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

Abstract

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.

Keywords: Aspirin-exacerbated respiratory disease; NSAID-exacerbated respiratory disease; P2Y(12); Samter triad; double-blind; leukotrienes; placebo-controlled crossover trial; prasugrel; randomized.

FIG 1.. Detailed Schema of the trial.

A, Study schema showing timeline and schedule of assessments. B, Table of time-points when assessments were collected on the day of the aspirin challenge.

FIG 2.

Patient flow through the study.

FIG 3.. Effect of prasugrel on PD₂ and TNSS.

(A) The primary outcome, change in the provocative dose of aspirin that would elicit an increase on the total nasal symptom score of 2 points (PD₂) is shown, with horizontal bars representing the mean PD₂ for each treatment arm. (B) The change in TNSS from the pre-aspirin baseline to the maximum TNSS recorded during each aspirin challenge is shown. 34 subjects reacted to aspirin at both challenges (black lines), 1 subject reacted to aspirin only on the prasugrel arm (red line), and 5 subjects reacted only on the placebo arm (blue lines).

FIG 4.. Platelet-leukocyte aggregation, platelet activation, and plasma tryptase.

Percentages of leukocytes with adherent platelets (as determined by staining with CD61) before aspirin administration (solid columns) and 1 hour after the onset of reaction (striped columns) are shown for each treatment arm for eosinophils (A), neutrophils (B), monocytes (C), and lymphocytes (D). Percentages of platelets that expressed surface CD62P (E) and total plasma tryptase levels (F) are shown at the same timepoints. Data are expressed as mean +SE.

FIG 5.. Urinary eicosanoid levels.

Baseline pre-aspirin and aspirin-induced reaction levels of urinary eicosanoid levels analyzed by gas chromatography-mass spectrometry are shown for both treatment arms. (A) LTE₄, (B) PGD₂-M, (C) PGE-M, and (D) TXB₂. Data are expressed as mean +SE.

FIG 6.. Responder vs non-responder differences in aspirin-induced urinary eicosanoid and plasma tryptase levels.

Placebo arm urinary levels of LTE₄ (A), PGD-M (B), and TXB₂ (C) before aspirin administration (white columns) and at the aspirin reaction-induced peak (striped columns) are shown for the responders (blue lines) and the nonresponders. Placebo arm plasma tryptase levels (D) before aspirin administration and 1 hour after the onset of reaction are shown for the same patient subgroups. Data are expressed as mean +SE. P-values with a * are significant using a False Discovery Rate of 0.05 to correct for multiple comparisons.

FIG 7.. Responder vs non-responder platelet activation and platelet-leukocyte aggregates.

(A) Percentages of eosinophils with adherent platelets before aspirin administration are shown for each treatment arm for the responders (n=5, blue lines) and the non-responders. (B) Percentages of platelets that expressed surface CD62P are shown for the two patient subgroups, at the same timepoints. Data are expressed as mean + SE. P-values with a * are significant using a False Discovery Rate of 0.05 to correct for multiple comparisons.