1/21 In this #CME, Geoff Barnes, MD provides the latest information on investigational factor XI/XIa (FXI/XIa) inhibitors and their potential role in managing stroke risk in patients with AF. Get credit: link.med-iq.com/PBVC33

3/Aren’t DOACs enough?

4/Why FXI/XIa? 🔹It is important for thrombosis, but less so for hemostasis 🔹It strengthens clot formation during hemostasis 🔹Its activation is necessary to form clots at injury sites in thrombosis

5/Where DOACs and VKAs target the thrombosis and hemostasis pathways: 🔹DOACs bind FXa to prevent it from converting prothrombin (FII) to thrombin (FIIa) 🔹VKAs inhibit production of clotting factors FII, FVII, FIX, and FX

6/FXI/XIa inhibitors decouple thrombosis from hemostasis by targeting the thrombin amplification loop (where thrombin normally acts on FXI to activate FXIa).

7/The following strategies are currently in clinical development.

8/The following investigational FXI/XIa inhibitors are currently in clinical trials; none have been approved yet for use in the US or Europe.

9/Findings from a meta-analysis of patients undergoing knee arthroplasty: 🔹41% reduction in VTE with an FXI inhibitor 🔹59% reduction in bleeding risk with an FXI inhibitor 🔹Asundexian was not included

10/Which clinical studies have investigated FXI/XIa inhibitor therapy in patients with AF so far? 🔹Abelacimab phase 2 AZALEA-TIMI 71 🔹Asundexian phase 3 OCEANIC-AF

11/Results for AZALEA-TIMI 71 (abelacimab phase 2): 🔹Stopped early—greater-than-expected reduction in bleeding events with abelacimab vs rivaroxaban 🔹Low rates of perioperative bleeding 🔹Favorable safety profile in those with CKD

12/Results for OCEANIC-AF (asundexian phase 3): 🔹Terminated early—rate of stroke and SE were higher in asundexian arm vs apixaban arm 🔹ISTH major bleeding scores were lower in asundexian arm

13/Possible explanations for OCEANIC-AF results:

14/Ongoing FXI/XIa clinical studies in patients with AF: 🔹Abelacimab phase 3 LILAC-TIMI 76 🔹Milvexian phase 3 LIBREXIA-AF

15/LILAC-TIMI 76 (abelacimab phase 3): 🔹For high-risk patients with AF or atrial flutter who are unable or unwilling to use anticoagulant therapy

16/LIBREXIA-AF (milvexian phase 3): 🔹For patients with AF or atrial flutter

17/What other clinical trials for FXI/XIa inhibitors are in progress?

18/Recommendations for the management of bleeding risk in patients participating in clinical trials for these investigational treatments.

19/Key takeaways: 🔹Despite DOAC use, patients with AF continue to have both increased stroke and bleeding risks 🔹Many patients with AF are not receiving any stroke-prevention therapy due to concerns about bleeding risk

20/Key takeaways (continued): 🔹FXI/XIa inhibitors offer a unique opportunity to reduce thrombotic risk without significantly increasing bleeding risk 🔹Ongoing phase 3 studies will determine whether FXI/XIa inhibitors can further reduce stroke risk in patients with AF