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

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.

• Rivaroxaban (Drug), also known as xarelto: 15 mg b.i.d. for 3 weeks and then 20 mg q.d. up to 6 month
• Diosmin (Drug), also known as flebodia: 600 mg q.d. for 12 month
• compression stockings (Other): above knee stocking for 12 month

Primary outcomes

• Number of Participants With Postthrombotic Syndrome as Determined by Villalta Score [12 months]: 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.

Secondary outcomes

• Number of Participants With Recurrent Symptomatic or Asymptomatic DVT [12 months]: detection of any episode of recurrent DVT with or without clinical signs verified by duplex ultrasound
• Number of Participants With Symptomatic Pulmonary Embolism [12 months]: detection of symptomatic pulmonary embolism verified with CT pulmonary angiogram
• The Value of Venous Clinical Severity Score [12 months]: 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)
• The Value of Chronic Lower Limb Venous Insufficiency Questionnaire - 20 Items [12 months]: 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.
• Number of Participants With Full Recanalization of the Popliteal Vein [12 months]: 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%.
• Extension of Residual Venous Obstruction by Marder Score [12 months]: 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).
• Adverse Events [12 months]: any adverse events detected or suspected
• Major Bleeding [12 months]: 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
• Clinically Relevant Non-major Bleeding [12 months]: any non-major bleeding requiring anticoagulant withdrawal, and/or performing haemostatic measures, and/or hospitalization, and/or an unscheduled medical appointment
• Minor Bleeding [12 months]: any non-major or non-clinically relevant bleeding does not require the suspension of therapy and changes in the patient's lifestyle

Sex: All, ages: 18 Years to any

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

Participant flow

Outcome results

• Number of Participants With Postthrombotic Syndrome as Determined by Villalta Score (Primary), Count of participants, Participants: Experimental: Rivaroxaban + Diosmin + Stockings 3; Control: Rivaroxaban + Stockings Only 22 (p <0.0001)
• Number of Participants With Recurrent Symptomatic or Asymptomatic DVT (Secondary), Count of participants, Participants: Experimental: Rivaroxaban + Diosmin + Stockings 1; Control: Rivaroxaban + Stockings Only 6 (p 0.049)
• Number of Participants With Symptomatic Pulmonary Embolism (Secondary), Count of participants, Participants: Experimental: Rivaroxaban + Diosmin + Stockings 0; Control: Rivaroxaban + Stockings Only 0
• The Value of Venous Clinical Severity Score (Secondary), Mean, VCSS score: Experimental: Rivaroxaban + Diosmin + Stockings 1.2 +/- 1.1; Control: Rivaroxaban + Stockings Only 4.4 +/- 2.1 (p <0.0001)
• The Value of Chronic Lower Limb Venous Insufficiency Questionnaire - 20 Items (Secondary), Mean, CIVIQ-20 scores: Experimental: Rivaroxaban + Diosmin + Stockings 22.1 +/- 3.3; Control: Rivaroxaban + Stockings Only 28.8 +/- 7.6 (p <0.0001)
• Number of Participants With Full Recanalization of the Popliteal Vein (Secondary), Count of participants, Participants: Experimental: Rivaroxaban + Diosmin + Stockings 42; Control: Rivaroxaban + Stockings Only 28
• Extension of Residual Venous Obstruction by Marder Score (Secondary), Mean, Marder score: Experimental: Rivaroxaban + Diosmin + Stockings 0.3 +/- 1.0; Control: Rivaroxaban + Stockings Only 1.9 +/- 2.4 (p 0.001)
• Adverse Events (Secondary), Count of participants, Participants: Experimental: Rivaroxaban + Diosmin + Stockings 5; Control: Rivaroxaban + Stockings Only 4 (p 1.000)
• Major Bleeding (Secondary), Count of participants, Participants: Experimental: Rivaroxaban + Diosmin + Stockings 0; Control: Rivaroxaban + Stockings Only 0
• Clinically Relevant Non-major Bleeding (Secondary), Count of participants, Participants: Experimental: Rivaroxaban + Diosmin + Stockings 1; Control: Rivaroxaban + Stockings Only 2
• Minor Bleeding (Secondary), Count of participants, Participants: Experimental: Rivaroxaban + Diosmin + Stockings 2; Control: Rivaroxaban + Stockings Only 2

Adverse events

Time frame: 12 months

Other adverse events by term

Limitations and caveats: Unsuspected high frequency of PTS in the Control group (standard treatment with rivaroxaban and compression stockings) led to early termination of enrollment (75% of planned sample size).

• Results publication: Lobastov K, Sautina E, Alencheva E, Bargandzhiya A, Schastlivtsev I, Barinov V, Laberko L, Rodoman G, Boyarintsev V. Intermittent Pneumatic Compression in Addition to Standard Prophylaxis of Postoperative Venous Thromboembolism in Extremely High-risk Patients (IPC SUPER): A Randomized Controlled Trial. Ann Surg. 2021 Jul 1;274(1):63-69. doi: 10.1097/SLA.0000000000004556. PMID 33201130

• Study Protocol and Statistical Analysis Plan (PDF, 2017-11-11)

• Ilya Schastlivtsev, PhD, Principal investigator, Pirogov Russian National Research Medical University