Clinical Research

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, Rogier Caluwé, Lotte Pyfferoen, Dirk De Bacquer, Koen De Boeck, Joost Delanote, Didier De Surgeloose, Piet Van Hoenacker, Bruno Van Vlem and Francis Verbeke
JASN January 2020, 31 (1) 186-196; DOI: https://doi.org/10.1681/ASN.2019060579

Significance Statement

Functional vitamin K deficiency, exacerbated by the use of vitamin K antagonists (VKAs), is thought to contribute to the rapid progression of vascular calcifications in patients on dialysis. We randomized patients receiving chronic hemodialysis with atrial fibrillation to VKAs, rivaroxaban, or rivaroxaban with high-dose vitamin K2 supplements. During 18 months of follow-up, vitamin K status improved significantly by withdrawal of VKAs and vitamin K2 supplementation. Nevertheless, changes in coronary artery, thoracic aorta, and cardiac valve calcium scores and pulse wave velocity were not different among the treatment arms. Replacement of VKAs by rivaroxaban was safe and potentially associated with less life-threatening and major bleeding. Further studies should determine whether earlier and multitargeted intervention can halt the progression of vascular calcifications in dialysis.

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 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.

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 hemodialysis, but have no significant favorable effect on VC progression. Severe bleeding complications may be lower with rivaroxaban than with VKAs.

The use of vitamin K antagonists (VKAs) in patients on hemodialysis with nonvalvular atrial fibrillation (AF) is the subject of an ongoing debate. The beneficial effects of VKAs have been mooted, owing to the lack of a straightforward relationship between AF and stroke in patients on dialysis and the absence of convincing evidence that VKAs reduce thromboembolic risk in this patient population.1,2 In addition, a disproportionately increased hazard of bleeding, in particular of hemorrhagic stroke, may tilt the benefit-to-risk ratio of VKAs toward a net harm.1,2 Finally, ample circumstantial evidence implicates VKAs in the development of vascular calcifications (VCs), although high-quality clinical data are currently lacking.3,4 VKAs exert their anticoagulant effects by blocking the ɤ-carboxylation of coagulation factors. Inevitably, they also prevent the activation of other vitamin K–dependent proteins, some of which play a germane role in the inhibition of VC, including matrix Gla protein (MGP), Gla-rich proteins, and growth arrest–specific protein 6. The procalcific effects of VKAs are thus intrinsic to their mode of action. Notwithstanding the controversy, current guidelines recommend the consideration of VKAs in patients with a CHA2DS2-VASc score ≥25,6 and VKAs are still commonly used in the dialysis population with AF, albeit with a large practice variability and physician uncertainty.7

In the past few years, the use of direct oral anticoagulants (DOACs) in the hemodialysis population as an alternative for VKAs has gathered momentum, despite a paucity of data on their safety and effectiveness and specific dosing guidelines. DOACs may have a better risk-benefit profile, because they provide more on-target anticoagulation and are associated 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 inhibition of factor Xa may even have beneficial effects on the development of atherosclerosis.8–10

Patients with CKD, and in particular those on dialysis, have a high prevalence of subclinical vitamin K deficiency.11 Because the propensity for VC may be a key corollary of vitamin K deficiency, vitamin K supplements have garnered attention as a means to improve the dismal cardiovascular prognosis in the dialysis population. However, whether correction of vascular vitamin K status has a beneficial effect on the progression of VC in patients on dialysis is currently unknown.11

This study was designed to examine the effect of vitamin K deficiency on the development of VC in the hemodialysis population. Patients on hemodialysis treated with VKAs epitomize a status of severe vitamin K deficiency, which we sought to compare with replete vitamin K stores as attained by withdrawal or avoidance of VKA plus administration of high-dose vitamin K supplements. To delineate the contribution of each measure, an intermediate group was included in whom anticoagulation was achieved by a DOAC without additional vitamin K supplements.

Computed tomography scan of the heart and thoracic aorta is a reliable technique to assess the extent of VC in patients on hemodialysis.12 High calcification scores identify patients at risk for cardiovascular events and death.13,14 Calcification scores have been widely used as surrogate markers to assess the effect of an intervention on cardiovascular risk in patients with CKD and on hemodialysis.15–17 Arterial stiffness quantified by pulse wave velocity (PWV) correlates with calcification scores and also predicts cardiovascular disease and mortality.18,19 We therefore used these methods to evaluate VC extent and progression in our study. Dephosphorylated uncarboxylated MGP (dp-ucMGP) is the inactive form of MGP and is currently considered to be the most accurate biomarker for vascular vitamin K stores when vascular end points are studied.11 Hence, systemic dp-ucMGP levels were also measured to assess vitamin K status in each treatment group.

Methods

Trial Design

This study is an investigator-driven, randomized, prospective, open-label interventional clinical trial, conducted at three sites in Belgium (AZ Sint-Jan Brugge, Onze Lieve Vrouw Ziekenhuis Aalst, ZNA Middelheim Antwerpen). The study was approved by appropriately authorized ethics committees in all participating sites and registered on ClinicalTrials.gov (identifier NCT02610933). The design of the study has been described in detail previously.4 The study has a three-arm parallel group design with a 1:1:1 allocation ratio (Supplemental Figure 1).

Participants

Adults on chronic hemodialysis with nonvalvular AF, with a CHA2DS2-VASc score of ≥2, and therefore candidates for anticoagulation therapy or already receiving VKAs, were eligible for inclusion. Inclusion and exclusion criteria are listed in the Supplemental Material. All patients provided written, informed consent.

Interventions and Measurements

Patients in the first treatment arm were started on a VKA or continued the VKA, with dose adjustments to achieve an international normalized ratio of 2–3 on the basis of weekly international normalized ratio measurements. Time in the therapeutic range was recorded. Patients in the second treatment arm received a daily dose of 10 mg rivaroxaban. The choice of this dose was on the basis of a comprehensive pharmacokinetic and pharmacodynamic analysis in patients on hemodialysis, revealing that a dose of 10 mg provided a similar exposure as a dose of 20 mg in healthy individuals.20 Patients in the third treatment arm received a daily dose of 10 mg rivaroxaban and 2000 µg menaquinone-7 (MK-7) thrice weekly after dialysis with directly observed therapy to ensure adherence. MK-7 is a form of vitamin K2 that has a superior absorption and bioavailability as compared with other menaquinones and vitamin K1.21,22 The choice of the dose was on the basis of a short-term dose-finding study in patients receiving chronic hemodialysis.23 Incremental doses of 360, 720, and 1080 µg MK-7 thrice weekly resulted in a dose-proportional decrease of the dp-ucMGP levels (17%, 33%, and 46%, respectively), without achieving a plateau phase.23 For this study, the dose of MK-7 was therefore increased to 2000 µg thrice weekly.

Clinical data, biochemical data, imaging data, and PWV data were collected at baseline, 6, 12, and 18 months. Subjective tolerability was evaluated by questioning the patients about adverse events or by spontaneous reporting of adverse events by the patients. Objective tolerability was evaluated by monitoring vital signs and routine clinical laboratory tests. Primary outcome measures were change of coronary artery calcification, thoracic aorta calcification, and PWV over 18 months versus baseline. Secondary outcome measures are listed in the Supplemental Material.

Biochemical Analysis

Blood samples were taken at the start of dialysis at the dialyzer inlet line. Plasma was obtained by 15 minutes of centrifugation with a Rotina 38R and stored at −80°C in three aliquots of 1 ml until dry-ice shipment for central analysis. Circulating dp-ucMGP was quantified using an automated assay (Ina K tif MGP iSYS kit; IDS, Boldon, UK).

Imaging

For calcification assessment, an unenhanced electrocardiographically gated computed tomography of the heart and thoracic aorta was performed at 120 kV on a Revolution (GE Healthcare), Aquillion One (Toshiba), or Somatom Definition Flash (Siemens) scanner. To limit artifacts owing to high heart rates (>70 Bpm), β-blockade (bisoprolol 2.5–5 mg) was administered orally 60 minutes before scanning when necessary. Calcium scores were calculated on 2.5-mm slices using Smartscore v.4.0 (GE Healthcare) by the Agatston method24 and by the volume method.25 All foci within the arteries with attenuation >130 Hounsfield units (Hu) and a minimum area of 1 mm2 were considered significant and were counted into the total score. An Agatston score for each calcific lesion was calculated by multiplying the density factor (1, 130–199 Hu; 2, 200–299 Hu; 3, 300–399 Hu; and 4, ≥400 Hu) by the area. A total Agatston score was obtained by adding the scores of all individual lesions in all slice levels. The total volume score was obtained by adding the volumes of all >130 Hu lesions. One experienced investigator (L.P.) reviewed all scans for consistency of interpretation. For each subject, all imaging procedures were done on the same equipment using the same parameters at each session to permit valid longitudinal image comparisons. Scans started in the upper thorax above the aortic arch, advancing caudally to the level of the diaphragm to include the coronary arteries, the aortic and mitral valve, and the ascending and descending thoracic aorta. Segments with stents were excluded from the analysis. In patients with coronary artery bypass grafts, the coronary arteries were excluded from the analysis in case of imaging artifacts.

PWV

Hemodynamic measurements were performed in the supine position by trained research nurses during the first hour of the midweek dialysis session. Mean arterial pressure (MAP) was calculated as diastolic BP+0.4×(systolic BP–diastolic BP), on the basis of the mean of two measurements. PWV was obtained by sequential recording of electrocardiogram-gated carotid and femoral artery pressure waves using applanation tonometry (SphygmoCor version 7; AtCor Medical, Sydney, Australia), as described previously.26 The path length was calculated as 0.8 times the direct distance between the carotid and femoral recording sites. PWV was calculated as the path length divided by transit time (m/s).

Statistical Methods

Sample size calculation, randomization method, and blinding considerations are described in the Supplemental Material. Descriptive statistics used were proportions, means, SDs, medians, and interquartile ranges (IQRs). Baseline and end-of-study characteristics at 18 months were compared between the study arms according to Fisher’s exact test for categoric variables and the Kruskal–Wallis test for continuous variables. Associations between baseline dp-ucMGP levels and PWV, calcification scores, and dialysis and warfarin vintages were evaluated using Spearman rho coefficients, partialized for age, sex, body mass index, systolic BP, presence of diabetes, parathyroid hormone, calcium, phosphate, cardiovascular history, and statin use. Percentage changes in calcification scores were calculated as the change in calcification scores from baseline divided by the baseline value+1, the latter to account for zero values at baseline. Percentage changes at 18 months were annualized by dividing them by a factor of 1.5. Proportions of “rapid progressors,” i.e., patients with an annualized percentage change of ≥15%, were compared between treatment groups according to Fisher’s exact test. To account for clustering of multiple observations over time within patients, changes from baseline were analyzed according to mixed linear regression modeling for continuous data (dp-ucMGP levels, other laboratory parameters, calcification scores, PWV, MAP) and mixed logistic regression modeling for binary data (use of cinacalcet, sevelamer, calcium containing binders, and alfacalcidol). In these models, a random intercept at the patient level was used, time as a fixed factor, and an unstructured covariance matrix. Differences in changes over time across treatment groups were analyzed by evaluating the treatment-by-time interaction in these mixed-effects models. To deal with the considerable skewness in both calcification scores and in their changes, Agatston and volume were entered in these models after square root transformation in line with previous studies.27 Goodness-of-fit statistics for all models demonstrated acceptable fit to the data. Estimated marginal mean changes from baseline and their 95% confidence intervals at 6, 12, and 18 months, as depicted in Figures 1, A and B and 2, A–D, were obtained from the mixed models. Survival times, as well as times to the first bleeding episode occurring during the total observation period of 18 months, were compared between the treatment arms using Cox proportional hazards models. The total number of bleeding events across patients was compared using Poisson regression analysis. We considered a two-sided P value <0.05 to indicate statistical significance. All analyses were on the basis of the intention-to-treat principle.

Figure 1.
Figure 1.

Changes in dp-ucMGP levels over time in the VKA (beige squares), rivaroxaban (blue triangles), and rivaroxaban+vitamin K2 (red circles) groups. (A) Estimated marginal mean changes from baseline (95% confidence interval) in the entire study population (P<0.001). (B) Estimated marginal mean changes from baseline (95% confidence interval) in the patients with a warfarin vintage of 0 (n=34) (P<0.01).

Figure 2.
Figure 2.

Changes in coronary artery and thoracic aorta calcium scores over time in the VKA (beige squares), rivaroxaban (blue triangles), and rivaroxaban+vitamin K2 (red circles) groups. (A) Estimated marginal mean changes in total coronary artery Agatston scores from baseline (95% confidence interval) (P=0.364). (B) Estimated marginal mean changes in total coronary artery volume scores from baseline (95% confidence interval) (P=0.616). (C) Estimated marginal mean changes in thoracic aorta Agatston scores from baseline (95% confidence interval) (P=0.210). (D) Estimated marginal mean changes in thoracic aorta volume scores from baseline (95% confidence interval) (P=0.707). Sqrt, square root.

Results

Participants

Between February of 2015 and July of 2017, 143 patients on hemodialysis with documented AF were evaluated and 132 enrolled (Supplemental Figure 2). The overall study population was almost exclusively of western European ancestry, and had a median dialysis vintage of 2.4 years with 16.7% patients receiving incident dialysis, a median CHA2DS2-VASc score of 5.0 with a 30.3% history of stroke, a median warfarin vintage of 1.1 years including 34.8% patients with a warfarin vintage <3 months and 25.8% patients who were warfarin-naïve, and a median HAS-BLED score of 5.0 with a 28.0% history of gastrointestinal bleeding. Baseline demographic and clinical characteristics (Table 1), baseline biochemical characteristics (Supplemental Table 1), and baseline maintenance medication (Supplemental Table 2) were not different between the groups. Baseline calcification scores (Table 2) and baseline hemodynamic parameters and PWV (Table 3) were not significantly different across the treatment arms.

View this table:
Table 1.

Baseline demographic and clinical characteristics

View this table:
Table 2.

Baseline calcification scores

View this table:
Table 3.

Baseline hemodynamic parameters and PWV

The 132 patients represented 163.5 person-years of observation over the course of the study. Follow-up was incomplete in 55 patients, due to death (n=47) or withdrawal of consent (n=8). In 14 patients, the study drug (VKA or rivaroxaban) was discontinued, in all but one case (patient unwilling) as a consequence of a bleeding event. In the rivaroxaban+vitamin K2 arm, only rivaroxaban was withdrawn and vitamin K2 supplements were continued (Supplemental Figure 2).

Median (IQR) dp-ucMGP at baseline was 1983 (1486–3087) pmol/L in the VKA arm, 1632 (1083–2390) pmol/L in the rivaroxaban arm, and 1598 (1058–3324) pmol/L in the rivaroxaban+vitamin K2 arm (P=0.12). Baseline dp-ucMGP levels were strongly correlated with warfarin vintage (partial Spearman rho, +0.44, P<0.001) after adjustment for age, sex, body mass index, systolic BP, presence of diabetes, parathyroid hormone, calcium, phosphate, cardiovascular history, and statin use. No significant associations between baseline dp-ucMGP and baseline calcification scores, baseline PWV (partial Spearman rho, −0.19, P=0.17), or dialysis vintage (partial Spearman rho, −0.09, P=0.32) were observed.

Mixed modeling demonstrated that the change in dp-ucMGP levels over time was significantly different across treatment arms (P<0.001) (Figure 1A). Dp-ucMGP levels increased significantly in the VKA arm (P=0.03), whereas levels decreased significantly in the rivaroxaban arm (P=0.04) and the rivaroxaban+vitamin K2 arm (P=0.04). In the rivaroxaban and rivaroxaban+vitamin K2 groups, dp-ucMGP levels dropped significantly after 6 months and remained stable from then on throughout the entire observation period (P=0.65). Decreases in dp-ucMGP levels were significantly larger when vitamin K2 was added to rivaroxaban (P=0.004). At 18 months, median (IQR) dp-ucMGP was 2967 (1982–4737) pmol/L in the VKA group, 981 (729–1453) pmol/L in the rivaroxaban group, and 853 (707–1176) pmol/L in the rivaroxaban+vitamin K2 group (P<0.001). Drops in dp-ucMGP levels induced by vitamin K2 were not associated with diabetes status (P=0.48) or with the use of phosphate binders (P=0.42). In the subgroup of patients who were warfarin-naïve (n=34, 25.8%), the change in dp-ucMGP levels over time was also significantly different across treatment arms (P<0.01), with an increase in the VKA group, stable levels in the rivaroxaban group, and a decrease in the rivaroxaban+vitamin K2 group (Figure 1B).

Over the course of the 18 months of observation, changes in calcium, phosphate, parathyroid hormone levels, and HgA1c (in patients with diabetes); in MAP; and in use of phosphate binders, cinacalcet, and active vitamin D were not significantly different between the study groups (Supplemental Table 3).

Primary Outcomes

Mixed model analyses revealed that longitudinal changes in calcification were not significantly different between the treatment groups (total coronary arteries Agatston score P=0.36, total coronary arteries volume score P=0.62, thoracic aorta Agatston score P=0.21, thoracic aorta volume score P=0.71; Figure 2, A–D). The percentage changes from baseline values over 18 months in Agatston calcification scores and calcium volume scores were not significantly different between the treatment groups (Tables 4 and 5). After 18 months, the proportion of patients with an annualized percentage change in Agatston calcification scores of ≥15% was not different between the VKA, rivaroxaban, and rivaroxaban+vitamin K2 arms: 50.0%, 47.4%, and 40.0% (P=0.87) for the sum of the coronary arteries and 50%, 44.4%, and 50.0% (P=0.91) for the thoracic aorta, respectively. Similarly, the proportion of patients with an annualized percentage change in volume scores of ≥15% was not different between the VKA, rivaroxaban, and rivaroxaban+vitamin K2 arms: 50.0%, 38.9%, and 50.0% (P=0.75) for the sum of the coronary arteries and 50.0%, 38.5%, and 46.2% (P=0.76) for the thoracic aorta, respectively.

View this table:
Table 4.

Percentage changes of Agatston scores

View this table:
Table 5.

Percentage changes of volume scores

Mixed modeling revealed that the change in PWV over time was not significantly different across treatment arms (P=0.56). When MAP was included as a time-varying covariate in the model, the change in PWV over time was also not significantly different across treatment arms (P=0.12).

Secondary Efficacy Outcomes

The rates of all cause death were 36.0/100 person-years in the VKA group, 26.0/100 person-years in the rivaroxaban group, and 24.6/100 person-years in the rivaroxaban+vitamin K2 group (Supplemental Figure 3; P=0.47). The main causes of death were withdrawal of dialysis, infectious disease, and sudden death (Supplemental Table 4). An ischemic or uncertain type of stroke occurred in eight of the 132 patients, corresponding with a stroke rate of 4.89/100 person-years. A hemorrhagic stroke was diagnosed in two of the 132 patients, corresponding with a stroke rate of 1.22/100 person-years. The number of strokes did not differ between the treatment groups, although it is noticeable that both hemorrhagic strokes occurred in the VKA group (Table 6). Mean (SD) CHA2DS2-VASc score was 5.13 (1.13) in the patients that developed an ischemic stroke versus 4.67 (1.44) in those that did not (P=0.26). A history of stroke was recorded in 62.5% (five of eight) of patients with an ischemic stroke and in 28.2% (35 of 124) of those without a stroke during the study period (P=0.06). An exploratory analysis of stroke and systemic embolism events in the pooled rivaroxaban arms versus the VKA arm revealed no significant difference between the groups (Supplemental Table 5).

View this table:
Table 6.

Secondary efficacy outcomes

Adverse Events

No adverse events related to the intake of vitamin K2 thrice weekly after dialysis were reported. Thirty-six life-threatening or major bleeding episodes occurred in the 132 patients, corresponding with a rate of 22.0/100 person-years. Given multiplicity of bleeding episodes within patients, which may be more related to underlying patient characteristics (e.g., angiodysplasia of the bowel) than to the type of anticoagulant, bleeding rates were analyzed both as times to first occurrence of bleeding episode and as total number of bleeding episodes. No statistically significant differences in the bleeding outcomes were found, except for the total number of combined life-threatening and major bleeding episodes being lower in both rivaroxaban arms as compared with the VKA arm (Table 7). An exploratory analysis of the bleeding rates in the pooled rivaroxaban arms versus the VKA arm revealed significantly fewer major bleedings as well as combined life-threatening and major bleedings in the pooled rivaroxaban arms than in the VKA arm (Supplemental Table 6).

View this table:
Table 7.

Bleeding outcomes

Discussion

This multicenter randomized, controlled trial is the first to report the effects of vitamin K status on the progression of VC in patients on chronic hemodialysis. We did not find a difference in the progression of VC over the course of 18 months among patients treated with VKA, patients in whom the VKA was replaced by rivaroxaban, and patients treated with rivaroxaban that additionally received high-dose vitamin K2 supplements, despite significant differences in dp-ucMGP levels, considered to be the most accurate marker of vascular vitamin K status.

The conviction that correction of functional vitamin K deficiency may retard the development of VC has led to the initiation of several randomized, controlled trials of vitamin K supplements in prevalent or incident patients in hemodialysis,11 including this study. However, this conviction rests heavily on the assumption that vitamin K deficiency can be corrected in patients on hemodialysis. Unfortunately, the results of our study reveal that withdrawal of VKAs and long-term vitamin K2 administration at pharmacologic doses does not normalize systemic dp-ucMGP levels. Initiation or continuation of VKAs led to a steady rise in dp-ucMGP concentrations. In the rivaroxaban group, dp-ucMGP decreased as a consequence of the wash-out of the VKA, but rivaroxaban had no intrinsic effect on dp-ucMGP levels, as revealed in the subgroup of patients that were VKA-naïve. Although an additional drop in dp-ucMGP was observed with vitamin K2 supplements, the median levels remained between 800 and 900 pmol/L, which is still about two-fold the value observed in healthy volunteers of the same age group that do not receive supplements.28,29

The question of why dp-ucMGP cannot be normalized in patients on hemodialysis is intriguing. Inactive uncarboxylated MGP is converted to active carboxylated MGP by the γ-carboxylase enzyme that operates in the endoplasmic reticulum of vascular smooth muscle cells and requires vitamin K as an essential cofactor. High levels of the inactive dp-ucMGP can be taken as a prima facie confirmation of vitamin K deficiency. Multiple issues contribute to vitamin K deficiency in patients on dialysis.11 However, long-term high-dose supplementation can be expected to overrule most of these, including the effects of deficient dietary intake, potential exhaustion of stores by high demands from the procalcific uremic environment, and abnormalities of the gut microbiome. In addition, there was no demonstrable interference by phosphate binder intake in our study. Compliance with the supplements was ascertained by administration after each dialysis session under supervision of a dialysis nurse. Finally, vitamin K removal by dialysis can be expected to be negligible due to its lipophilic nature. An alternative potential explanation for the failure to normalize dp-ucMGP is that the γ-carboxylase enzyme itself is defective in uremia, even when there is an abundant supply of its cofactor vitamin K. Indeed, in experimental uremia the activity of the γ-carboxylase was impaired whereas gene expression was normal.30 Finally, MGP is produced and secreted by vascular smooth muscle cells that are known to transdifferentiate into osteoblast-like cells during the course of VC. It is tempting to speculate that the transdifferentiation process adversely affects the synthesis of active MGP.

In patients on hemodialysis, the process of VC is governed by a mosaic of factors, including disruption of calcium and phosphate metabolism and imbalance between calcification promotors and inhibitors.31 Vitamin K deficiency thus represents only one of many pathways by which VC is accelerated. So far, single therapeutic interventions aiming at VC progression, including more frequent and extended hemodialysis, cinacalcet, phosphate binders, and cholecalciferol, have had limited success in the dialysis population.31 Recently, magnesium oxide supplementation was found to retard the progression of calcification in the coronary arteries but not in the thoracic aorta of predialysis patients with CKD.17 Perhaps treatment should be directed at multiple targets simultaneously; although a number of biologic processes such as oxidative stress and chronic inflammation currently remain beyond our therapeutic reach. As a final point, once VCs are advanced past a certain stage, they may no longer be susceptible to reversal and opportunities to intervene may have been missed.

Our study is the first randomized trial to report on the long-term use of DOACs to reduce thromboembolic risk in patients on hemodialysis. The overall stroke risk in our study was 4.89/100 person-years, taking into account that patients had a median CHA2DS2-VASc score of 5 and a 30% history of stroke. For comparison, stroke risk was 7.8/100 person-years in a Taiwanese hemodialysis population with a CHA2DS2-VASc score of 5 that did not receive oral anticoagulation.32 A meta-analysis of 13 studies reported a stroke rate of 5.2/100 person-years in patients on hemodialysis with AF, but details on anticoagulation coverage and CHA2DS2-VASc scores were not available.33 The incidence of ischemic or hemorrhagic stroke did not differ significantly between the rivaroxaban and VKA groups. However, it is worth noting that hemorrhagic strokes only occurred in the VKA group.

In our study, the incidence of life-threatening or major bleeding was 22/100 person-years, with patients having a median HAS-BLED score of 5 and a 28% history of gastrointestinal bleeding. In the Dialysis Outcomes and Practice Patterns Study, major bleeding rates were 7.8/100 person-years in patients on oral anticoagulation and 20/100 person-years in patients with a history of gastrointestinal bleeding.34 The results of our study reveal that severe bleeding complications may occur less frequently with rivaroxaban than with VKA.

Our study was not designed or powered to address the comparative benefits of DOACs versus VKAs with respect to stroke prevention and bleeding complications. However, because our data on stroke and bleeding are the first to be generated in a randomized, controlled trial setting, they may serve as a pilot to inform the design of larger, definitive trials to determine the optimal anticoagulation strategy in patients on hemodialysis with AF. Pending further evidence, our results suggest that rivaroxaban 10 mg once daily can be used safely and effectively in patients on hemodialysis.

The main limitation of our study is the relatively small sample size. Because it is the first clinical study to address the effects of VKAs and vitamin K supplements on the progression of VC in patients on dialysis, projections of effect size were on the basis of preliminary evidence and in hindsight appeared to have been too optimistic. Also, between-patient variability in baseline calcification scores and progression of VC was larger than anticipated. Therefore, our study has limited ability to exclude a type 2 error. Another limitation is that the population consisted mainly of prevalent patients receiving dialysis, with a high burden of cardiovascular disease as revealed by the elevated baseline calcification score and PWV, of whom the majority was taking a VKA at inclusion. As such, vascular damage may have progressed beyond a point of no return and any intervention at this stage may prove to be futile. Conversely, our study population consists of an unselected real-life cohort of patients on dialysis from three large European dialysis units. Our results therefore have direct implications for clinical practice.

In conclusion, we did not find an effect of vitamin K status on VC progression in patients receiving chronic hemodialysis with AF. The results of our study highlight the complexity of the VC process, which apparently cannot be redeemed by a single intervention. Further research should be directed at optimizing vitamin K status, combining multiple interventions, and identifying a window of therapeutic opportunity perhaps long before stigmata of VC become detectable with standard techniques.

Disclosures

Dr. Caluwé reports personal fees from Bayer, outside the submitted work. Dr. De Vriese reports personal fees from Ablynx, Achillion, Alexion, Amgen and Baxter and grants from Amgen, outside the submitted work. Dr. Van Vlem reports grants from Baxter, grants from Fresenius Medical Care, and grants from Amgen, outside the submitted work. All remaining authors have nothing to disclose.

Funding

The conduction of this trial was financially supported by Kaydence Pharma (New Brunswick, NJ, USA). Nattopharma (Lysaker, Norway) provided the MK-7 study medication.

Supplemental Material

This article contains the following supplemental material online at http://jasn.asnjournals.org/lookup/suppl/doi:10.1681/ASN.2019060579/-/DCSupplemental.

Patient inclusion and exclusion criteria.

Secondary end points.

Sample size calculation.

Randomization and blinding.

Supplemental Table 1. Baseline biochemical characteristics.

Supplemental Table 2. Baseline maintenance medication.

Supplemental Table 3. Characteristics during follow-up.

Supplemental Table 4. Causes of death.

Supplemental Table 5. Stroke or systemic embolism in the VKA versus pooled rivaroxaban arms.

Supplemental Table 6. Bleeding outcomes in the VKA versus pooled rivaroxaban arms.

Supplemental Figure 1. Study design.

Supplemental Figure 2. CONSORT diagram.

Supplemental Figure 3. Kaplan–Meier curves for patient survival.

Acknowledgments

The authors are indebted to Bart Beauprez, David Bosman, Kaatje Bruggeman, Mieke Debou, Mirjam Demesmaecker, Xandra Smeulders, Antje Straeten, Karel Van Hese, and Gwendolyn Verbeerst for their invaluable help in the collection of the patient data.

Kaydence Pharma and Nattopharma had no role in the design of the trial; collection, analysis, and interpretation of the data; or in the submission of the results.

Dr. Caluwé, Dr. De Vriese, and Dr. Verbeke designed the study. Dr. Caluwé, Dr. De Boeck, Dr. Delanote, Dr. De Surgeloose, Dr. De Vriese, Dr. Van Hoenacker, and Dr. Van Vlem collected the data. Dr. Pyfferoen read the computed tomography scans, Dr. Verbeke analyzed the PWV curves, Dr. De Bacquer analyzed the data, and Dr. De Vriese drafted the manuscript. All authors revised the manuscript and approved the final version of the manuscript.

Footnotes

  • Published online ahead of print. Publication date available at www.jasn.org.

References

  1. ↵
    1. De Vriese AS,
    2. Caluwé R,
    3. Raggi P
    : The atrial fibrillation conundrum in dialysis patients. Am Heart J 174: 111–119, 2016pmid:26995377
  2. ↵
    1. Van Der Meersch H,
    2. De Bacquer D,
    3. De Vriese AS
    : Vitamin K antagonists for stroke prevention in hemodialysis patients with atrial fibrillation: A systematic review and meta-analysis. Am Heart J 184: 37–46, 2017pmid:27892885
    OpenUrlCrossRefPubMed
  3. ↵
    1. Chatrou ML,
    2. Winckers K,
    3. Hackeng TM,
    4. Reutelingsperger CP,
    5. Schurgers LJ
    : Vascular calcification: The price to pay for anticoagulation therapy with vitamin K-antagonists. Blood Rev 26: 155–166, 2012pmid:22520397
    OpenUrlCrossRefPubMed
  4. ↵
    1. Caluwé R,
    2. Pyfferoen L,
    3. De Boeck K,
    4. De Vriese AS
    : The effects of vitamin K supplementation and vitamin K antagonists on progression of vascular calcification: Ongoing randomized controlled trials. Clin Kidney J 9: 273–279, 2016pmid:26985380
  5. ↵
    1. January CT,
    2. Wann LS,
    3. Alpert JS,
    4. Calkins H,
    5. Cigarroa JE,
    6. Cleveland JC Jr., et al.: American College of Cardiology/American Heart Association Task Force on Practice Guidelines
    : 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 64: e1–e76, 2014pmid:24685669
    OpenUrlFREE Full Text
  6. ↵
    1. Potpara TS,
    2. Ferro CJ,
    3. Lip GYH
    : Use of oral anticoagulants in patients with atrial fibrillation and renal dysfunction. Nat Rev Nephrol 14: 337–351, 2018pmid:29578207
  7. ↵
    1. Königsbrügge O,
    2. Posch F,
    3. Antlanger M,
    4. Kovarik J,
    5. Klauser-Braun R,
    6. Kletzmayr J, et al
    .: Prevalence of atrial fibrillation and antithrombotic therapy in hemodialysis patients: Cross-sectional results of the Vienna InVestigation of AtriaL Fibrillation and Thromboembolism in Patients on HemoDIalysis (VIVALDI). PLoS One 12: e0169400, 2017pmid:28052124
  8. ↵
    1. Schurgers LJ,
    2. Spronk HM
    : Differential cellular effects of old and new oral anticoagulants: Consequences to the genesis and progression of atherosclerosis. Thromb Haemost 112: 909–917, 2014pmid:25298033
    OpenUrlCrossRefPubMed
    1. Hara T,
    2. Fukuda D,
    3. Tanaka K,
    4. Higashikuni Y,
    5. Hirata Y,
    6. Nishimoto S, et al
    .: Rivaroxaban, a novel oral anticoagulant, attenuates atherosclerotic plaque progression and destabilization in ApoE-deficient mice. Atherosclerosis 242: 639–646, 2015pmid:25817329
    OpenUrlCrossRefPubMed
  10. ↵
    1. Rattazzi M,
    2. Faggin E,
    3. Bertacco E,
    4. Nardin C,
    5. Pagliani L,
    6. Plebani M, et al
    .: Warfarin, but not rivaroxaban, promotes the calcification of the aortic valve in ApoE-/- mice. Cardiovasc Ther 36: e12438, 2018pmid:29847020
    OpenUrlCrossRefPubMed
  11. ↵
    1. Caluwé R,
    2. Verbeke F,
    3. De Vriese AS
    : Evaluation of vitamin K status and rationale for vitamin K supplementation in dialysis patients [published online ahead of print Dec 26, 2018]. Nephrol Dial Transplant doi: 10.1093/ndt/gfy373pmid:30590803
  12. ↵
    1. Bellasi A,
    2. Raggi P
    : Vascular imaging in chronic kidney disease. Curr Opin Nephrol Hypertens 21: 382–388, 2012pmid:22531162
    OpenUrlCrossRefPubMed
  13. ↵
    1. Bellasi A,
    2. Ferramosca E,
    3. Ratti C,
    4. Block G,
    5. Raggi P
    : The density of calcified plaques and the volume of calcium predict mortality in hemodialysis patients. Atherosclerosis 250: 166–171, 2016pmid:27084530
    OpenUrlCrossRefPubMed
  14. ↵
    1. Raggi P
    : Cardiovascular disease: Coronary artery calcification predicts risk of CVD in patients with CKD. Nat Rev Nephrol 13: 324–326, 2017pmid:28480902
    OpenUrlPubMed
  15. ↵
    1. Block GA,
    2. Spiegel DM,
    3. Ehrlich J,
    4. Mehta R,
    5. Lindbergh J,
    6. Dreisbach A, et al
    .: Effects of sevelamer and calcium on coronary artery calcification in patients new to hemodialysis. Kidney Int 68: 1815–1824, 2005pmid:16164659
    OpenUrlCrossRefPubMed
    1. Raggi P,
    2. Chertow GM,
    3. Torres PU,
    4. Csiky B,
    5. Naso A,
    6. Nossuli K, et al.: ADVANCE Study Group
    : The ADVANCE study: A randomized study to evaluate the effects of cinacalcet plus low-dose vitamin D on vascular calcification in patients on hemodialysis. Nephrol Dial Transplant 26: 1327–1339, 2011pmid:21148030
    OpenUrlCrossRefPubMed
  17. ↵
    1. Sakaguchi Y,
    2. Hamano T,
    3. Obi Y,
    4. Monden C,
    5. Oka T,
    6. Yamaguchi S, et al
    .: A randomized trial of magnesium oxide and oral carbon adsorbent for coronary artery calcification in predialysis CKD. J Am Soc Nephrol 30: 1073–1085, 2019pmid:31036759
    OpenUrlAbstract/FREE Full Text
  18. ↵
    1. Raggi P,
    2. Bellasi A,
    3. Ferramosca E,
    4. Islam T,
    5. Muntner P,
    6. Block GA
    : Association of pulse wave velocity with vascular and valvular calcification in hemodialysis patients. Kidney Int 71: 802–807, 2007pmid:17311068
    OpenUrlCrossRefPubMed
  19. ↵
    1. Verbeke F,
    2. Van Biesen W,
    3. Honkanen E,
    4. Wikström B,
    5. Jensen PB,
    6. Krzesinski JM, et al.: CORD Study Investigators
    : Prognostic value of aortic stiffness and calcification for cardiovascular events and mortality in dialysis patients: Outcome of the calcification outcome in renal disease (CORD) study. Clin J Am Soc Nephrol 6: 153–159, 2011pmid:20829424
    OpenUrlAbstract/FREE Full Text
  20. ↵
    1. De Vriese AS,
    2. Caluwé R,
    3. Bailleul E,
    4. De Bacquer D,
    5. Borrey D,
    6. Van Vlem B, et al
    .: Dose-finding study of rivaroxaban in hemodialysis patients. Am J Kidney Dis 66: 91–98, 2015pmid:25804678
    OpenUrlCrossRefPubMed
  21. ↵
    1. Schurgers LJ,
    2. Teunissen KJ,
    3. Hamulyák K,
    4. Knapen MH,
    5. Vik H,
    6. Vermeer C
    : Vitamin K-containing dietary supplements: Comparison of synthetic vitamin K1 and natto-derived menaquinone-7. Blood 109: 3279–3283, 2007pmid:17158229
    OpenUrlAbstract/FREE Full Text
  22. ↵
    1. Marles RJ,
    2. Roe AL,
    3. Oketch-Rabah HA
    : US Pharmacopeial Convention safety evaluation of menaquinone-7, a form of vitamin K. Nutr Rev 75: 553–578, 2017pmid:28838081
  23. ↵
    1. Caluwé R,
    2. Vandecasteele S,
    3. Van Vlem B,
    4. Vermeer C,
    5. De Vriese AS
    : Vitamin K2 supplementation in haemodialysis patients: A randomized dose-finding study. Nephrol Dial Transplant 29: 1385–1390, 2014pmid:24285428
    OpenUrlPubMed
  24. ↵
    1. Agatston AS,
    2. Janowitz WR,
    3. Hildner FJ,
    4. Zusmer NR,
    5. Viamonte M Jr.,
    6. Detrano R
    : Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol 15: 827–832, 1990pmid:2407762
    OpenUrlFREE Full Text
  25. ↵
    1. Callister TQ,
    2. Cooil B,
    3. Raya SP,
    4. Lippolis NJ,
    5. Russo DJ,
    6. Raggi P
    : Coronary artery disease: Improved reproducibility of calcium scoring with an electron-beam CT volumetric method. Radiology 208: 807–814, 1998pmid:9722864
    OpenUrlCrossRefPubMed
  26. ↵
    1. Caluwé R,
    2. De Vriese AS,
    3. Van Vlem B,
    4. Verbeke F
    : Measurement of pulse wave velocity, augmentation index, and central pulse pressure in atrial fibrillation: A proof of concept study. J Am Soc Hypertens 12: 627–632, 2018pmid:30049625
  27. ↵
    1. Budoff MJ,
    2. Hokanson JE,
    3. Nasir K,
    4. Shaw LJ,
    5. Kinney GL,
    6. Chow D, et al
    .: Progression of coronary artery calcium predicts all-cause mortality. JACC Cardiovasc Imaging 3: 1229–1236, 2010pmid:21163451
    OpenUrlAbstract/FREE Full Text
  28. ↵
    1. Cranenburg EC,
    2. Koos R,
    3. Schurgers LJ,
    4. Magdeleyns EJ,
    5. Schoonbrood TH,
    6. Landewé RB, et al
    .: Characterisation and potential diagnostic value of circulating matrix Gla protein (MGP) species. Thromb Haemost 104: 811–822, 2010pmid:20694284
    OpenUrlCrossRefPubMed
  29. ↵
    1. Schlieper G,
    2. Westenfeld R,
    3. Krüger T,
    4. Cranenburg EC,
    5. Magdeleyns EJ,
    6. Brandenburg VM, et al
    .: Circulating nonphosphorylated carboxylated matrix gla protein predicts survival in ESRD. J Am Soc Nephrol 22: 387–395, 2011pmid:21289218
    OpenUrlAbstract/FREE Full Text
  30. ↵
    1. Kaesler N,
    2. Magdeleyns E,
    3. Herfs M,
    4. Schettgen T,
    5. Brandenburg V,
    6. Fliser D, et al
    .: Impaired vitamin K recycling in uremia is rescued by vitamin K supplementation. Kidney Int 86: 286–293, 2014pmid:24429407
    OpenUrlCrossRefPubMed
  31. ↵
    1. Ruderman I,
    2. Holt SG,
    3. Hewitson TD,
    4. Smith ER,
    5. Toussaint ND
    : Current and potential therapeutic strategies for the management of vascular calcification in patients with chronic kidney disease including those on dialysis. Semin Dial 31: 487–499, 2018pmid:29733462
    OpenUrlCrossRefPubMed
  32. ↵
    1. Chao TF,
    2. Liu CJ,
    3. Wang KL,
    4. Lin YJ,
    5. Chang SL,
    6. Lo LW, et al
    .: Incidence and prediction of ischemic stroke among atrial fibrillation patients with end-stage renal disease requiring dialysis. Heart Rhythm 11: 1752–1759, 2014pmid:24952148
    OpenUrlCrossRefPubMed
  33. ↵
    1. Zimmerman D,
    2. Sood MM,
    3. Rigatto C,
    4. Holden RM,
    5. Hiremath S,
    6. Clase CM
    : Systematic review and meta-analysis of incidence, prevalence and outcomes of atrial fibrillation in patients on dialysis. Nephrol Dial Transplant 27: 3816–3822, 2012pmid:23114904
    OpenUrlCrossRefPubMed
  34. ↵
    1. Sood MM,
    2. Larkina M,
    3. Thumma JR,
    4. Tentori F,
    5. Gillespie BW,
    6. Fukuhara S, et al
    .: Major bleeding events and risk stratification of antithrombotic agents in hemodialysis: Results from the DOPPS. Kidney Int 84: 600–608, 2013pmid:23677245
    OpenUrlCrossRefPubMed
Back to top

In this issue

View Selected Citations (0)
Print
Download PDF
Email Article
Citation Tools
Request Permissions
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, Rogier Caluwé, Lotte Pyfferoen, Dirk De Bacquer, Koen De Boeck, Joost Delanote, Didier De Surgeloose, Piet Van Hoenacker, Bruno Van Vlem, Francis Verbeke
JASN Jan 2020, 31 (1) 186-196; DOI: 10.1681/ASN.2019060579
del.icio.us logo Digg logo Reddit logo Twitter logo Facebook logo Google logo Mendeley logo

Jump to section

Keywords