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Vascular CalcIfiCation and sTiffness Induced by ORal antIcoAgulation (VICTORIA)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02161965
Recruitment Status : Completed
First Posted : June 12, 2014
Last Update Posted : November 7, 2019
Information provided by (Responsible Party):
University Hospital, Angers

Brief Summary:
The VICTORIA Study (Vascular CalcIfiCation and sTiffness induced by ORal antIcoAgulation) is a comparative, parallel, prospective, controlled and randomized study of the structural and functional impact of rivaroxaban versus anti-vitamin K drugs on the arterial vasculature.

Condition or disease Intervention/treatment Phase
Permanent Atrial Fibrillation Venous Thrombosis Pulmonary Embolism Anticoagulation Treatment at Least > or = to 12-month Drug: Rivaroxaban Drug: Fluindione Drug: Warfarin Phase 4

Detailed Description:

Long term oral anticoagulant treatment (> 12 month) is mainly indicated for atrial fibrillation, prosthetic valves and conditions with high risk for recurrent or deep venous thrombosis. For more than 60 years, vitamin K antagonists have been the only oral anticoagulant drugs available to prevent thrombus formation. The use of vitamin K antagonists is associated to the major constraint of a well-adjusted anticoagulation leading to minor/major risk of life threatening bleeds. They also exhibit other rare side-effects including skin eruption and necrosis, hepatic disorders, alopecia. A less known side effect is an increase in soft tissue calcification, including the cardiac valves and the peripheral arterial system. This side effect is explained by the inhibitory effect of vitamin K antagonists on the central (liver) and peripheral (e.g. vascular) carboxylation cycle synthesis of several vitamin K-dependant calcification inhibiting factors, such as the matrix gamma-carboxyglutamate protein, osteocalcin or Gas6 (1). The active form of gamma-carboxyglutamate protein is now identified as a potent local tissue inhibitor of vascular calcification. The calcifying effect of a decrease in gamma-carboxyglutamate protein or the ratio of carboxylated (i.e. active) /uncarboxylated (i.e. inactive) forms of gamma-carboxyglutamate protein have been reported in various acquired metabolic diseases such as chronic renal insufficiency, aging and of genetic origin (e.g. Cutis Laxa, Keutel syndrome,…) (2, 3) as well as in mouse gamma-carboxyglutamate protein -/- models (4). Furthermore, administration of warfarin in rats is a well-known pharmacological model to induce a vascular calcification within 2-4 weeks with an increase in systolic and pulse arterial blood pressure (5).

Vascular calcification is an independent risk factor for cardiovascular morbi-mortality and it is well-demonstrated that an increase in coronary calcium, as measured by the scan Agatston score, is independently linked to a higher risk for events (6, 7). The lower limb mediacalcosis (i.e. Monckeberg disease) is also a risk factor for limb amputation and calcification (8) of the atheromatous plaque represents a risk factor for plaque instability and rupture (9). The pathophysiological mechanisms linking the dystrophic calcification process to morbi-mortality are still unclear. Calcium deposit within the arterial intimal layer is generally associated to atherosclerosis with an increased risk for plaque rupture whereas deposit of calcium within the medial layer of the peripheral arteries (i.e. mediacalcosis) is rather responsible for an increased arterial stiffness and the development of arterial hypertension (10). Recent data from the investigators laboratory have showed site heterogeneity assessed by scan scoring in the calcifying process in the general population and also in a genetically-determined calcifying disease (i.e the pseudoxantoma elasticum).

Two recently published studies have pointed out a link between the use of vitamin K antagonists and an enhanced coronary (11) and extra-coronary (6) calcifications. Although the conclusions of these studies remains limited by a cross-sectional and retrospective design, a small number of patients and a large range of exposure to vitamin K antagonists (from 6 to 143 months - mean 46) they questioned a potential deleterious effect on the peripheral vasculature mainly for the long term use of non-vitamin K antagonists anticoagulants. One prospective controlled study in post-menopaused woman has demonstrated a long-term beneficial effect only of a supplement containing vitamins K1 and D on the elastic properties of the carotid artery (12). Therefore, in the present study, the investigators propose to determine the structural (i.e. calcification) and functional (i.e. stiffness) impact of the anti-Xa inhibitor rivaroxaban compared to vitamin K antagonists on the arterial structure in a longitudinal, prospective comparative study.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 51 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Investigator)
Primary Purpose: Treatment
Official Title: The VICTORIA Study (Vascular CalcIfiCation and sTiffness Induced by ORal antIcoAgulation) Comparison Anti-vitamin K Versus Anti-Xa.
Actual Study Start Date : May 21, 2013
Actual Primary Completion Date : December 31, 2016
Actual Study Completion Date : February 16, 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Minerals Vitamin K
Drug Information available for: Rivaroxaban

Arm Intervention/treatment
Experimental: Rivaroxaban

Rivaroxaban (oral tablet) for patients with atrial fibrillation:

20 mg once daily for patients with GFR > 49 ml per minute and 15 mg rivaroxaban once daily for patients with GFR of 15 to 49 ml.

Rivaroxaban (oral tablet) for patients with pulmonary embolism: 2 x a day 15 mg at day 1-21 and 1x 20 mg from day 22 ongoing

Drug: Rivaroxaban
20mg or 15mg
Other Name: Xarelto

Active Comparator: vitamin K antagonists
Adjusted dose of warfarin or fluindione (oral tablet) titrated according to target international normalized ratio with a target range 2.0 to 3.0.
Drug: Fluindione
Other Name: Previscan

Drug: Warfarin
Other Name: Previscan

Primary Outcome Measures :
  1. Calcification score measured by CT scan [ Time Frame: 2 months ]
    Rate of coronary and lower Limb calcifications between oral inhibitor of Xa activity and vitamin K antagonists

Secondary Outcome Measures :
  1. Arterial stiffness measured by ultrasounds [ Time Frame: 3 months ]
    Compare the impact of an oral anti-Xa and vitamin K antagonist on the arterial stifffness.

Other Outcome Measures:
  1. Dosage of circulating anti-calcifying factors and extra-cellular matrix remodelling [ Time Frame: 2 months ]

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Male or female patient aged > 18 years
  • Female patient capable of bearing children with highly effective methods of birth control
  • Creatinine clearance > 30 ml/min
  • Normal hepatic function based on hepatic enzymes
  • Treated for atrial fibrillation according a score superior at 1
  • Treatment duration 12 months according to the actual recommendations
  • Treated by vitamine K antagonist less than 2 months before entering the study
  • Patient willing to participate with a signed informed consent
  • Patient covered by a healthcare insurance

Exclusion Criteria:

  • Patient has any clinical condition which does not allow initiation of long-term including all contraindications such as hypersensitivity to active ingredient or other excipients, clinically relevant acute bleedings and all other risk circumstances according to Summary of Medicinal Product in which all warnings and preventive measures and precautions are described and have to be kept.
  • Patients had a previous coronary stent implantation
  • Creatinine clairance <30 mL)
  • Liver disease with coagulopathy or other bleeding disorders including cirrhotic patients with Child Pugh
  • Hyperthryroidism
  • Hypercalcemia
  • Hyperphosphatemia
  • Acute gastrointestinal diseases
  • Mental condition rendering the patient unable to understand the nature, scope and possible consequences of the study
  • Patient is unwilling or unable to give informed consent
  • Patient is unlikely to comply with protocol, e.g. uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study
  • Participation in a parallel interventional clinical trial
  • Patient has been committed to an institution by legal or regulatory order
  • Pregnant or lactating women
  • Female patient capable of bearing children without highly effective methods of birth control
  • Patient with history of myocardial infarction and/or coronary disease.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02161965

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University Hospital Angers
Angers, France, 49933
Sponsors and Collaborators
University Hospital, Angers
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Principal Investigator: Georges LEFTHERIOTIS, MD, PhD University hospital, Angers, FRANCE
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Responsible Party: University Hospital, Angers Identifier: NCT02161965    
Other Study ID Numbers: 2012-005354-27
First Posted: June 12, 2014    Key Record Dates
Last Update Posted: November 7, 2019
Last Verified: November 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Data and biological samples could be shared upon acceptance between both organizations
Keywords provided by University Hospital, Angers:
Coronary and peripheral calcification
Arterial stiffness
Additional relevant MeSH terms:
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Pulmonary Embolism
Atrial Fibrillation
Venous Thrombosis
Vascular Calcification
Arrhythmias, Cardiac
Heart Diseases
Cardiovascular Diseases
Pathologic Processes
Embolism and Thrombosis
Vascular Diseases
Lung Diseases
Respiratory Tract Diseases
Calcium Metabolism Disorders
Metabolic Diseases
Factor Xa Inhibitors
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action