Making anticoagulation safer

Abstract

Oral anticoagulants currently used for prevention or treatment of thrombosis inhibit the proteases factor Xa (FXa) or thrombin, or lower the plasma concentrations of their precursors, factor X and prothrombin. Numerous studies document the effectiveness of these agents. However, their use also leads to substantial increases in major and minor bleeding. 1 Jiang H Jiang Y Ma H Zeng H Lv J Effects of rivaroxaban and warfarin on the risk of gastrointestinal bleeding and intracranial hemorrhage in patients with atrial fibrillation: systematic review and meta-analysis. Clin Cardiol. 2021; 44: 1208-1215 Google Scholar , 2 Wysowski DK Nourjah P Swartz L Bleeding complications with warfarin use: a prevalent adverse effect resulting in regulatory action. Arch Intern Med. 2007; 167: 1414-1419 Google Scholar This is not surprising; FXa and thrombin are at the core of the system that stems bleeding after blood vessel injury. Drugs targeting these proteases, therefore, can compromise haemostasis, and bleeding restricts the intensity of anticoagulation that can be tolerated. Furthermore, many patients who would benefit from anticoagulation are ineligible for treatment because co-existing conditions place them at unacceptable risk for bleeding. Clearly, safer antithrombotic strategies are required. Specifically, we need to identify drug targets that are important for driving or sustaining pathological thrombus formation, but that are less important to haemostasis than are FXa and thrombin. 3 Hsu C Hutt E Bloomfield DM Gailani D Weitz JI Factor XI inhibition to uncouple thrombosis from hemostasis: JACC review topic of the week. J Am Coll Cardiol. 2021; 78: 625-631 Google Scholar Mounting evidence indicates the plasma protease factor XIa (FXIa) is such a target. Safety of the oral factor XIa inhibitor asundexian compared with apixaban in patients with atrial fibrillation (PACIFIC-AF): a multicentre, randomised, double-blind, double-dummy, dose-finding phase 2 studyThe FXIa inhibitor asundexian at doses of 20 mg and 50 mg once daily resulted in lower rates of bleeding compared with standard dosing of apixaban, with near-complete in-vivo FXIa inhibition, in patients with atrial fibrillation. Full-Text PDF