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

Background: Theextentandtheprogressionofvascularcalcification(VC)areindependentpredictorsofcardiovascularriskinthe 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, haemodialysispatientsarefrequentlytreatedwithvitaminKantagonists,mainlytopreventstrokeinatrial fibrillation,potentially compounding the cardiovascular risk in these already vulnerable patients. New oral anticoagulants (NOACs) are valuable alternativestovitaminKantagonistsinthe generalpopulation, but theiruseindialysishasbeenencumberedbysubstantialrenal 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 calcificationandchangesinPWV.Secondaryendpointsareprogressionofaorticandmitralvalvecalcification,all-causemortality, 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.