Trial of thromboxane receptor inhibition with ifetroban: TP receptors regulate eicosanoid homeostasis in aspirin-exacerbated respiratory disease

Abstract

Background: Aspirin-exacerbated respiratory disease (AERD) is the triad of asthma, nasal polyposis, and respiratory reactions to COX-1 inhibitors. Overproduction of cysteinyl leukotrienes and underproduction of prostaglandin E₂ (PGE₂) are hallmarks of AERD. A mouse model predicted a key role for the thromboxane-prostanoid (TP) receptor in AERD.

Objective: Our aim was to determine whether ifetroban, a TP receptor antagonist, attenuates aspirin-induced respiratory symptoms in patients with AERD.

Methods: A total of 35 patients with AERD completed a 4-week double-blinded, placebo-controlled trial of ifetroban and underwent an oral aspirin challenge. The primary outcome was change in the provocative dose of aspirin that caused a 2-point increase in Total Nasal Symptom Score. Changes in lung function, eicosanoid levels, and platelet and mast cell activation were assessed. Cultured human nasal fibroblasts were stimulated with or without the TP agonist U46619 and assayed for prostanoid production.

Results: Ifetroban was well tolerated in AERD and did not change the mean 2-point increase in Total Nasal Symptom Score (P = .763). Participants taking ifetroban had greater aspirin-induced nasal symptoms and a greater decline in FEV₁ value than did participants receiving placebo (-18.8% ± 3.6% with ifetroban vs -8.4% ± 2.1% with placebo [P = .017]). Four weeks of ifetroban significantly increased urinary leukotriene E₄ levels and decreased nasal PGE₂ levels compared with placebo. Peak aspirin-induced urinary thromboxane levels correlated with peak urinary leukotriene E₄ and prostaglandin D₂ metabolite levels in participants taking ifetroban. U46119 significantly potentiated the production of PGE₂ by cultured nasal fibroblasts from subjects with AERD but not by cultured nasal fibroblasts from controls without polypoid sinusitis.

Conclusion: Contrary to our hypothesis, TP receptor blockade worsened aspirin-induced reactions in AERD, possibly by exacerbating dysregulation of the eicosanoid system. TP signaling on stromal cells may be critical to maintaining PGE₂ production when COX-2 function is low.

Keywords: AERD; Aspirin-exacerbated respiratory disease; Samter triad; ifetroban; mast cell; platelet; thromboxane receptor.

FIG 1.. Detailed trial schema.

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 ifetroban on PD2, TNSS+ and FEV₁ during reaction to aspirin.

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, along with the maximum increase in total nasal symptom score (TNSS+) and maximum % decrease in FEV₁ during aspirin-induced reactions are shown for participants on placebo and ifetroban.

FIG 4.. Urinary and nasal eicosanoid levels before and after 1 month of treatment.

Pretreatment (pre-ifetroban/placebo at Visit 1) and post-treatment (Visit 2, before start of aspirin challenge) levels of urinary (top row) and nasal (bottom row) eicosanoids analyzed by mass spectrometry are shown. P-values compare delta between placebo and ifetroban treatment arms.

FIG 5.. Effect of ifetroban on urinary and nasal eicosanoids during reaction to aspirin.

Aspirin-induced maximum change from pre-aspirin baseline in urinary (top row) and nasal (bottom row) eicosanoids during aspirin-induced reactions are shown for participants on placebo and ifetroban. P-values compare delta between placebo and ifetroban treatment arms.

FIG 6.. Relationship between urinary eicosanoid levels during aspirin-induced reactions.

Correlation between peak urinary TXB₂ and peak urinary LTE₄ and urinary PGD-Metabolite levels during the aspirin-induced reaction are shown for participants on the ifetroban (A,C, triangles) and placebo (B,D, circles) treatment arms.

FIG 7.. Prostanoid production by cultured nasal fibroblasts.

Fibroblasts cultured from surgically excised nasal tissue from patients with AERD (n=5, white columns) or CRSsNP (n=5, lined columns) were stimulated with or without IL-1β and the TP receptor agonist U46619 for 24 hours. Levels of PGE₂ (A) and the PGI₂ metabolite 6-keto PGF1α (B) were measured by ELISA in the supernatants.