Long-lasting Rivaroxaban Use Is Associated With Lower Aortic Valve Leaflet Calcification in Severe Aortic Stenosis

In vitro studies have demonstrated that direct oral anticoagulants (DOACs) downregulate expression of proteins involved in calcification and inflammation. In this hypothesis-testing study we evaluated whether DOAC therapy was associated with decreased valvular calcification in patients with aortic stenosis (AS) who were anticoagulated due to concomitant atrial fibrillation (AF).

In this case-control study, 72 Caucasian patients with isolated severe AS were compared with 53 individuals with AF concomitant to severe AS who were treated with DOACs for 28.7 ± 13.8 months. Sixteen valves from AS patients on rivaroxaban (20 mg/day, AS-RIVA group) and 20 valves from age- and sex-matched non-anticoagulated patients with AS were subjected to microcomputed tomography (micro-CT) to estimate valvular calcification ex vivo. Calcium volume (CV), surface volume (SV), CV/SV ratio, and trabecular thickness (TbTh) were assessed. Valvular expression of osteopontin, nuclear factor-kappaB (NF-κB), and interleukin-6 (IL-6) were evaluated by immunostaining.

Micro-CT showed that patients taking rivaroxaban had a lower CV (-62.7%), lower SV (-46.2%), decreased CV/SV ratio (-35.6%), and maximal TbTh (-21.1%) when compared with patients not taking the drug (P < 0.05 for all). The duration of rivaroxaban use correlated inversely with micro-CT parameters, peak transvalvular velocity, and maximal transvalvular pressure gradient. Decreased valvular expression of osteopontin (-20.4%) and NF-κB (-26%) and 2-fold lower IL-6 fluorescence intensity were observed in the AS-RIVA group compared with the remainder (P < 0.05 for all). Moreover, osteopontin expression was inversely associated with duration of rivaroxaban use and positively with micro-CT parameters.

Long-term rivaroxaban use in AS patients was associated with lower aortic valve leaflet calcification, -as reflected by micro-CT parameters, and osteopontin expression, suggesting a potential impact of rivaroxaban on valvular calcification.