platelet activation and milder upper respiratory symptoms during aspirin-induced reactions, P2Y₁₂ receptor antagonism with prasugrel completely inhibited all aspirin-induced reaction symptoms, suggesting a contribution from P2Y₁₂ receptor signaling in this subset.

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