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

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

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.

Study Overview

• Status: Completed
• Conditions: Vascular Calcification
• Intervention / Treatment: Drug: rivaroxaban; Dietary supplement: Vitamin K2

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 117
• Phase: Phase 4

Contacts and Locations

Study Locations

• Belgium
  • Aalst, Belgium, 9300
    • OLV Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Onze Lieve Vrouw Hospital
• Investigators: Principal Investigator: Rogier Caluwé, MD, Nephrology Department OLV Hospital Aalst Belgium

Study record dates

Study Major Dates

• Study Start: November 1, 2015
• Primary Completion (Actual): January 23, 2019
• Study Completion (Actual): January 23, 2019

Study Registration Dates

• First Submitted: November 16, 2015
• First Submitted That Met QC Criteria: November 19, 2015
• First Posted (Estimate): November 20, 2015

Study Record Updates

• Last Update Posted (Actual): January 28, 2019
• Last Update Submitted That Met QC Criteria: January 25, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Keywords: hemodialysis; rivaroxaban; vascular calcification; vitamin K2
• Additional Relevant MeSH Terms: Metabolic Diseases; Calcium Metabolism Disorders; Calcinosis; Vascular Calcification; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Fibrin Modulating Agents; Protease Inhibitors; Micronutrients; Vitamins; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Antifibrinolytic Agents; Hemostatics; Coagulants; Vitamin K; Rivaroxaban; Vitamin K 2
• Other Study ID Numbers: 2014/065