2) Our returning esteemed guest faculty is C. Michael Gibson MD @CMichaelGibson, Non-Profit Founder/Leader &❤️ Doc from @harvardmed. #cmg will review the #ESC2024 presentations on #OCEANIC_AF (#asundexian) and periprocedural ?from #AZALEA #TIMI-71 (#abelacimab). pic.twitter.com/zDJ0qlDaYr
— cardio-met (@cardiomet_CE) September 2, 2024
3b) Which of these is FALSE about #FXI-targeted agents currently in development?
— cardio-met (@cardiomet_CE) September 2, 2024
a. multiple #MOAs are being tested
b. both FXI & FXIa are potential targets
c. 3 Ph 3 trials are underway in #AFib
d. a Ph 2 trial of a FXI inhibitor was stopped early for superior safety v a DOAC
4a) Reminder: Despite great advances in #anticoagulation tx (#warfarin➡️#DOACs), unmet needs persist:
— cardio-met (@cardiomet_CE) September 2, 2024
1⃣ 1 in 4 deaths globally are due to #thrombosis
2⃣ #DOACs safer than warfarin (esp re #ICH) but major/fatal bleeds still occur
(cont)
5) If we were to specifically & solely impact the INTRINSIC pathway, either at #FXI or #FXII (NB so far anti-FXII approaches haven't worked), we could #uncouple the intersecting processes of (physiologic) #hemostasis & (pathologic) #thrombosis.
— cardio-met (@cardiomet_CE) September 2, 2024
7) This allows us to see a potential way to "divide and conquer" this process UPSTREAM of the common pathway: by specifically inhibiting (only) #FXI: pic.twitter.com/AO7mY6ElFQ
— cardio-met (@cardiomet_CE) September 2, 2024
8b) Dominant approaches for #stroke ⬇️ in #AFib have been #MAb against #FXI and small molecule inhibitors of #FXIa. Leading candidate from each of these categories currently in Ph 3 trials: MAb #abelacimab in #LILAC #TIMI-76 & small molec #milvexian in #LIBREXIA_AF.
— cardio-met (@cardiomet_CE) September 2, 2024
10a) First, #OCEANIC_AF. At #ESC24, @manesh_patelMD presented the primary analysis. The primary objective was to evaluate whether the oral FXIa small molec inhibitor asundexian when compared w/ apixaban leads to a lower incidence of bleeding in participants with #AF. pic.twitter.com/P8THthR8Tn
— cardio-met (@cardiomet_CE) September 2, 2024
12) Here are the study design, primary #endpoints, and #inclusion & #exclusion criteria. Patients already on #OACs could be enrolled, and target n was 18,000 pts. Randomization was 1:1. pic.twitter.com/JHf4jaucmF
— cardio-met (@cardiomet_CE) September 2, 2024
14) #OCEANIC_AF patient demographics & disposition are shown here. Cohorts were well matched: pic.twitter.com/2iBtSjs6Z8
— cardio-met (@cardiomet_CE) September 2, 2024
16) Here are the efficacy events, safety findings, and adverse event #AE readouts at that juncture. The rate of #SSE overall was lower than expected, and bleeding rates were indeed lower with asundexian: pic.twitter.com/XKOLXlozbN
— cardio-met (@cardiomet_CE) September 2, 2024
18a) ?subgroups generally followed the overall results, but 1 prespecified analysis of interest showed that pts who had been #OAC-naïve prior to rand had similar outcomes with #apixaban or #asundexian . . .
— cardio-met (@cardiomet_CE) September 2, 2024
19a) Per #ESC2024 #ESCCongress presentation from @manesh_patelMD, these are the conclusions & implications from #OCEANIC_AF: pic.twitter.com/szBLQRiMnW
— cardio-met (@cardiomet_CE) September 2, 2024
19c)
— cardio-met (@cardiomet_CE) September 2, 2024
?unlike the other two #FXI/XIa-targeted agents being studied in #AF, #asundexian was not studied for #VTE #prophy in #TKA, & so less is known about its dose-related efficacy to carry into an #AFib population. The drug may have been underdosed in #OCEANIC_AF.
20) Now, on to #AZALEA #TIMI-71. Need a refresher? You can still earn credit by reviewing our live #tweeetorial from #AHA23 at https://t.co/BmdD71IbpA. AZALEA was a Ph 2 comparison of #abelacimab vs #rivaroxaban in pts w/#AF + mod/high risk of #stroke. pic.twitter.com/PWx4Q4rGSN
— cardio-met (@cardiomet_CE) September 2, 2024
22) The ?reduction with investigational #abelacimab compared with on-label #rivaroxaban was indeed impressive: pic.twitter.com/n4O1wVtIzN
— cardio-met (@cardiomet_CE) September 2, 2024
24a) A logical concern arises, however: with activity of #FXI essentially eliminated in #AZALEA pts treated with #abelacimab, did those pts have ⬆️bleeding liability when they had to undergo surgery or other invasive procedures while on therapy?
— cardio-met (@cardiomet_CE) September 2, 2024
25) At #ESC2024, @SidPatelMD shared the characteristics and outcomes of those patients with us. pic.twitter.com/rIzuinHg41
— cardio-met (@cardiomet_CE) September 2, 2024
27a) As a need for both planned (after randomization) and unplanned procedures was anticipated among patients enrolled in #AZALEA #TIMI 71 and therefore maintained on active anticoagulation, the protocol provided guidance on peri-procedural management: pic.twitter.com/oiK9vrrXYj
— cardio-met (@cardiomet_CE) September 2, 2024
28) And, as anticipated, procedures were commonly required during treatment, for about ~1 in 3 patients over median follow-up of 2.1 years. Baseline characteristics among the affected patients was similar. pic.twitter.com/68vUmmnIJn
— cardio-met (@cardiomet_CE) September 2, 2024
30) The median time from last #abelacimab dose (half-life 28d) to procedure was 29d (25-75: 20-42d), and 26% of those undergoing a procedure on abelacimab within 30d of last dose (so no dose interruption) had high expected procedural bleeding risk. pic.twitter.com/gBzXfL2Vzk
— cardio-met (@cardiomet_CE) September 2, 2024
31b) Major or #CRNM ? was uncommon overall & was numerically less common with abelacimab. It was particularly low in the key subgroup (56%) of patients on #abelacimab who underwent procedures within 30d of last dose. Pt-level results were largely consistent. pic.twitter.com/GPZ7ao0GYE
— cardio-met (@cardiomet_CE) September 2, 2024
33) @sidpatel and the #TIMI investigators offered this summary of these #AZALEA secondary analysis data: pic.twitter.com/pj5BzyefiH
— cardio-met (@cardiomet_CE) September 2, 2024
34b) Consistent with epidemiologic data collected from pts with congenital #FXI deficiency, bleeding in such procedures among pts on #abelacimab appears uncommon and of low severity. Certainly, however, more data are needed, especially for higher risk procedures.
— cardio-met (@cardiomet_CE) September 2, 2024
35) Thank you for joining us for this update from #ESC2024 #ESCCongress ! You may now proceed to https://t.co/T6f0nRVJgb and collect your ?CE/#CME certificate! Thanks as always to @CMichaelGibson for leading us through these hot-off-the-presses data!
— cardio-met (@cardiomet_CE) September 2, 2024