Abstract 4001: Relationship between Exposure to the Prasugrel Active Metabolite with TIMI Major/Minor Bleeding in TRITON-TIMI 38
In TRITON-TIMI 38, patients treated with prasugrel had a higher incidence of TIMI bleeding compared to treatment with clopidogrel. Increased bleeding was most evident in patients <60 kg or ≥75 years. The relationship between exposure to prasugrel active metabolite (Pras-AM) and TIMI Major/Minor (M/M) bleeding was assessed in 1159 patients enrolled in the TRITON pharmacokinetic substudy ~17% of treated population. The relationship between exposure and bleeding was also assessed in the subset of patients <60 kg or ≥75 years. A multi-linear regression model was used to quantitatively predict Pras-AM from measurement of its 2 downstream inactive metabolites. Exposure quartiles for Pras-AM were constructed for all patients, as well as for patients ≥60 kg or <75 years. TIMI bleeding by exposure quartiles was assessed. The risk of bleeding for patients <60 kg or ≥75 years was assessed using the quartiles constructed for the complementary population. Relationship between exposure and bleeding was analyzed through 3 days from the first dose of study drug to evaluate the effect of the loading dose (LD; prasugrel 60 mg) and after 3 days from the first dose of study drug to evaluate the effect of the maintenance dose (MD; prasugrel 10 mg). In the overall population, a higher estimated exposure to Pras-AM was associated with a higher incidence of bleeding after 3 days (P<0.05), but not through 3 days from the first dose of study drug. For patients ≥75 years, TIMI M/M bleeding was higher in the upper 2 quartiles of exposure (12.5%) compared to the lower 2 quartiles (2.5%). Patients ≥75 years in the lower quartile of exposure to Pras-AM had similar TIMI M/M bleeding compared to patients <75 years. For patients <60 kg, TIMI M/M bleeding was observed only in the upper quartile of exposure (14.8%). Increased estimated exposure to Pras-AM with the MD was associated with increased bleeding but exposure during LD was not associated with increased bleeding. In patients ≥75 years or <60 kg, increased TIMI M/M bleeding was confined to patients in the highest exposure quartiles to Pras-AM. Patients <75 years or 60 kg in the lower estimated exposure quartiles to Pras-AM had similar TIMI M/M bleeding compared to patients <75 years or ≥60 kg, respectively.