Multicenter Randomized Controlled Trial of Vitamin K Antagonist Replacement by Rivaroxaban with or without Vitamin K2 in Hemodialysis Patients with Atrial Fibrillation: the Valkyrie Study

Abstract

BackgroundVitamin K antagonists (VKAs), although commonly used to reduce thromboembolic risk in atrial fibrillation, have been incriminated as probable cause of accelerated vascular calcification (VC) in patients on hemodialysis. Functional vitamin K deficiency may further contribute to their susceptibility for VC. We investigated the effect of vitamin K status on VC progression in 132 patients on hemodialysis with atrial fibrillation treated with VKAs or qualifying for anticoagulation.MethodsPatients were randomized to VKAs with target INR 2–3, rivaroxaban 10 mg daily, or rivaroxaban 10 mg daily plus vitamin K2 2000 µg thrice weekly during 18 months. Systemic dp-ucMGP levels were quantified to assess vascular vitamin K status. Cardiac and thoracic aorta calcium scores and pulse wave velocity were measured to evaluate VC progression.ResultsBaseline dp-ucMGP was severely elevated in all groups. Initiation or continuation of VKAs further increased dp-ucMGP, whereas levels decreased in the rivaroxaban group and to a larger extent in the rivaroxaban+vitamin K2 group, but remained nevertheless elevated. Changes in coronary artery, thoracic aorta, and cardiac valve calcium scores and pulse wave velocity were not significantly different among the treatment arms. All cause death, stroke, and cardiovascular event rates were similar between the groups. Bleeding outcomes were not significantly different, except for a lower number of life-threatening and major bleeding episodes in the rivaroxaban arms versus the VKA arm.ConclusionsWithdrawal of VKAs and high-dose vitamin K2 improve vitamin K status in patients on hemodialysis, but have no significant favorable effect on VC progression. Severe bleeding complications may be lower with rivaroxaban than with VKAs.

Vitamin K Supplementation for the Prevention of Cardiovascular Disease: Where Is the Evidence? A Systematic Review of Controlled Trials

“…Otherwise, sequence generation and allocation concealment was deemed unclear if not reported and was high in one trial due to deviation from the intended intervention [ 18 ]. Two trials were at high risk of bias with regard to blinding of participants and personnel based on their open-label study design [ 13 , 14 ]. In the majority of cases, blinding of outcome assessors was deemed either low risk or unclear if it was not specifically reported.…”

“…Three studies examined changes in coronary artery calcification (CAC) scores. All three found no significant difference with vitamin K supplementation in their intention-to-treat analyses [ 14 , 17 , 19 ]. However, Shea et al found a positive impact of vitamin K1 supplementation on attenuating CAC progression in two subgroups: those who were >85% adherent to the treatment protocol, and those who had pre-existing CAC (baseline Agatston scores ≥10) [ 19 ].…”

Reduced Vitamin K Status as A Potentially Modifiable Prognostic Risk Factor in COVID-19

“…Dp-ucMGP inversely relates to mortality and other clinical meaningful endpoints in various cohorts [12,15,[23][24][25][26][27][28][29][30]. Supplementation of vitamin K has a reducing effect on dp-ucMGP levels [22,31], and the opposite holds true with regard of the use of VKAs [22,[32][33][34]. Furthermore, vitamin K administration decelerated progression of aortic valve calcification [35], arterial stiffness [36], and bone loss [37].…”

Molecular and Cellular Mechanisms that Induce Arterial Calcification by Indoxyl Sulfate and P-Cresyl Sulfate

“…All of these data suggest that coagulation and vascular calcification are interconnected and that the uremic toxins IS and PCS could play an important role herein. However, a recent multicenter randomized controlled trial showed that withdrawal of vitamin K antagonists in hemodialysis patients did not influence progression of arterial calcification progression after 18 months [40]. These conflicting data again indicate that the arterial calcification process is the result of a complex interplay between different pathological pathways.…”