Rivaroxaban Counteracts the Adverse Effects of Warfarin on Plaque Vulnerability and Vessel Wall Remodelling

Atherosclerosis is a major cause of cardiovascular diseases (CVDs) globally, characterized by vascular calcification (VC), increasing the risk of myocardial infarction and stroke. Oral anticoagulants are widely prescribed to prevent recurrent thrombotic events. However, increasing concern surrounds warfarin, whose unfavorable pharmacokinetic profile and interference with vitamin K-dependent pathways have been implicated in VC. Rivaroxaban represents an alternative anticoagulant, yet its ability to mitigate warfarin-induced vascular injury remains insufficiently defined. This study investigated whether switching from warfarin to rivaroxaban benefits plaque progression and might hold progression of calcification. Apolipoprotein E-deficient (Apoe−/− ) mice were fed a Western-type diet (WTD) for 18 weeks, supplemented without (control) or with either warfarin or rivaroxaban. An additional group received warfarin for 6 weeks, after which they switched to rivaroxaban for 12 weeks. Plaque size was comparable in both the continuous rivaroxaban group and the switching group and was decreased compared with 18 weeks in both the warfarin and control groups. Notably, VC was decreased in both rivaroxaban groups, with a more significant decrease observed in the switching group compared with continuous warfarin treatment. The switching group showed better vascular integrity with lower vascular stiffness and fewer elastic fiber breaks. Additionally, the switching group showed features of a more stable plaque phenotype with increased α-smooth muscle actin (αSMA)-positive vascular smooth muscle cells and a higher collagen content. Interestingly, all three anticoagulation therapies showed decreased expression of protease-activated receptor 2 (PAR2) together with a decrease in oxidative stress in the plaques. However, only rivaroxaban treatments showed reduced matrix metalloproteinase 9 (MMP-9) expression in plaques compared with both control and warfarin groups. Our results suggest that rivaroxaban ameliorates the adverse effects of warfarin, offering significant benefits on atherosclerotic burden and plaque stability. Transitioning from warfarin to rivaroxaban has the potential to reshape clinical practice by offering anticoagulation and reducing the practical limitations associated with vitamin K antagonists, particularly in patients with coexisting CVDs.