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Multicenter Randomized Controlled Trial of Vitamin K Antagonist CLINICAL RESEARCH www.jasn.org 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 An S. De Vriese ,1,2 Rogier Caluwé ,3 Lotte Pyfferoen,4 Dirk De Bacquer,5 Koen De Boeck,6 Joost Delanote,4 Didier De Surgeloose,7 Piet Van Hoenacker,8 Bruno Van Vlem,3 and Francis Verbeke 9 1Division of Nephrology and Infectious Diseases and 4Department of Medical Imaging, AZ Sint-Jan Brugge, Brugge, Belgium; Departments of 2Internal Medicine and 5Public Health, Ghent University, Ghent, Belgium; 3Division of Nephrology and 8Department of Medical Imaging, Onze Lieve Vrouw Hospital, Aalst, Belgium; 6Division of Nephrology and 7Department of Medical Imaging, ZNA Middelheim, Antwerp, Belgium; and 9Division of Nephrology, University Hospital, Ghent, Belgium ABSTRACT Background Vitamin 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. Methods Patients were randomized to VKAs with target INR 2–3, rivaroxaban 10 mg daily, or rivaroxaban 10 mg daily plus vitamin K2 2000 mg 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. Results Baseline 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. Conclusions Withdrawal of VKAs and high-dose vitamin K2 improve vitamin K status in patients on hemo- dialysis, but have no significant favorable effect on VC progression. Severe bleeding complications may be lower with rivaroxaban than with VKAs. JASN 31: ccc–ccc, 2020. doi: https://doi.org/10.1681/ASN.2019060579 Received June 8, 2019. Accepted September 11, 2019. The use of vitamin K antagonists (VKAs) in patients Published online ahead of print. Publication date available at on hemodialysis with nonvalvular atrial fibrillation www.jasn.org. (AF) is the subject of an ongoing debate. The ben- fi Correspondence: Prof. An S. De Vriese, Division of Nephrology e cial effects of VKAs have been mooted, owing to and Infectious Diseases, AZ Sint-Jan Brugge, Brugge, and De- the lack of a straightforward relationship between partment of Internal Medicine, Ghent University, Ghent, Bel- AF and stroke in patients on dialysis and the ab- gium.Email:[email protected] sence of convincing evidence that VKAs reduce Copyright © 2020 by the American Society of Nephrology JASN 31: ccc–ccc,2020 ISSN : 1046-6673/3101-ccc 1 CLINICAL RESEARCH www.jasn.org thromboembolic risk in this patient population.1,2 In Significance Statement addition, a disproportionately increased hazard of bleeding, in particular of hemorrhagic stroke, may tilt the benefit-to- Functional vitamin K deficiency, exacerbated by the use of vitamin K risk ratio of VKAs toward a net harm.1,2 Finally, ample cir- antagonists (VKAs), is thought to contribute to the rapid progression of vascular calcifications in patients on dialysis. We randomized cumstantial evidence implicates VKAs in the development of fi fi patients receiving chronic hemodialysis with atrial brillation to vascular calci cations (VCs), although high-quality clinical VKAs, rivaroxaban, or rivaroxaban with high-dose vitamin K2 sup- data are currently lacking.3,4 VKAs exert their anticoagulant plements. During 18 months of follow-up, vitamin K status improved effects by blocking the ɤ-carboxylation of coagulation factors. significantly by withdrawal of VKAs and vitamin K2 supplementation. Inevitably, they also prevent the activation of other vitamin Nevertheless, changes in coronary artery, thoracic aorta, and K–dependent proteins, some of which play a germane role in cardiac valve calcium scores and pulse wave velocity were not different among the treatment arms. Replacement of VKAs by the inhibition of VC, including matrix Gla protein (MGP), rivaroxaban was safe and potentially associated with less life- Gla-rich proteins, and growth arrest–specific protein 6. The threatening and major bleeding. Further studies should deter- procalcific effects of VKAs are thus intrinsic to their mode of mine whether earlier and multitargeted intervention can halt the action. Notwithstanding the controversy, current guidelines progression of vascular calcifications in dialysis. recommend the consideration of VKAs in patients with a $ 5,6 CHA2DS2-VASc score 2 and VKAs are still commonly calcification scores and also predicts cardiovascular disease used in the dialysis population with AF, albeit with a large and mortality.18,19 We therefore used these methods to eval- 7 practice variability and physician uncertainty. uate VC extent and progression in our study. Dephosphory- In the past few years, the use of direct oral anticoagulants lated uncarboxylated MGP (dp-ucMGP) is the inactive form (DOACs) in the hemodialysis population as an alternative for of MGP and is currently considered to be the most accurate VKAs has gathered momentum, despite a paucity of data on biomarker for vascular vitamin K stores when vascular end fi their safety and effectiveness and speci cdosingguidelines. points are studied.11 Hence, systemic dp-ucMGP levels were fi fi DOACs may have a better risk-bene tpro le, because they also measured to assess vitamin K status in each treatment provide more on-target anticoagulation and are associated group. with lower rates of intracerebral bleeding. Furthermore, they are not expected to accelerate the progression of VC, because they do not interfere with vitamin K metabolism. Selective METHODS inhibition of factor Xa may even have beneficial effects on – the development of atherosclerosis.8 10 Trial Design Patientswith CKD, andin particular those on dialysis, havea This study is an investigator-driven, randomized, prospec- high prevalence of subclinical vitamin K deficiency.11 Because tive, open-label interventional clinical trial, conducted at the propensity for VC may be a key corollary of vitamin K three sites in Belgium (AZ Sint-Jan Brugge, Onze Lieve deficiency, vitamin K supplements have garnered attention Vrouw Ziekenhuis Aalst, ZNA Middelheim Antwerpen). as a means to improve the dismal cardiovascular prognosis The study was approved by appropriately authorized ethics in the dialysis population. However, whether correction of committees in all participating sites and registered on Clin- vascular vitamin K status has a beneficial effect on the pro- icalTrials.gov (identifier NCT02610933). The design of the gression of VC in patients on dialysis is currently unknown.11 study has been described in detail previously.4 The study This study was designed to examine the effect of vitamin K has a three-arm parallel group design with a 1:1:1 allocation deficiency on the development of VC in the hemodialysis pop- ratio (Supplemental Figure 1). ulation. Patients on hemodialysis treated with VKAs epitomize a status of severe vitamin K deficiency, which we Participants sought to compare with replete vitamin K stores as attained by Adults on chronic hemodialysis with nonvalvular AF, with a withdrawal or avoidance of VKA plus administration of high- CHA2DS2-VASc score of $2, and therefore candidates for an- dose vitamin K supplements. To delineate the contribution of ticoagulation therapy or already receiving VKAs, were eligible each measure, an intermediate group was included in whom for inclusion. Inclusion and exclusion criteria are listed in the anticoagulation was achieved by a DOAC without additional Supplemental Material. All patients provided written, in- vitamin K supplements. formed consent. Computed tomography scan of the heart and thoracic aorta is a reliable technique to assess the extent of VC in patients on Interventions and Measurements hemodialysis.12 High calcification scores identify patients at Patients in the first treatment arm were started on a VKA or risk for cardiovascular events and death.13,14 Calcification continued the VKA, with dose adjustments to achieve an in- scores have been widely used as surrogate markers to assess ternational normalized ratio of 2–3 on the basis of weekly the effect of an intervention on cardiovascular risk in patients international normalized ratio measurements. Time in the with CKD and on hemodialysis.15–17 Arterial stiffness quan- therapeutic range was recorded. Patients in the second treat- tified by pulse wave velocity (PWV) correlates with ment arm received a daily dose of 10 mg rivaroxaban. The 2 JASN JASN 31: ccc–ccc,2020 www.jasn.org CLINICAL RESEARCH choice of this dose was on the basis of a comprehensive
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