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

Rogier Caluwé, Lotte Pyfferoen, Koen De Boeck, An S De Vriese, Rogier Caluwé, Lotte Pyfferoen, Koen De Boeck, An S De Vriese

Abstract

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.

Keywords: haemodialysis; rivaroxaban; vascular calcifications; vitamin K; vitamin K antagonists.

Figures

Fig. 1.
Fig. 1.
Trial design.

References

    1. Bellasi A, Raggi P. Vascular imaging in chronic kidney disease. Curr Opin Nephrol Hypertens 2012; 21: 382–388
    1. Brandenburg VM, Schurgers LJ, Kaesler N, et al. Prevention of vasculopathy by vitamin K supplementation: can we turn fiction into fact? Atherosclerosis 2015; 240: 10–16
    1. Cranenburg ECM, Schurgers LJ, Uiterwijk HH, et al. Vitamin K intake and status are low in hemodialysis patients. Kidney Int 2012; 82: 605–610
    1. Caluwé R, Vandecasteele S, Van Vlem B, et al. Vitamin K2 supplementation in haemodialysis patients: a randomized dose-finding study. Nephrol Dial Transplant 2013; 29: 1385–1390
    1. Kaesler N, Magdeleyns E, Herfs M, et al. Impaired vitamin K recycling in uremia is rescued by vitamin K supplementation. Kidney Int 2014; 86: 286–293
    1. Schurgers LJ, Barreto DV, Barreto FC, et al. The circulating inactive form of matrix gla protein is a surrogate marker for vascular calcification in chronic kidney disease: a preliminary report. Clin J Am Soc Nephrol 2010; 5: 568–575
    1. Westenfeld R, Krueger T, Schlieper G, et al. Effect of vitamin K2 supplementation on functional vitamin K deficiency in hemodialysis patients: a randomized trial. Am J Kidney Dis 2012; 59: 186–195
    1. Pucaj K, Rasmussen H, Møller M, et al. Safety and toxicological evaluation of a synthetic vitamin K2, menaquinone-7. Toxicol Mech Methods 2011; 21: 520–532
    1. 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
    1. Inoue T, Fujita T, Kishimoto H, et al. Randomized controlled study on the prevention of osteoporotic fractures (OF study): a phase IV clinical study of 15-mg menatetrenone capsules. J Bone Miner Metab 2009; 27: 66–75
    1. Vissers LET, Dalmeijer GW, Boer JMA, et al. Intake of dietary phylloquinone and menaquinones and risk of stroke. J Am Heart Assoc 2013; 2: e000455–e000455
    1. Gundberg CM, Lian JB, Booth SL. Vitamin K-dependent carboxylation of osteocalcin: friend or foe? Adv Nutr 2012; 3: 149–157
    1. Winkelmayer WC, Patrick AR, Liu J, et al. The increasing prevalence of atrial fibrillation among hemodialysis patients. J Am Soc Nephrol 2011; 22: 349–357
    1. Zhang Y-T, Tang Z-Y. Research progress of warfarin-associated vascular calcification and its possible therapy. J Cardiovasc Pharmacol 2014; 63: 76–82
    1. Krüger T, Floege J. Vitamin K antagonists: beyond bleeding. Semin Dial 2014; 27: 37–41
    1. Fusaro M, Tripepi G, Noale M, et al. Prevalence of vertebral fractures, vascular calcifications, and mortality in warfarin treated hemodialysis patients. Curr Vasc Pharmacol 2015; 13: 248–258
    1. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365: 883–891
    1. De Vriese AS, Caluwé R, Bailleul E, et al. Dose-finding study of rivaroxaban in hemodialysis patients. Am J Kidney Dis 2015; 66: 91–98
    1. January CT, Wann LS, Alpert JS, et al. 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 2014; 64: e1–e76
    1. Langou RA, Huang EK, Kelley MJ, et al. Predictive accuracy of coronary artery calcification and abnormal exercise test for coronary artery disease in asymptomatic men. Circulation 1980; 62: 1196–1203
    1. Verbeke F, Van Biesen W, Honkanen E, et al. 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 2011; 6: 153–159
    1. Cranenburg E, Koos R, Schurgers LJ, et al. Characterisation and potential diagnostic value of circulating matrix Gla protein (MGP) species. Thromb Haemost 2010; 104: 811–822
    1. 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
    1. 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
    1. Van Bortel LM, Laurent S, Boutouyrie P, et al. Expert consensus document on the measurement of aortic stiffness in daily practice using carotid-femoral pulse wave velocity. J Hypertens 2012; 30: 445–448
    1. Di Iorio B, Nazzaro P, Cucciniello E, et al. Influence of haemodialysis on variability of pulse wave velocity in chronic haemodialysis patients. Nephrol Dial Transplant 2010; 25: 1579–1583
    1. Chertow GM, Burke SK, Raggi P, Treat to Goal Working Group. Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients. Kidney Int 2002; 62: 245–252
    1. Barreto DV, Barreto F de C, de Carvalho AB, et al. Phosphate binder impact on bone remodeling and coronary calcification—results from the BRiC study. Nephron Clin Pract 2008; 110: c273–c283
    1. Qunibi W, Moustafa M, Muenz LR, et al. A 1-year randomized trial of calcium acetate versus sevelamer on progression of coronary artery calcification in hemodialysis patients with comparable lipid control: the Calcium Acetate Renagel Evaluation-2 (CARE-2) study. Am J Kidney Dis 2008; 51: 952–965
    1. 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
    1. Geleijnse JM, Vermeer C, Grobbee DE, et al. Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: the Rotterdam Study. J Nutr 2004; 134: 3100–3105
    1. Beulens JWJ, Bots ML, Atsma F, et al. High dietary menaquinone intake is associated with reduced coronary calcification. Atherosclerosis 2009; 203: 489–493
    1. Gast GCM, de Roos NM, Sluijs I, et al. A high menaquinone intake reduces the incidence of coronary heart disease. Nutr Metab Cardiovasc Dis 2009; 19: 504–510
    1. Maas AHEM, van der Schouw YT, Beijerinck D, et al. Vitamin K intake and calcifications in breast arteries. Maturitas 2007; 56: 273–279
    1. Villines TC, Hatzigeorgiou C, Feuerstein IM, et al. Vitamin K1 intake and coronary calcification. Coron Artery Dis 2005; 16: 199.
    1. Fusaro M, Noale M, Viola V, et al. Vitamin K, vertebral fractures, vascular calcifications, and mortality: VItamin K Italian (VIKI) dialysis study. J Bone Miner Res 2012; 27: 2271–2278
    1. 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
    1. Braam LAJLM, Hoeks APG, Brouns F, et al. Beneficial effects of vitamins D and K on the elastic properties of the vessel wall in postmenopausal women: a follow-up study. Thromb Haemost 2004; 91: 373–380
    1. 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
    1. Knapen MHJ, Braam LAJLM, Drummen NE, et al. Menaquinone-7 supplementation improves arterial stiffness in healthy postmenopausal women. Thromb Haemost 2015; 113: 1135–1144
    1. Kurnatowska I, Grzelak P, Masajtis-Zagajewska A. Effect of vitamin K2 on progression of atherosclerosis and vascular calcification in non-dialyzed patients with chronic kidney disease stage 3-5. Pol Arch Med Wewn 2015; 125: 631–640
    1. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014; 383: 955–962

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