Nephrol Dial Transplant (2014) 29: 1633–1638 doi: 10.1093/ndt/gft459 Advance Access publication 26 November 2013

NDT Perspectives Vitamin K1 to slow vascular calcification in haemodialysis patients (VitaVasK trial): a rationale and study protocol Thilo Krueger1, Georg Schlieper1, Leon Schurgers2, Tom Cornelis3, Mario Cozzolino4, Johannes Jacobi5, Sebastian Reinartz12, Ralf-Dieter Hilgers13 and Jürgen Floege1 1

Department of Nephrology and Immunology, Uniklinik RWTH Aachen, Aachen, Germany, 2Cardiovascular Research Institute Maastricht

(CARIM), University of Maastricht, Maastricht, The Netherlands, 3Department of Internal Medicine, Division of Nephrology, Maastricht University Medical Center, Maastricht, The Netherlands, 4Renal Division, University of Milan, Milan, Italy, 5Department of Nephrology and Hypertension, University of Erlangen-Nuremberg, Erlangen, Germany, 6Division of Nephrology, Cliniques universitaires Saint-Luc Université catholique de Louvain, Brussels, Belgium, 7Department of Nephrology, Klinikum Coburg, Coburg, Germany, 8Department of Nephrology, University Hospital of Duesseldorf, Germany, 9Department of Renal Medicine, Karolinska University Hospital at Huddinge, Stockholm, Sweden, 10Department of Cardiology, University Hospital of Duesseldorf, Duesseldorf, Germany, 11Department of Nephrology, Endocrinology and Metabolic Diseases, Medical University of Silesia, Katowice, Poland, 12Department of Radiology, Uniklinik RWTH Aachen, Aachen, Germany and 13Institute of Medical Statistics, RWTH University Aachen, Aachen, Germany

Correspondence and offprint requests to: T. Krueger; E-mail: [email protected]

A B S T R AC T Background. Patients on haemodialysis (HD) exhibit increased cardiovascular mortality associated with accelerated vascular calcification (VC). VC is influenced by inhibitors such as matrix Gla protein (MGP), a protein activated in the presence of vitamin K. HD patients exhibit marked vitamin K deficiency, and supplementation with vitamin K reduces inactive MGP levels in these patients. The VitaVasK trial analyses whether vitamin K1 supplementation affects the progression of coronary and aortic calcification in HD patients. Methods. VitaVasK is a prospective, randomized, parallel group, multicentre trial (EudraCT No.: 2010-021264-14) that will include 348 HD patients in an open-label, two-arm design. After baseline multi-slice computed tomography (MSCT) of the heart and thoracic aorta, patients with a coronary calcification volume score of at least 100 will be randomized to continue on standard care or to receive additional supplementation with 5 mg vitamin K1 orally thrice weekly. Treatment duration will be 18 months, and MSCT scans will be repeated after 12 and 18 months. Primary end points are © The Author 2013. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

the progression of thoracic aortic and coronary artery calcification (calculated as absolute changes in the volume scores at the 18-month MSCT versus the baseline MSCT). Secondary end points comprise changes in Agatston score, mitral and aortic valve calcification as well as major adverse cardiovascular events (MACE) and all-cause mortality. VitaVask also aims to record MACE and all-cause mortality in the follow-up period at 3 and 5 years after treatment initiation. This trial may lead to the identification of an inexpensive and safe treatment or prophylaxis of VC in HD patients. Keywords: haemodialysis, matrix Gla protein, vascular calcification, vitamin K

I N T R O D U C T I O N A N D R AT I O N A L E Patients on haemodialysis (HD) suffer from extensive cardiovascular calcifications (VCs). VC is an independent risk factor and might explain the excessively increased cardiovascular mortality in this population [1, 2]. In the past, the development of VC was discovered to be actively regulated and influenced by inhibitors of calcification [e.g. matrix Gla protein 1633

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Michel Jadoul6, Markus Ketteler7, Lars C. Rump8, Peter Stenvinkel9, Ralf Westenfeld10, Andrzej Wiecek11,

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very rare and have only been reported after intravenous or intramuscular administration: anaphylactic reactions, venous irritation, sclerodermiform skin infiltration and pigmentation. Particularly, no increased risk of thromboembolism occurred during trials administering vitamin K [18]. In VitaVasK, we administer vitamin K1 orally. The daily recommended allowance of phylloquinone in the European Union is 75 µg. Thus, our weekly dose of 15 mg exceeds the weekly recommended vitamin K1 allowance 29-fold. However, there are no safety concerns with such doses since, apart from the lack of toxicity of even very high doses [19], other clinical studies have administered similar vitamin K1 amounts (0.5–1 mg/day) for up to 36 months without observing treatmentemergent adverse effects [20–22]. Finally, given that HD patients exhibit significantly lower vitamin K levels than nonCKD individuals [16, 23, 24], we feel that a high dosage may be justified in this population, and that the possible advantages of high-dose oral vitamin K1 replacement outweigh the potential risks in HD patients.

TRIAL DESIGN The VitaVasK study is a randomized, prospective, multicentre, and open-label interventional clinical trial. The study protocol has been submitted to the relevant local ethics committees for final approval. The study is in adherence with the Declaration of Helsinki. Two treatments will be compared in different groups providing a two-arm parallel group design with 348 patients in total. The study design is illustrated in Figure 1. Due to the very specific taste and yellowish appearance of the oily liquid vitamin K1 ( phylloquinone), an adequate placebo would be challenging; therefore, the study will be performed open-labelled. However, because the primary end points— i.e. thoracic aortic and coronary calcification—will be objectively measured, and because the radiologists evaluating the computed tomography (CT) scans will be blinded as to the treatment, information bias is excluded.

TRIAL OBJECTIVES AND PURPOSE The first major question is whether oral supplementation of vitamin K1 is able to slow the progression of VC in the coronaries and thoracic aorta in HD patients. Further questions are whether this treatment is also able to slow aortic and mitral valve calcification and regress the extent of coronary and thoracic aortic VC as well as reducing the major adverse cardiovascular events (MACE) and all-cause mortality. The total expected trial duration is 2.5 years. The recruitment of patients is scheduled to start in October 2013 and should take 1 year. All patients who are eligible and who have signed the informed consent will be screened by a first multislice computed tomography (MSCT) scan of the heart and thoracic aorta. Patients who are eligible after this scan will be randomized to one of the two treatment groups. Treatment in both groups will last for 18 months, and the follow-up period will be 5 years after commencement of the treatment.

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(MGP), fetuin-A] [3–5]. MGP is a powerful vascular wallbased inhibitor of VC. It is produced by vascular smooth muscle cells and requires vitamin K-dependent post-translational modification, namely gamma carboxylation, to be fully active. The role of MGP was discovered in knock-out mice, that died from rupture of a massively calcified aorta [6]. Warfarin, a vitamin K antagonist, inhibits the activation of MGP thereby mimicking the MGP knock-out phenotype. Indeed, functional vitamin K deficiency, induced by warfarin, accelerates VC in the normal population [7] and in HD patients [8], as well as in rodents [9]. Warfarin is also a potent risk factor for the development of calciphylaxis, a life-threatening complication in HD patients characterized by calcified cutaneous vessels [10]. In rodents, warfarin-induced VC can be inhibited and even regressed by subsequent administration of vitamin K2 [9, 11]. In a trial in elderly non-chronic kidney disease (CKD) patients, daily administration of 500 µg vitamin K1 ( phylloquinone) failed to affect the progress of coronary artery VC on an intention-to-treat basis. In subgroups with >85% compliance and in those with some degree of baseline VC, however, the progress of calcification was significantly retarded [12]. The administration of vitamin K1 in this trial also reduced elevated levels of undercarboxylated (uc)MGP and undercarboxylated osteocalcin (OC). In another trial, supplementing 500 µg/day vitamin K1 over 3 years in 190 individuals reduced circulating levels of ucMGP from 485 to 97 pmol/L, but failed to reduce or slow progression of coronary calcification. A possible explanation is that this trial was conducted in non-CKD patients with little baseline VC [13], and thus, its design may not have been suitable to detect small changes. At present, there is no clinical evidence supporting the hypothesis that vitamin K supplementation attenuates the progression of VC in HD patients. These patients exhibit reduced vitamin K intake [14], and uraemia, at least experimentally, also interferes with vitamin K recycling (similar to warfarin; Kaesler et al. under submission). Indeed, the levels of another vitamin K-dependent protein, PIVKA-II [a protein induced by vitamin K absence or antagonism factor II ( prothrombin)], which are normally below the detection limit in healthy serum, are elevated in 97% of all HD patients [15]. In combination with the elevated uncarboxylated MGP and OC, HD patients, therefore, represent a population with a very high overall vitamin K deficiency. Taken together with their massively increased VC prevalence, they represent an ideal population for proof-of-concept trials involving the vitamin K system. Recently, we demonstrated that supplementation of vitamin K in HD patients induces a rapid decrease (on average 60%) of ucMGP, but also ucOC and PIVKA-II in serum over a 6-week period [16]. We observed almost no evidence for biochemical non-responders, indicating that all patients suffered from functional vitamin K deficiency and thus, incomplete MGP carboxylation. Vitamin K1 is a registered and approved drug worldwide (e.g. KA-Vit®, Infectopharm, Heppenheim, Germany). Among others, it is approved for newborns and infants, as well as during pregnancy and in breast-feeding women [17]. No known toxicity exists for vitamin K1 in adults. Side effects are

INCLUSION CRITERIA Patients with the following criteria will be included in the trial: Males or females ≥18 years of age,

(ii)

not less than 6 months on HD,

(iii)

presence of significant coronary calcification (coronary artery volume score of >100) in the baseline MSCT,

(iv) (v)

signed informed consent, life expectancy not less than 18 months.

(xiii)

people unlikely to comply with the protocol, e.g. uncooperative attitude, inability to return for follow-up visits and unlikelihood of completing the study, any other illness or medical treatment that could interfere with the assessment of safety, tolerability and efficacy,

(xiv)

simultaneous participation in another trial or interfering examination or participation in a study within 90 days or five half-lives of an appropriate study drug (whichever is longer) prior to screening,

(xv)

lack of safe contraceptive measures.

EXCLUSION CRITERIA Patients who meet any one of the following exclusion criteria will not be included in the trial: (i) History of thrombosis, (ii) intake of vitamin K antagonists (coumarins, e.g. Marcumar®) at baseline or in the 3 months prior to baseline, (iii) inflammatory bowel disease, (iv) short-bowel syndrome, (v) liver dysfunction, (vi) haemoglobin 100, is supposed to hamper patient recruitment. Patients in both arms will continue their standard treatment care. Patients in arm two will additionally receive vitamin K1 ( phylloquinone) at 5 mg orally three times per week. Phylloquinone is a common and well-known substance with a publicly available chemical formula. The substance used in this trial is from Infectopharm which produces and sells the product under the trade name KA-Vit®. The study medication will be administered in the form of liquid drops under supervision at each HD session, thus ensuring very high compliance with the medication. The exact time point during the dialysis session at which the study medication will be administered is flexible,

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(i)

(xii)

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F I G U R E 1 : Trial design of VitaVasK.

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M U LT I - S L I C E C O M P U T E D T O M O G R A P H Y Calcium scoring will be performed using ECG-triggered or high-pitch MSCT, and dual-source CT of the coronaries without radiocontrast. Scan length is defined by a scout view from the tracheal bifurcation to the bottom of the heart silhouette. All patients should have a resting pulse frequency of 130 and a minimum size of 0.5 mm3 based on isotropic interpolation [26]. The Agatston score will be calculated by multiplying the density and size of the calcified areas as previously described [27].

PRIMARY END POINTS We will consider two independent hierarchically ordered primary end points:

performed within 2 weeks of starting the treatment. The variability of this method is 8%. (ii) Progression of coronary artery calcification (absolute change in the volume score at the 18-month MSCT versus the baseline MSCT). Both end points are assumed to be independent. The same measurement method and time points will be used for this end point.

SECONDARY END POINTS We consider the following as secondary end points: (i) Progression of thoracic aortic calcification (absolute change in the Agatston score at the 18-month MSCT versus the baseline MSCT). (ii) Progression of coronary artery calcification (absolute change in the Agatston score at the 18-month MSCT versus the baseline MSCT). (iii)

Progression of aortic valve calcification (absolute change in the Agatston and volume scores at the 18month MSCT versus the baseline MSCT). (iv) Progression of mitral valve calcification (absolute change in the Agatston and volume scores at the 18month MSCT versus the baseline MSCT). (v) Mortality from any cause after 18 months following start of the treatment. (vi) MACE: myocardial infarction, stroke, acute coronary syndrome, embolism, symptom-driven revascularization and death from cardiovascular cause after 18 months following start of the treatment.

The following parameters will be assessed as further outcome parameters without being a primary or secondary end point: (i) Per cent of patients with regression of thoracic aortic calcification of at least 10% compared with baseline measure (an 18-month Agatston and volume score) as measured by MSCT. (ii) Per cent of patients with regression of coronary artery calcification of at least 10% compared with baseline measure (an 18-month Agatston and volume score) as measured by MSCT. (iii)

(i)

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Progression of thoracic aortic calcification (absolute change in the volume score at the 18-month MSCT versus the baseline MSCT). The amount of calcification will be measured by MSCT and assessed as the volume score. The progression will be determined by the absolute change in the volume score at the 18-month MSCT compared with the volume score immediately before the first treatment (baseline). Baseline MSCTs will be

All radiological analyses mentioned above in both primary and secondary end points will also be performed at 12 months (defined as 12 months ± 4 weeks) after baseline. The 12-month observations will be used to better describe the temporal evolution of calcifications. It will also serve as an added database, which may become important should there be technical problems in individual patients (e.g. MSCT cannot be evaluated for technical reasons).

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since vitamin K1 is fat soluble and thus, is not eliminated by HD nor is its absorption affected by the dialysis procedure. At baseline, i.e. prior to the first intake of vitamin K1, serum and plasma samples will be obtained to assess biochemical parameters, including routine laboratory parameters plus ionized calcium, phosphate, iPTH, 25-OH vitamin D3, bone alkaline phosphatase, HbA1c, total magnesium and ionized magnesium. Additional parameters that will be obtained are MGP isoforms, OC isoforms, PIVKA-II and vitamin K plasma levels. During the treatment phase, three study visits will take place at 1, 12 and 18 months. At the 1-month study visit, MGP and OC isoforms, PIVKA-II and vitamin K plasma levels will be reassessed. In case that ucMPG levels are not substantially reduced here (20% according to [16]), the vitamin K1 dose will be doubled (10 mg as a single dose) and treatment duration extended by 1 month. After 12 months, a second MSCT scan will be performed, and MGP isoforms and vitamin K plasma levels will be measured. After 18 months, the third MSCT scan will be performed, and the same serum and plasma parameters will be assessed as at the first visit (Figure 1). Three and 5 years after treatment start, telephone interviews will record MACE and mortality of enrolled patients.

(iv)

Measures to assess the biochemical effect of vitamin K1 administration (including plasma levels of dp-cMGP and dp-ucMGP at 12 and 18 months).

(v)

Mortality from any cause 3 and 5 years after starting the treatment.

(vi)

MACE 3 and 5 years after starting the treatment.

Values obtained after starting the treatment will be compared with baseline values. MGP isoform levels will be determined by IDS Inc. (the Netherlands).

S TAT I S T I C A L C O N S I D E R AT I O N S

Analysis of primary end points The primary efficacy end points ‘thoracic aortic calcification’ and ‘coronary artery calcification’ are defined as absolute changes in the thoracic aortic calcification and coronary artery calcification scores measured by the volume score at the 18month visit versus the baseline visit. We expect that the progression, expressed as the mean absolute difference between the thoracic aortic calcification score at the 18-month visit and the thoracic aortic calcification score at baseline, will be lower in the vitamin K1 maintenance

VitaVask trial

The study is supported by a grant from the ERA/EDTA.

C O N F L I C T O F I N T E R E S T S TAT E M E N T None declared.

REFERENCES 1. Kuzela DC, Huffer WE, Conger JD et al. Soft tissue calcification in chronic dialysis patients. Am J Pathol 1977; 86: 403–424 2. Blacher J, Guerin AP, Pannier B et al. Arterial calcifications, arterial stiffness, and cardiovascular risk in end-stage renal disease. Hypertension 2001; 38: 938–942 3. Doherty TM, Asotra K, Fitzpatrick LA et al. Calcification in atherosclerosis: bone biology and chronic inflammation at the arterial crossroads. Proc Natl Acad Sci USA 2003; 100: 11201–11206 4. Ketteler M, Bongartz P, Westenfeld R et al. Association of low fetuin-A (AHSG) concentrations in serum with cardiovascular mortality in patients on dialysis: a cross-sectional study. Lancet 2003; 361: 827–833 5. Schurgers LJ, Uitto J, Reutelingsperger CP. Vitamin K-dependent carboxylation of matrix Gla-protein: a crucial switch to control ectopic mineralization. Trends Mol Med 2013; 19: 217–226 6. Luo G, Ducy P, McKee MD et al. Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature 1997; 386: 78–81 7. Koos R, Krueger T, Westenfeld R et al. Relation of circulating matrix Glaprotein and anticoagulation status in patients with aortic valve calcification. Thromb Haemost 2009; 101: 706–713 8. Holden RM, Sanfilippo AS, Hopman WM et al. Warfarin and aortic valve calcification in hemodialysis patients. J Nephrol 2007; 20: 417–422 9. Price PA, Faus SA, Williamson MK. Warfarin causes rapid calcification of the elastic lamellae in rat arteries and heart valves. Arterioscler Thromb Vasc Biol 1998; 18: 1400–1407 10. Wilmer WA, Magro CM. Calciphylaxis: emerging concepts in prevention, diagnosis, and treatment. Semin Dial 2002; 15: 172–186 11. Schurgers LJ, Spronk HM, Soute BA et al. Regression of warfarin-induced medial elastocalcinosis by high intake of vitamin K in rats. Blood 2007; 109: 2823–2831

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Sample size Previous data [28] show an annual increase in thoracic aortic calcification in HD patients, measured by the volume score, of ∼200 (standard deviation [SD] 235) for patients with an initial score of ≥100. Thus, based on a treatment time of 18 months, the expected mean increase in the volume score is ∼300 (SD 235). We further assume that this increase will be 30% lower in the vitamin K1 group, resulting in an expected mean increase of ∼210 (SD 235) in the volume score. Based on the assumption that the treatment difference will occur to a similar degree in all centres, 108 patients per arm will be necessary to detect a mean difference of ∼90 (SD 235) (a two-sided significance level of 5%, t-test, 80% Power, nQuery—Advisor 7.0 under Windows 7). We further assume that comorbid conditions will result in an annual dropout rate of 25%, so that after an 18-month treatment period we expect an overall dropout rate of 37.5%. We also assume that the dropout rate will not depend on the treatment. When we correct our total sample size of 216 by a dropout rate of 37.5%, we end up with a total sample size of 348. To include this number of patients in the trial, we will need to screen ∼600 patients, given our main inclusion criterion of a volume score of >100.

AC K N O W L E D G E M E N T

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Randomization If a patient is eligible to participate in the study phase and has signed the informed consent, the patient will be randomly assigned to one of the two arms. The randomization will be stratified by centre and gender. Details will be given in a randomization report, which will be kept concealed until closure of the database.

therapy group than in the standard therapy group. Consequently, the progression will be expressed as the individual change between the thoracic aortic calcification after 18 months and the calcification at baseline. The hypotheses will be tested by means of fitting an analysis of covariance (ANCOVA) model to the ‘volume score at the 18-month visit’. The model consists of the factors ‘treatment’, the stratification factor ‘centre’ and the co-variable ‘baseline volume score’, but not treatment-by-centre interaction. The test of the main factor ‘treatment’ will be performed at the significance level of 5% based on the Type II sum of squares. In a sensitivity analysis, we will check for a possible treatment-by-centre interaction by including the corresponding interaction in our ANCOVA model. The results on mean baseline and post-treatment scores will also be given as per cent changes. Furthermore, we will describe our analysis results by 95% confidence intervals for the treatment difference in terms of the mean change.

21. Yoshida M, Jacques PF, Meigs JB et al. Effect of vitamin K supplementation on insulin resistance in older men and women. Diabetes Care 2008; 31: 2092–2096 22. Braam LA, Knapen MH, Geusens P et al. Vitamin K1 supplementation retards bone loss in postmenopausal women between 50 and 60 years of age. Calcif Tissue Int 2003; 73: 21–26 23. Schlieper G, Westenfeld R, Kruger T et al. Circulating nonphosphorylated carboxylated matrix Gla protein predicts survival in ESRD. J Am Soc Nephrol 2011; 22: 387–395 24. Pilkey RM, Morton AR, Boffa MB et al. Subclinical vitamin K deficiency in hemodialysis patients. Am J Kidney Dis 2007; 49: 432–439 25. Raggi P, Chertow GM, Torres PU et al. 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 2011; 26: 1327–1339 26. Callister TQ, Cooil B, Raya SP et al. Coronary artery disease: improved reproducibility of calcium scoring with an electron-beam CT volumetric method. Radiology 1998; 208: 807–814 27. Agatston AS, Janowitz WR, Hildner FJ et al. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol 1990; 15: 827–832 28. Mazzaferro S, Pasquali M, Taggi F et al. Progression of coronary artery calcification in renal transplantation and the role of secondary hyperparathyroidism and inflammation. Clin J Am Soc Nephrol 2009; 4: 685–690

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Received for publication: 16.8.2013; Accepted in revised form: 25.9.2013

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12. Shea MK, O’Donnell CJ, Hoffmann U et al. Vitamin K supplementation and progression of coronary artery calcium in older men and women. Am J Clin Nutr 2009; 89: 1799–1807 13. Shea MK, O’Donnell CJ, Vermeer C et al. Circulating uncarboxylated matrix gla protein is associated with vitamin K nutritional status, but not coronary artery calcium, in older adults. J Nutr 2011; 141: 1529–1534 14. Cranenburg EC, Schurgers LJ, Uiterwijk HH et al. Vitamin K intake and status are low in hemodialysis patients. Kidney Int 2012; 82: 605–610 15. Holden RM, Morton AR, Garland JS et al. Vitamins K and D status in stages 3–5 chronic kidney disease. Clin J Am Soc Nephrol 2010; 5: 590–597 16. Westenfeld R, Krueger T, Schlieper G et al. Effect of vitamin K(2) supplementation on functional Vitamin K deficiency in hemodialysis patients: a randomized trial. Am J Kidney Dis 2012; 59: 186–195 17. von Kries R, Shearer M, McCarthy PT et al. Vitamin K1 content of maternal milk: influence of the stage of lactation, lipid composition, and vitamin K1 supplements given to the mother. Pediatr Res 1987; 22: 513–517 18. Theuwissen E, Cranenburg EC, Knapen MH et al. Low-dose menaquinone-7 supplementation improved extra-hepatic vitamin K status, but had no effect on thrombin generation in healthy subjects. Br J Nutr 2012; 108: 1652–1657 19. Tsuchie H, Miyakoshi N, Hongo M et al. Amelioration of pregnancy-associated osteoporosis after treatment with vitamin K(2): a report of four patients. Ups J Med Sci 2012; 117: 336–341 20. Kumar R, Binkley N, Vella A. Effect of phylloquinone supplementation on glucose homeostasis in humans. Am J Clin Nutr 2010; 92: 1528–1532

Vitamin K1 to slow vascular calcification in haemodialysis patients (VitaVasK trial): a rationale and study protocol.

Patients on haemodialysis (HD) exhibit increased cardiovascular mortality associated with accelerated vascular calcification (VC). VC is influenced by...
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