edoxaban and Atherosclerosis

Non-vitamin K antagonist oral anticoagulants (NOACs) are well-established as inhibitors of factor Xa (FXa) and thrombin in the treatment and prevention of thrombosis. However, there is growing evidence that beneficial outcomes might be based on additional pleiotropic effects beyond anticoagulation. FXa and thrombin are also known to activate protease-activated receptors (PARs), which can mediate pro-inflammatory and pro-fibrotic effects. Since PAR‑1 and PAR‑2 play an important role in the development of atherosclerosis, the inhibition of this pathway represents an interesting potential target for preventing the progression of atherosclerosis and fibrosis. This review focuses on potential pleiotropic effects of FXa inhibition with edoxaban seen in a variety of studies in different in vitro and in vivo test systems. As common findings from these experiments, edoxaban was able to attenuate FXa- and thrombin-induced pro-inflammatory and pro-fibrotic effects and decrease pro-inflammatory cytokine expression. In some, but not all experiments edoxaban was also shown to decrease the levels of PAR‑1 and PAR‑2 expression. Further studies are required to clarify the clinical implications of the pleiotropic effects mediated by NOACs.. Nicht-Vitamin-K-antagonistische orale Antikoagulanzien (NOAK) sind als Inhibitoren von Faktor Xa (FXa) und Thrombin in der Behandlung und Prävention von Thrombosen etabliert. Es gibt jedoch zunehmend Hinweise darauf, dass die positiven Ergebnisse auf zusätzlichen pleiotropen Effekten beruhen, die über die Antikoagulation hinausgehen. Faktor Xa und Thrombin können proteaseaktivierte Rezeptoren (PAR) aktivieren, welche proinflammatorische und profibrotische Wirkungen vermitteln. Da PAR‑1 und PAR‑2 eine wichtige Rolle bei der Entstehung von Atherosklerose spielen, stellt die Hemmung dieses Signalwegs ein interessantes potenzielles Ziel dar, um das Fortschreiten von Atherosklerose und Fibrose zu inhibieren. Diese Übersichtsarbeit konzentriert sich auf die potenziellen pleiotropen Effekte der FXa-Hemmung durch Edoxaban, die in einer Vielzahl von Studien in verschiedenen In-vitro- und In-vivo-Testsystemen beobachtet wurden. Übereinstimmende Ergebnisse dieser Studien zeigten, dass Edoxaban die durch FXa und Thrombin induzierten proinflammatorischen und profibrotischen Effekte abschwächen und die Expression proinflammatorischer Zytokine verringern konnte. In einigen, aber nicht allen Experimenten konnte Edoxaban auch die Expression von PAR‑1 und PAR‑2 reduzieren. Weitere Studien sind erforderlich, um die klinischen Auswirkungen der von NOAKs vermittelten pleiotropen Effekte zu untersuchen.

Topics: Administration, Oral; Anticoagulants; Atherosclerosis; Humans; Thrombin

To evaluate the current interpretation of the lower doses of direct oral anticoagulants (DOAC) dabigatran, apixaban, edoxaban and rivaroxaban in nonvalvular atrial fibrillation.. A questionnaire of 14 statements to which the possible answers were fully agree/partially agree/partially disagree/fully disagree or yes/no was prepared within the board of the Italian Atherosclerosis, Thrombosis and Vascular Biology Study Group and forwarded to individual Italian physicians.. A total of 620 complete questionnaires were received from nearly all the Italian regions and physicians of various medical specialists, either enabled or not for the prescription of DOAC. A wide agreement was found as regards the pharmacological, as well as clinical consequences of the administration of the lower dose of factor-Xa inhibitors both in patients with and without clinical and/or laboratory criteria requiring dose reduction. Wide agreement was also found as regards the presence of moderate kidney insufficiency in selecting the dose of DOAC. Instead, more debated were issues regarding the proportionality between dabigatran dose and plasma concentration and selection of dabigatran dose, as well as the role of measuring drug plasma concentration and/or determine the anticoagulant activity of factor-Xa inhibitors when used at the lower dose.. The interpretation of the lower doses of DOAC in current Italian clinical practice appears largely correct and shared. Because of the persistence of some residual uncertainties, essentially regarding dabigatran, however, continuous educational effort still appears warranted.

Topics: Administration, Oral; Anticoagulants; Atherosclerosis; Atrial Fibrillation; Dabigatran; Dose-Response Relationship, Drug; Factor Xa Inhibitors; Humans; Italy; Pyrazoles; Pyridines; Pyridones; Renal Insufficiency; Rivaroxaban; Surveys and Questionnaires; Thiazoles; Thrombosis; Treatment Outcome

Oral anticoagulation prevents thromboembolism in atrial fibrillation. Factor Xa inhibitors, like edoxaban, are known to reduce inflammation and proliferation of smooth muscle cells, while vitamin K antagonism can cause vascular calcific damage. The influence of edoxaban compared to warfarin on vascular remodeling, atherosclerosis and arteriogenesis is unknown.. Apolipoprotein E knockout (ApoE. There was no difference in hind-limb perfusion restoration between the three groups after 14 days (Co 0.36 ± 0.05 vs. Warf 0.39 ± 0.09 (p = .39), Co vs. Edo 0.51 ± 0.06 (p = .089), Warf vs. Edo (p = .83)) after ligation. Immuno-histologically, there was no difference in smooth muscle cell count in both hindlimbs between the three groups or in the amount of perivascular macrophages in collateral-bearing hindlimb tissue. Edoxaban showed the lowest amount of plaque tissue in the aortic sinus tissue (Co 74 ± 11% vs. Edo 62 ± 12% (p = .024), Co vs. Warf 69 ± 14% (p = .30), Edo vs. Warf (p = .14)) as well as the least amount of fibrosis (Co 3.1 ± 0.9% vs. Edo 1.7 ± 0.6% (p = .027), Co vs. Warf 4.1 ± 0.7% (p = .081), Edo vs. Warf (p < .001)). No difference in mRNA content of inflammatory cytokines in muscle tissue or spleen was detected between the three groups.. These data suggest that treatment with edoxaban unlike warfarin prevents vascular maladaptive remodeling, which may be clinically important.

Topics: Animals; Anticoagulants; Atherosclerosis; Collateral Circulation; Disease Models, Animal; Factor Xa Inhibitors; Fibrosis; Hindlimb; Ischemia; Mice, Inbred C57BL; Mice, Knockout, ApoE; Muscle, Skeletal; Neovascularization, Physiologic; Plaque, Atherosclerotic; Pyridines; Thiazoles; Vascular Remodeling; Warfarin