Vascular CalcIfiCation and sTiffness Induced by ORal antIcoAgulation (VICTORIA)

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by University Hospital, Angers
Sponsor:
Information provided by (Responsible Party):
University Hospital, Angers
ClinicalTrials.gov Identifier:
NCT02161965
First received: June 2, 2014
Last updated: June 10, 2014
Last verified: June 2014
  Purpose

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 Intervention Phase
Permanent Atrial Fibrillation
Venous Thrombosis
Pulmonary Embolism
Anticoagulating Treatment on a Duration at Least 12-month-old Superior
Drug: Rivaroxaban
Drug: Fluindione
Drug: Warfarin
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Investigator)
Primary Purpose: Treatment
Official Title: The VICTORIA Study (Vascular CalcIfiCation and sTiffness Induced by ORal antIcoAgulation) Comparison Anti-vitamin K Versus Anti-Xa.

Resource links provided by NLM:


Further study details as provided by University Hospital, Angers:

Primary Outcome Measures:
  • Calcification score by scanography [ Time Frame: 2 months ] [ Designated as safety issue: No ]
    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


Secondary Outcome Measures:
  • Vascular ultrasound for arterial rigidity [ Time Frame: 3 months ] [ Designated as safety issue: No ]
    to Compare the impact of an oral anti Xa and an vitamin K antagonists on the arterial rigidity.


Other Outcome Measures:
  • Dosage of circulants calcifiants factors testifying of the reshaping of the extra-cellular matrix [ Time Frame: 2 months ] [ Designated as safety issue: No ]

Estimated Enrollment: 150
Study Start Date: May 2013
Estimated Study Completion Date: May 2017
Estimated Primary Completion Date: May 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Rivaroxaban

Rivaroxaban (oral tablet) for patients with atrial fibrillation:

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

Rivaroxaban (oral tablet) for patients with pulmonary embolism: 2x 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

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02161965

Contacts
Contact: Georges LEFTHERIOTIS, MD,PhD +33(0)241353689 geleftheriotis@chu-angers.fr

Locations
France
University Hospital Angers Recruiting
Angers, France, 49933
Contact: Georges LEFTHERIOTIS, MD,PhD    +33(0)241353689    geleftheriotis@chu-angers.fr   
Sub-Investigator: Jean-Marc DUPUIS, Ph         
Sub-Investigator: Aude TASSIN, Ph         
Sub-Investigator: Maxime QUERCY, Ph         
Sponsors and Collaborators
University Hospital, Angers
Investigators
Principal Investigator: Georges LEFTHERIOTIS, MD, PhD University Hospital, Angers, France
  More Information

No publications provided

Responsible Party: University Hospital, Angers
ClinicalTrials.gov Identifier: NCT02161965     History of Changes
Other Study ID Numbers: 2012-005354-27
Study First Received: June 2, 2014
Last Updated: June 10, 2014
Health Authority: France: Ministry of Health

Keywords provided by University Hospital, Angers:
Anticoagulating treatment
Coronary and limbs calcification
Arterial rigidity
Biomarker

Additional relevant MeSH terms:
Atrial Fibrillation
Calcinosis
Pulmonary Embolism
Thrombosis
Vascular Calcification
Venous Thromboembolism
Venous Thrombosis
Arrhythmias, Cardiac
Calcium Metabolism Disorders
Cardiovascular Diseases
Embolism
Embolism and Thrombosis
Heart Diseases
Lung Diseases
Metabolic Diseases
Pathologic Processes
Respiratory Tract Diseases
Thromboembolism
Vascular Diseases
Fluindione
Rivaroxaban
Anticoagulants
Hematologic Agents
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on October 21, 2014