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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.
 
ClinicalTrials.gov Identifier: NCT02161965
Recruitment Status : Completed
First Posted : June 12, 2014
Last Update Posted : November 7, 2019
Sponsor:
Information provided by (Responsible Party):
University Hospital, Angers

Tracking Information
First Submitted Date  ICMJE June 2, 2014
First Posted Date  ICMJE June 12, 2014
Last Update Posted Date November 7, 2019
Actual Study Start Date  ICMJE May 21, 2013
Actual Primary Completion Date December 31, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 20, 2016)
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
Original Primary Outcome Measures  ICMJE
 (submitted: June 10, 2014)
Calcification score by scanography [ Time Frame: 2 months ]
Rate of coronary calcification and the arterial site of calcification at the level of lower limbs between an inhibitor of the anti-Xa activity by oral way versus an vitamin K antagonists
Change History Complete list of historical versions of study NCT02161965 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: May 20, 2016)
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.
Original Secondary Outcome Measures  ICMJE
 (submitted: June 10, 2014)
Vascular ultrasound for arterial rigidity [ Time Frame: 3 months ]
to Compare the impact of an oral anti Xa and an vitamin K antagonists on the arterial rigidity.
Current Other Pre-specified Outcome Measures
 (submitted: May 20, 2016)
Dosage of circulating anti-calcifying factors and extra-cellular matrix remodelling [ Time Frame: 2 months ]
Original Other Pre-specified Outcome Measures
 (submitted: June 10, 2014)
Dosage of circulants calcifiants factors testifying of the reshaping of the extra-cellular matrix [ Time Frame: 2 months ]
 
Descriptive Information
Brief Title  ICMJE Vascular CalcIfiCation and sTiffness Induced by ORal antIcoAgulation
Official Title  ICMJE The VICTORIA Study (Vascular CalcIfiCation and sTiffness Induced by ORal antIcoAgulation) Comparison Anti-vitamin K Versus Anti-Xa.
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.
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Investigator)
Primary Purpose: Treatment
Condition  ICMJE
  • Permanent Atrial Fibrillation
  • Venous Thrombosis
  • Pulmonary Embolism
  • Anticoagulation Treatment at Least > or = to 12-month
Intervention  ICMJE
  • Drug: Rivaroxaban
    20mg or 15mg
    Other Name: Xarelto
  • Drug: Fluindione
    Other Name: Previscan
  • Drug: Warfarin
    Other Name: Previscan
Study Arms  ICMJE
  • 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

    Intervention: Drug: Rivaroxaban
  • 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.
    Interventions:
    • Drug: Fluindione
    • Drug: Warfarin
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: November 5, 2019)
51
Original Estimated Enrollment  ICMJE
 (submitted: June 10, 2014)
150
Actual Study Completion Date  ICMJE February 16, 2018
Actual Primary Completion Date December 31, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02161965
Other Study ID Numbers  ICMJE 2012-005354-27
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Data and biological samples could be shared upon acceptance between both organizations
Responsible Party University Hospital, Angers
Study Sponsor  ICMJE University Hospital, Angers
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Georges LEFTHERIOTIS, MD, PhD University hospital, Angers, FRANCE
PRS Account University Hospital, Angers
Verification Date November 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP