A trial of P2Y(12) receptor inhibition with prasugrel identifies a potentially distinct endotype of patients with aspirin-exacerbated respiratory disease

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is characterized by asthma, recurrent nasal polyposis, and respiratory reactions upon ingestion of cyclooxygenase-1 inhibitors. Increased numbers of platelet-leukocyte aggregates are present in the sinus tissue and blood of patients with AERD, compared to aspirin-tolerant patients, and platelet activation may contribute to aspirin-induced reactions. OBJECTIVE: We sought to determine whether treatment with prasugrel, which inhibits platelet activation by blocking the P2Y(12) receptor, would attenuate the severity of sinonasal and respiratory symptoms induced during aspirin challenge in subjects with AERD. METHODS: 40 subjects with AERD completed a 10-week, double-blinded, placebo-controlled crossover trial of prasugrel. All subjects 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 of 2 points (PD(2)). 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 PD(2) (79 ±15 on placebo and 139 ±32 on prasugrel, P = 0.10), platelet-leukocyte aggregates, or increases in urinary leukotriene E4 (LTE(4)) and prostaglandin D2 metabolite (PGD-M) levels during aspirin-induced reactions in the study population as a whole. Five subjects (“responders”) reacted to aspirin while on placebo but did not develop 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 show significant aspirin-induced increases in urinary LTE(4), PGD-M, or thromboxane B(2) levels, and failed to display increases in serum tryptase levels during the 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 higher baseline platelet activation and milder upper respiratory symptoms during aspirin reactions, P2Y(12) antagonism with prasugrel completely inhibited all aspirin-induced reaction symptoms, suggesting a contribution from P2Y(12) signaling in this subset. CLINICAL IMPLICATIONS: P2Y(12) antagonism with prasugrel prevents aspirin-induced reactions in only a subset of AERD patients with a component of P2Y(12)-dependent mechanisms of reaction to aspirin. CAPSULE SUMMARY: Platelet activation increased in AERD. In a randomized placebo-controlled cross-over trial, platelet inhibition through P2Y(12) antagonism with prasugrel neither prevented nor lessened aspirin-induced reactions in most patients with AERD, though did identify a small subset of responders who may have a distinct P2Y(12)-dependent mechanism of reaction to aspirin.