Effect on Vascular Calcification of Replacing Warfarin by Rivaroxaban With or Without VitK2 in Hemodialysis Patients

Study Overview
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Brief Summary
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This study examines patients on chronic hemodialysis with non-valvular atrial fibrillation, who have a CHA2DS2-VASc Score of ≥ 2 and therefore are candidates for or already receive a vitamin K antagonist. The first question is whether replacement of the vitamin K antagonist by rivaroxaban is able to slow progression of vascular calcification. The second question is whether addition of vitamin K2 to rivaroxaban can further slow down or even halt the progression of vascular calcification.

Detailed Description
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The present study targets dialysis patients with non-valvular atrial fibrillation requiring treatment with vitamin K antagonists. It addresses the question whether replacement of the vitamin K antagonist by rivaroxaban is able to slow progression of vascular calcification (VC). The second research question is whether addition of vitamin K2 to rivaroxaban can further beneficially affect the progression of VC. Two non-invasive methods are used to evaluate the impact of interventions on the progression of VC: i.e. coronary artery calcification (CAC) and pulse wave velocity (PWV) measurements. The detection of CAC is predictive for the presence of obstructive coronary artery disease and future coronary events. VC and stiffening of the central elastic-type arteries are independent predictors of cardiovascular morbidity and mortality in hemodialysis patients.

Official Title
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The Effect of Replacement of Vitamin K Antagonist by Rivaroxaban With or Without Vitamin K2 Supplementation on Vascular Calcifications in Chronic Hemodialysis Patients: A Randomized Controlled Trial

Conditions
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Vascular Calcification

Intervention / Treatment
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* Drug: rivaroxaban
* Dietary Supplement: Vitamin K2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: end stage renal failure treated with chronic hemodialysis atrial fibrillation CHA2DS2-VASc Score ≥ 2 ability to provide informed consent Exclusion Criteria: known intestinal malabsorption or inability to take oral medication inability to stop co-medication that causes major interactions with rivaroxaban (e.g. ketoconazole, itraconazole, voriconazole, posaconazole, ritonavir, rifampicin, phenytoin, carbamazepine, phenobarbital or St John's wort) investigator's assessment that the subject's life expectancy is less than 1 year prosthetic mechanical heart valve contraindication for anticoagulation liver dysfunction Child-Pugh grade B-C pregnancy, breastfeeding, inadequate contraception incompliance with medication and scheduled investigations

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Vitamin K antagonist<br>Vitamin K antagonist treatment targeting an international normalized ratio of 2 to 3 for 18 months | |
| Active Comparator: rivaroxaban<br>Rivaroxaban 10 mg tablet by mouth once daily for 18 months | Drug: rivaroxaban<br>* replacement of vitamin K antagonist by rivaroxaban<br>|
| Active Comparator: rivaroxaban and vitamin K2<br>Rivaroxaban 10 mg tablet by mouth once daily and MK-7 2000 microgram tablet by mouth thrice weekly for 18 months | Drug: rivaroxaban<br>* replacement of vitamin K antagonist by rivaroxaban<br>Dietary Supplement: Vitamin K2<br>* Vitamin K2 supplementation<br>* Other names: MK-7;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| absolute and relative change in coronary artery calcification score | score measured by unenhanced electrocardiographically-gated CT of the heart and thoracic aorta and calculated on 2.5 mm slices using Smartscore v.4.0 (GE Healthcare) | 18 months | 
| absolute and relative change in thoracic aortic calcification score | score measured by unenhanced electrocardiographically-gated CT of the heart and thoracic aorta and calculated on 2.5 mm slices using Smartscore v.4.0 (GE Healthcare) | 18 months | 
| absolute and relative change in pulse wave velocity |  | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| absolute and relative change in aortic valve calcification score | score measured by unenhanced electrocardiographically-gated CT of the heart and thoracic aorta and calculated on 2.5 mm slices using Smartscore v.4.0 (GE Healthcare) | 18 months | 
| absolute and relative change in mitral valve calcification score | score measured by unenhanced electrocardiographically-gated CT of the heart and thoracic aorta and calculated on 2.5 mm slices using Smartscore v.4.0 (GE Healthcare) | 18 months | 
| mortality from any cause |  | 18 months | 
| myocardial infarction, acute coronary syndrome, symptom-driven coronary revascularization and death from cardiovascular cause |  | 18 months | 
| Stroke, defined as sudden onset of focal neurological deficit consistent with the territory of a major cerebral artery and categorised as ischaemic, haemorrhagic, or unspecified. |  | 18 months | 
| Systemic embolism, defined as an acute vascular occlusion of a limb or organ documented by imaging, surgery, or autopsy. |  | 18 months | 
| Major bleeding, defined as a requirement for transfusion of two or more units of blood or a decrease in haemoglobin of 2 g/dL or more. |  | 18 months | 
| Life-threatening bleeding, defined as fatal bleeding, symptomatic intracranial bleeding, a decrease in haemoglobin of 5 g/dL or more, or a requirement for transfusion of four or more units of blood, inotropic agents, or surgery. |  | 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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vascular calcification, hemodialysis, rivaroxaban, vitamin K2