Safety and Efficacy of Vitamin K Antagonists versus Rivaroxaban in Hemodialysis Patients with Atrial Fibrillation: A Multicenter Randomized Controlled Trial.

BACKGROUND: In patients with normal renal function or early stage CKD, the risk-benefit profile of direct oral anticoagulants (DOACs) is superior to that of vitamin K antagonists (VKAs). In patients on hemodialysis, the comparative efficacy and safety of DOACs versus VKAs are unknown. METHODS: In the Valkyrie study, 132 patients on hemodialysis with atrial fibrillation were randomized to a VKA with a target INR of 2-3, 10 mg rivaroxaban daily, or rivaroxaban and vitamin K2 for 18 months. Patients continued the originally assigned treatment and follow-up was extended for at least an additional 18 months. The primary efficacy end point was a composite of fatal and nonfatal cardiovascular events. Secondary efficacy end points were individual components of the composite outcome and all-cause death. Safety end points were life-threatening, major, and minor bleeding. RESULTS: Median (IQR) follow-up was 1.88 (1.01-3.38) years. Premature, permanent discontinuation of anticoagulation occurred in 25% of patients. The primary end point occurred at a rate of 63.8 per 100 person-years in the VKA group, 26.2 per 100 person-years in the rivaroxaban group, and 21.4 per 100 person-years in the rivaroxaban and vitamin K2 group. The estimated competing risk-adjusted hazard ratio for the primary end point was 0.41 (95% CI, 0.25 to 0.68; P=0.0006) in the rivaroxaban group and 0.34 (95% CI, 0.19 to 0.61; P=0.0003) in the rivaroxaban and vitamin K2 group, compared with the VKA group. Death from any cause, cardiac death, and risk of stroke were not different between the treatment arms, but symptomatic limb ischemia occurred significantly less frequently with rivaroxaban than with VKA. After adjustment for competing risk of death, the hazard ratio for life-threatening and major bleeding compared with the VKA group was 0.39 (95% CI, 0.17 to 0.90; P=0.03) in the rivaroxaban group, 0.48 (95% CI, 0.22 to 1.08; P=0.08) in the rivaroxaban and vitamin K2 group and 0.44 (95% CI, 0.23 to 0.85; P=0.02) in the pooled rivaroxaban groups. CONCLUSIONS: In patients on hemodialysis with atrial fibrillation, a reduced dose of rivaroxaban significantly decreased the composite outcome of fatal and nonfatal cardiovascular events and major bleeding complications compared with VKA. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Oral Anticoagulation in Hemodialysis, NCT03799822.

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.

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.

Evaluation of vitamin K status and rationale for vitamin K supplementation in dialysis patients.

The cardinal biological role of vitamin K is to act as cofactor for the carboxylation of a number of vitamin K-dependent proteins, some of which are essential for coagulation, bone formation and prevention of vascular calcification. Functional vitamin K deficiency is common and severe among dialysis patients and has garnered attention as a modifiable risk factor in this population. However, no single biochemical parameter can adequately assess vitamin K status. For each biological function of vitamin K, the degree of carboxylation of the relevant vitamin K-dependent protein most accurately reflects vitamin K status. Dephosphorylated uncarboxylated matrix Gla protein (dp-ucMGP) is the best biomarker for vascular vitamin K status when cardiovascular endpoints are studied. Dp-ucMGP levels are severely elevated in haemodialysis patients and correlate with markers of vascular calcification and mortality in some but not all studies. The aetiology of vitamin K deficiency in haemodialysis is multifactorial, including deficient intake, uraemic inhibition of the vitamin K cycle and possibly interference of vitamin K absorption by phosphate binders. The optimal vitamin K species, dose and duration of supplementation to correct vitamin K status in dialysis patients are unknown. Dp-ucMGP levels dose-proportionally decrease with supraphysiological vitamin K2 supplementation, but do not normalize even with the highest doses. In the general population, long-term vitamin K1 or K2 supplementation has beneficial effects on cardiovascular disease, bone density and fracture risk, and insulin resistance, although some studies reported negative results. In haemodialysis patients, several trials on the effects of vitamin K on surrogate markers of vascular calcification are currently ongoing.

The effects of vitamin K supplementation and vitamin K antagonists on progression of vascular calcification: ongoing randomized controlled trials.

BACKGROUND: The extent and the progression of vascular calcification (VC) are independent predictors of cardiovascular risk in the haemodialysis population. Vitamin K is essential for the activation of matrix gla protein (MGP), a powerful inhibitor of tissue calcification. Functional vitamin K deficiency may contribute to the high VC burden in haemodialysis patients. In addition, haemodialysis patients are frequently treated with vitamin K antagonists, mainly to prevent stroke in atrial fibrillation, potentially compounding the cardiovascular risk in these already vulnerable patients. New oral anticoagulants (NOACs) are valuable alternatives to vitamin K antagonists in the general population, but their use in dialysis has been encumbered by substantial renal clearance. However, a recent pharmacokinetic study provided information on how to use rivaroxaban in haemodialysis patients. METHODS: We conduct a randomized, prospective, multicentre, open-label interventional clinical trial that will include 117 chronic haemodialysis patients with non-valvular atrial fibrillation, treated with or candidates for treatment with vitamin K antagonists. Patients will be randomized to a vitamin K antagonist titrated weekly to an international normalized ratio between 2 and 3, a daily dose of rivaroxaban of 10 mg, or a daily dose of rivaroxaban 10 mg with a thrice weekly supplement of 2000 µg vitamin K2. Cardiac computed tomography, pulse wave velocity (PWV) measurements and MGP sampling will be performed at baseline, 6 months, 12 months and 18 months. Primary endpoints include progression of coronary artery and thoracic aorta calcification and changes in PWV. Secondary endpoints are progression of aortic and mitral valve calcification, all-cause mortality, major adverse cardiovascular events, stroke and bleeding. The ClinicalTrials.gov database was searched to retrieve related trials. RESULTS: Seven trials, three of which are performed in the haemodialysis population, evaluate whether pharmacological doses of vitamin K1 or K2 retard progression of VC. Five studies compare the effect of warfarin and NOACs on progression of VC, the present study being the only conducted in the dialysis population. CONCLUSION: Vitamin K deficiency may be a modifiable cardiovascular risk factor in the haemodialysis population. Conversely, vitamin K antagonists may aggravate VC burden in haemodialysis patients. Several ongoing trials may provide an answer to these questions in the near future.

Vitamin K2 supplementation in haemodialysis patients: a randomized dose-finding study.

BACKGROUND: Haemodialysis patients suffer from accelerated vascular calcification. The vitamin K-dependent matrix Gla protein (MGP) is one of the most powerful inhibitors of vascular calcification. Haemodialysis patients have high levels of the inactive form of MGP (desphosphorylated-uncarboxylated-MGP, dp-uc-MGP) and may benefit from pharmacological doses of vitamin K2 (menaquinone) to improve the calcification inhibitory activity of MGP. METHODS: To determine the optimal dose of menaquinone-7 (MK-7) for MGP activation, 200 chronic haemodialysis patients were recruited to randomly receive 360, 720 or 1080 µg of MK-7 thrice weekly for 8 weeks. Dp-uc-MGP was measured at baseline and after 8 weeks. Dietary intake of vitamin K1 (phylloquinone) and menaquinone was estimated based on a detailed questionnaire. RESULTS: At baseline, dp-uc-MGP was not associated with phylloquinone intake (P = 0.92), but correlated inversely with menaquinone intake (P = 0.023). MK-7 supplementation dose dependently reduced dp-uc-MGP. The levels decreased by 17, 33 and 46% in the respective groups. Drop-outs were mainly due to gastrointestinal side-effects related to the unpleasant smell of the tablets. CONCLUSIONS: Chronic haemodialysis patients have high levels of inactive MGP, possibly related to a low dietary vitamin K intake. Pharmacological doses of MK-7 dose-dependently reduce dp-uc-MGP. Menaquinone supplementation may be a novel approach to prevent vascular calcifications in chronic haemodialysis patients.

Diffuse alveolar hemorrhage induced by everolimus.

Pulmonary toxicity is a known complication of the proliferation signal inhibitor (PSI) sirolimus and consists of diverse entities such as interstitial pneumonitis, lymphocytic alveolitis, bronchiolitis obliterans with organizing pneumonia, and diffuse alveolar hemorrhage. Several cases of interstitial pneumonitis have also been reported with the more recently developed PSI everolimus. In this report, a case of diffuse alveolar hemorrhage attributed to everolimus is described. The patient presented with respiratory symptoms of insidious onset, ultimately resulting in severe respiratory failure characterized by high lactate dehydrogenase levels, patchy ground-glass infiltrates, and bloody BAL fluid with predominance of iron-loaded macrophages and monocytes. Withdrawal of the offending drug and temporary association of high-dose steroids resulted in a rapid recovery. Given that prompt drug discontinuation is potentially life saving, PSI-induced pulmonary toxicity should be considered in the differential diagnosis of patients treated with PSIs and presenting with respiratory symptoms or pulmonary lesions.

Oral vitamin C administration increases lipid peroxidation in hemodialysis patients.

BACKGROUND: Since vitamin C (ascorbic acid, AA) deficiency is common in hemodialysis patients, systematic supplementation has been recommended. Further, vitamin C has been advocated as a potential adjuvant to erythropoietin by virtue of its capacity to improve iron utilization. However, vitamin C may have a paradoxical pro-oxidant effect in the presence of iron. METHODS: In 109 hemodialysis patients, oral vitamin C was administered at 360 and 1,500 mg/week during 3 months each, followed by a wash-out period of 3 months. RESULTS: Serum AA increased from 0.22 to 0.33 and 0.63 mg/dl after 360 and 1,500 mg/week, respectively. However, a commensurate increase of plasma malondialdehyde (MDA), a parameter of lipid peroxidation, with 9 and 26% was observed. Serum AA and plasma MDA returned to baseline after withdrawal of vitamin C. Parameters of iron status, nutrition, inflammation, dialysis efficiency and plasma lipids remained unaltered. In a stepwise multiple regression analysis, serum AA and ferritin were strong and independent predictors of MDA. CONCLUSION: Oral vitamin C supplementation in hemodialysis patients increases lipid peroxidation, especially in patients with increased serum ferritin. The potential benefits of restored vitamin C status and improved erythropoiesis may be entirely overruled by the adverse consequences of oxidative tissue injury.

Creatine supplementation does not decrease total plasma homocysteine in chronic hemodialysis patients.

BACKGROUND: Hyperhomocysteinemia is present in the majority of chronic hemodialysis patients. Treatment with folic acid, vitamin B12, and vitamin B6 cannot fully normalize plasma homocysteine concentrations (tHcy). Previously we have demonstrated the tHcy-lowering effect of creatine supplementation in an animal model of uremia (Kidney Int 64:1331-1337, 2003). The present study investigates the effects of creatine supplementation on tHcy in a vitamin-repleted chronic hemodialysis population. METHODS: Forty-five hemodialysis patients receiving folic acid and vitamin B6 and B12 were included. Patients were treated with creatine (2 g/day) or placebo during 2 treatment periods of 4 weeks, separated by a washout of 4 weeks. Plasma tHcy, creatine, Kt/V(urea), folic acid, vitamin B12, and routine biochemistry were determined, as well as the prognostic inflammatory and nutritional index. RESULTS: All patients had elevated tHcy concentrations (21.2 +/- 5.6 micromol/L). Creatine treatment resulted in increased plasma and red blood cell creatine levels, documenting uptake of creatine. Creatine did not affect tHcy concentrations. There was no relationship between plasma creatine concentrations and tHcy concentrations. No changes in body weight, routine biochemistry, nutritional status, folic acid, or vitamin B12 were observed during the study. CONCLUSION: Creatine supplementation at a rate of 2 g/day does not further decrease tHcy concentrations in chronic dialysis patients already treated with high dose folic acid, vitamin B6, and B12 supplementation.

Effect of dialyser membrane pore size on plasma homocysteine levels in haemodialysis patients.

BACKGROUND: Hyperhomocysteinaemia is a putative risk factor for atherothrombotic cardiovascular disease in the haemodialysis population. High-dose vitamin B therapy does not entirely normalize elevated plasma total homocysteine (tHcy) levels in haemodialysis patients. Alternative therapies to reduce tHcy further are therefore required. Modifications of the dialysis regimen may result in a better removal of Hcy. We examined the effect of dialyser membrane pore size on tHcy levels in vitamin-replete chronic haemodialysis patients. METHODS: Forty-five haemodialysis patients were dialysed during 4 weeks with a low-flux, a high-flux and a super-flux membrane, in random order. Pre-dialysis tHcy was determined at baseline and every 4 weeks. In 18 patients, plasma tHcy before and after dialysis and dialysate tHcy concentrations were measured. RESULTS: Pre-dialysis tHcy decreased significantly during 4 weeks super-flux dialysis (-14.6 +/- 2.8%), whereas it remained stable during high-flux (+0.5 +/- 2.4%) and low-flux dialysis (+1.7 +/- 3.2%). The homocysteine reduction ratio was not different for the three membranes: 0.39 +/- 0.03 for the super-flux, 0.47 +/- 0.02 for the high-flux and 0.39 +/- 0.02 for the low-flux dialyser. The amount of Hcy recovered in the dialysate during a single dialysis session was also similar: 117.5 +/- 3.6 micro mol during super-flux, 95.3 +/- 11.5 micro mol during high-flux and 116.5 +/- 11.6 micro mol during low-flux dialysis. CONCLUSION: Super-flux dialysis significantly lowers tHcy in chronic haemodialysis patients. Improved removal of middle-molecule uraemic toxins with inhibitory effects on Hcy-metabolizing enzymes, rather than better dialytic clearance of Hcy itself, may explain the beneficial effect of the super-flux membrane.

Creatine supplementation decreases homocysteine in an animal model of uremia.

BACKGROUND: Hyperhomocysteinemia is prevalent in more than 85% of patients with end-stage renal disease (ESRD) and is thought to contribute to the excess cardiovascular mortality and morbidity. Creatine is synthesized by methylation of guanidinoacetate with formation of S-adenosylhomocysteine and subsequently, homocysteine (Hcy). Creatine supplementation down-regulates its endogenous synthesis and, thus, may reduce Hcy production. The present study investigates the effect of creatine supplementation on Hcy concentrations in an animal model of uremia. METHODS: Male Wistar rats were either sham-operated and received a control diet (N = 8) or a 2% creatine-supplemented diet (N = 8), or underwent subtotal nephrectomy and received a control diet (N = 10) or a 2%-supplemented creatine diet (N = 10). After 2 weeks of treatment, total plasma Hcy, creatine, creatinine, folate, and vitamin B12 were determined, as well as hepatic folate and vitamin B12 concentrations. RESULTS: Plasma creatinine concentrations were higher in nephrectomized animals, but similar in creatine-supplemented and control diet-fed animals. Plasma Hcy was higher in nephrectomized animals but lower in creatine-supplemented nephrectomized animals compared to nephrectomized control diet-fed animals (12.1 +/- 2.4 micromol/L vs. 15.4 +/- 1.7 micromol/L; P < 0.01). Total plasma Hcy inversely correlated with plasma creatine concentrations (r =-0.39; P = 0.02). Plasma folate was higher in supplemented animals and hepatic tetrahydrofolate (THF) was higher in nephrectomized supplemented animals. Plasma vitamin B12 was similar in all groups, whereas hepatic vitamin B12 was higher in nephrectomized animals. CONCLUSION: Creatine supplementation can effectively lower plasma Hcy concentrations in an animal model of uremia and should be further investigated as a potential treatment for hyperhomocysteinemia in patients with ESRD.

Is folate a promising agent in the prevention and treatment of cardiovascular disease in patients with renal failure?

Management of the conventional cardiovascular risk factors is insufficient to prevent the dramatic increase in atherosclerotic cardiovascular morbidity and mortality in patients with renal failure. Folate recently received attention as a potential alternative treatment option to decrease the excess cardiovascular risk in the uremic population. Folate administration is the principal treatment modality for hyperhomocysteinemia. Hyperhomocysteinemia is prevalent in more than 85% of patients with end-stage renal disease (ESRD) and is independently associated with increased odds for atherosclerotic cardiovascular disease. Several attempts have been made to normalize homocysteine levels in uremic patients with folate-based vitamin regimens. Although supraphysiologic doses of folic acid afford greater reductions in homocysteine levels than standard doses, the response to treatment is generally only partial and the large majority of ESRD patients have residual hyperhomocysteinemia. Several defects in folate metabolism have been described in uremia, which may explain the relative folate resistance in patients with renal failure, but their clinical relevance remains uncertain. It appears unlikely that the hyperhomocysteinemia in ESRD can be cured solely with folic acid supplements, since folate does not affect the prolonged plasma elimination of homocysteine, which is the primary defect in homocysteine metabolism in uremia. Folate restores endothelial dysfunction, associated with hyperlipidemia, diabetes and hyperhomocysteinemia. The beneficial effect appears to be independent of its homocysteine-lowering capacity and is possibly related to an improved bioavailability of nitric oxide. However, folate has failed to improve endothelial dysfunction in uremic patients. In the ESRD population, multiple metabolic and hemodynamic abnormalities adversely affect endothelial function. In addition, irreversible structural vascular disease already may be present. Folate should, therefore, probably be an integral part of an "endothelial protective regimen," consisting of lipid-lowering agents, antihypertensives and antioxidant vitamins and started very early in patients with renal failure. Before large-scale folate administration can be recommended, effects on hard endpoints of cardiovascular disease need to be demonstrated in randomized trials. Such trials are currently underway in patients with normal renal function at high risk for cardiovascular disease, and one trial has recently been initiated in stable renal transplant recipients.