Vascular CalcIfiCation and sTiffness Induced by ORal antIcoAgulation (VICTORIA)
|Permanent Atrial Fibrillation Venous Thrombosis Pulmonary Embolism Anticoagulation Treatment at Least > or = to 12-month||Drug: Rivaroxaban Drug: Fluindione Drug: Warfarin||Phase 4|
|Study Design:||Allocation: Randomized
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.|
- 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
- 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.
- Dosage of circulating anti-calcifying factors and extra-cellular matrix remodelling [ Time Frame: 2 months ]
|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)|
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
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.
Other Name: PreviscanDrug: Warfarin
Other Name: Previscan
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT02161965
|Contact: Georges LEFTHERIOTIS, MD,PhD||+33(0)firstname.lastname@example.org|
|University Hospital Angers||Recruiting|
|Angers, France, 49933|
|Contact: Georges LEFTHERIOTIS, MD,PhD +33(0)241353689 email@example.com|
|Sub-Investigator: Jean-Marc DUPUIS, Ph|
|Sub-Investigator: Aude TASSIN, Ph|
|Sub-Investigator: Maxime QUERCY, Ph|
|Principal Investigator:||Georges LEFTHERIOTIS, MD, PhD||University Hospital, Angers, France|