Rivaroxaban With Diosmin in Long-term Treatment of Deep Vein Thrombosis

Study Overview
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Brief Summary
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The randomized clinical study aimed to assess the efficacy and safety of standard anticoagulation with rivaroxaban in combination with diosmin compared to the isolated use of standard rivaroxaban for prolonged therapy of acute femoro-popliteal deep vein thrombosis reflected the speed of deep vein recanalization and incidence of post-thrombotic syndrome.

Detailed Description
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Deep vein thrombosis is an acute inflammatory disease that affects vein wall and leads to the structural changes in the wall and valves reflected with chronic venous insufficiency that called postthrombotic syndrome (PTS). Diosmin as a flavonoid agent has properties to reduce leukocyte-endothelial interaction and inflammatory response, that could reduce the damage to venous wall and valves. The hypothesis of the study is based on assumption that diosmin combined with standard anticoagulation can improve outcomes of femoro-popliteal DVT due to increase speed of veins recanalization, decrease of vein wall inflammation and finally decrease the incidence of PTS at 6 month and 1 year after index DVT.

Official Title
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The Efficacy of Rivaroxaban With Diosmin in the Long-term Treatment of Acute Proximal Deep Vein Thrombosis

Conditions
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Deep Vein Thrombosis, Postthrombotic Syndrome

Intervention / Treatment
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* Drug: Rivaroxaban
* Drug: Diosmin
* Other: compression stockings


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age over 18 years The first episode of femoro-popliteal deep vein thrombosis (DVT) Verification of DVT by duplex ultrasound Informed consent signed Exclusion Criteria: Suspicion of pulmonary embolism (PE) Verified PE Bilateral DVT Contraindications for rivaroxaban (in accordance with the official instructions) Contraindications for diosmin (in accordance with the official instructions) Active cancer Verified severe thrombophilia (antiphospholipid antibodies, deficiency of proteins C, S, antithrombin 3) Use of other anticoagulants for more than 7 days from the DVT verification Impossibility of using compression stocking after 3 days from DVT verification Performed surgical intervention on the superficial or deep veins of the lower extremities (thrombolysis, thrombectomy, vein ligation, implantation of the inferior cava filter) Continuous use of other drugs that affect the hemostasis system (except for acetylsalicylic acid in a dose of not more than 100 mg). Low compliance

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized open-labeled clinical trial with a masked outcomes assessor
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental: Rivaroxaban + Diosmin + Stockings<br>treatment of deep vein thrombosis with anticoagulation (rivaroxaban), elastic compression stockings and additional prescription of diosmin | Drug: Rivaroxaban<br>* 15 mg b.i.d. for 3 weeks and then 20 mg q.d. up to 6 month<br>* Other names: xarelto;Drug: Diosmin<br>* 600 mg q.d. for 12 month<br>* Other names: flebodia;Other: compression stockings<br>* above knee stocking for 12 month<br>|
| Active Comparator: Control: Rivaroxaban + Stockings only<br>standard treatment of deep vein thrombosis with anticoagulation (rivaroxaban) and elastic compression stockings | Drug: Rivaroxaban<br>* 15 mg b.i.d. for 3 weeks and then 20 mg q.d. up to 6 month<br>* Other names: xarelto;Other: compression stockings<br>* above knee stocking for 12 month<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Postthrombotic Syndrome as Determined by Villalta Score | Detection of the postthrombotic syndrome (PTS) was made according to the Villalta score (a combination of 5 subjective symptoms and 6 objective signs of chronic venous disease) ranged from 0 (no signs) to 33 scores (maximal severity). PTS defined as 5 and more scores; mild PTS as 5-9 scores; moderate PTS as 10-14 scores; severe PTS as 15 and more scores. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Recurrent Symptomatic or Asymptomatic DVT | detection of any episode of recurrent DVT with or without clinical signs verified by duplex ultrasound | 12 months | 
| Number of Participants With Symptomatic Pulmonary Embolism | detection of symptomatic pulmonary embolism verified with CT pulmonary angiogram | 12 months | 
| The Value of Venous Clinical Severity Score | Venous Clinical Severity Score (VCSS) is a combination of subjective symptoms and objective signs of CVD aimed to assess the severity of disease and ranges from 0 (no signs and symptoms of CVD) to 30 (severe signs and symptoms of CVD) | 12 months | 
| The Value of Chronic Lower Limb Venous Insufficiency Questionnaire - 20 Items | Chronic Lower Limb Venous Insufficiency Questionnaire - 20 items (CIVIQ-20) is a venous specific questionnaire to assess the disease-specific quality of life (QoL). It contains 20 items of 1-5 scores, totally, from 20 (best QoL) to100 (worst QoL) scores. | 12 months | 
| Number of Participants With Full Recanalization of the Popliteal Vein | Full recanalization of popliteal vein suggests the residual venous obstruction (RVO) less than 20%. The RVO was assessed by duplex ultrasound and calculated as the vein cross-sectional diameter under the maximal compression divided on the diameter without any compression multiplied by 100%. | 12 months | 
| Extension of Residual Venous Obstruction by Marder Score | Residual venous obstruction (RVO) defined as a thrombotic masses occupying 20% and more of the vein cross-sectional diameter was measured by duplex ultrasound and calculated as the vein cross-sectional diameter under the maximal compression divided on the diameter without compression and multiplied by 100%. The extension of RVO was assessed by Marder score, the sum of all affected venous segments, evaluated by different scores (see Appendix of the Protocol), that ranged from 0 (no RVO) to 34 (RVO in all possible venous segments in one limb). | 12 months | 
| Adverse Events | any adverse events detected or suspected | 12 months | 
| Major Bleeding | according to the International Society of Thrombosis and Hemostasis (ISTH) definition, major bleeding defined as fatal bleeding, and/or symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with compartment syndrome, and/or bleeding causing a fall in hemoglobin level of 20 g/L or 1.24 mmol/L or more, or leading to transfusion of two or more units of whole blood or red cells | 12 months | 
| Clinically Relevant Non-major Bleeding | any non-major bleeding requiring anticoagulant withdrawal, and/or performing haemostatic measures, and/or hospitalization, and/or an unscheduled medical appointment | 12 months | 
| Minor Bleeding | any non-major or non-clinically relevant bleeding does not require the suspension of therapy and changes in the patient's lifestyle | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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deep vein thrombosis, postthrombotic syndrome, anticoagulation, treatment, prevention