Deep Vein Thrombosis, Postthrombotic Syndrome
Conditions
Keywords
deep vein thrombosis, postthrombotic syndrome, anticoagulation, treatment, prevention
Brief summary
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
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.
Interventions
DRUGRivaroxaban
15 mg b.i.d. for 3 weeks and then 20 mg q.d. up to 6 month
DRUGDiosmin
600 mg q.d. for 12 month
above knee stocking for 12 month
Sponsors
Pirogov Russian National Research Medical University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
Outcomes assessor does not involve in randomisation and treatment process, has no information about the patient's belonging to one of the study groups
Intervention model description
Randomized open-labeled clinical trial with a masked outcomes assessor
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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%. |
| 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 |
| 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 |
| 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). |
Countries
Russia
Participant flow
Pre-assignment details
Admitted to the hospital with the suspicion for DVT: 202; DVT verified: 158; Eligible DVT: 102; Rejected to participate: 12; Randomized: 90
Participants by arm
| Arm | Count |
|---|---|
| Experimental: Rivaroxaban + Diosmin + Stocking treatment of DVT with anticoagulation (rivaroxaban), elastic compression stockings and additional prescription of diosmin
Rivaroxaban: 15 mg b.i.d. for 3 weeks and then 20 mg q.d. up to 6 month
Diosmin: 600 mg q.d. for 12 month
compression stockings: above knee stocking for 12 month | 45 |
| Control: Rivaroxaban + Stockings Only standard treatment of DVT with anticoagulation (rivaroxaban) and elastic compression stockings
Rivaroxaban: 15 mg b.i.d. for 3 weeks and then 20 mg q.d. up to 6 month
compression stockings: above knee stocking for 12 month | 45 |
| Total | 90 |
Baseline characteristics
| Characteristic | Experimental: Rivaroxaban + Diosmin + Stocking | Control: Rivaroxaban + Stockings Only | Total |
|---|---|---|---|
| Age, Continuous | 57.4 years STANDARD_DEVIATION 13.8 | 60.2 years STANDARD_DEVIATION 13.1 | 58.8 years STANDARD_DEVIATION 13.4 |
| Preexisting chronic venous disease | 23 Participants | 32 Participants | 55 Participants |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Region of Enrollment Russia | 45 participants | 45 participants | 90 participants |
| Sex: Female, Male Female | 17 Participants | 17 Participants | 34 Participants |
| Sex: Female, Male Male | 28 Participants | 28 Participants | 56 Participants |
| Thrombus burden | 15.2 Marder score STANDARD_DEVIATION 4.7 | 11.6 Marder score STANDARD_DEVIATION 4.1 | 13.4 Marder score STANDARD_DEVIATION 4.7 |
| Time to randomization | 3.4 days STANDARD_DEVIATION 1.2 | 3.5 days STANDARD_DEVIATION 1.6 | 3.5 days STANDARD_DEVIATION 1.4 |
| Unprovoked DVT | 29 Participants | 33 Participants | 62 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 45 | 0 / 45 |
| other Total, other adverse events | 5 / 45 | 4 / 45 |
| serious Total, serious adverse events | 0 / 45 | 0 / 45 |
Outcome results
Primary
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.
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Experimental: Rivaroxaban + Diosmin + Stockings | Number of Participants With Postthrombotic Syndrome as Determined by Villalta Score | 3 Participants |
| Control: Rivaroxaban + Stockings Only | Number of Participants With Postthrombotic Syndrome as Determined by Villalta Score | 22 Participants |
p-value: <0.0001Fisher Exact
Secondary
Adverse Events
any adverse events detected or suspected
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Experimental: Rivaroxaban + Diosmin + Stockings | Adverse Events | 5 Participants |
| Control: Rivaroxaban + Stockings Only | Adverse Events | 4 Participants |
p-value: 1Fisher Exact
Secondary
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
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Experimental: Rivaroxaban + Diosmin + Stockings | Clinically Relevant Non-major Bleeding | 1 Participants |
| Control: Rivaroxaban + Stockings Only | Clinically Relevant Non-major Bleeding | 2 Participants |
Secondary
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).
Time frame: 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Experimental: Rivaroxaban + Diosmin + Stockings | Extension of Residual Venous Obstruction by Marder Score | 0.3 Marder score | Standard Deviation 1 |
| Control: Rivaroxaban + Stockings Only | Extension of Residual Venous Obstruction by Marder Score | 1.9 Marder score | Standard Deviation 2.4 |
p-value: 0.001Fisher Exact
Secondary
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
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Experimental: Rivaroxaban + Diosmin + Stockings | Major Bleeding | 0 Participants |
| Control: Rivaroxaban + Stockings Only | Major Bleeding | 0 Participants |
Secondary
Minor Bleeding
any non-major or non-clinically relevant bleeding does not require the suspension of therapy and changes in the patient's lifestyle
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Experimental: Rivaroxaban + Diosmin + Stockings | Minor Bleeding | 2 Participants |
| Control: Rivaroxaban + Stockings Only | Minor Bleeding | 2 Participants |
Secondary
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%.
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Experimental: Rivaroxaban + Diosmin + Stockings | Number of Participants With Full Recanalization of the Popliteal Vein | 42 Participants |
| Control: Rivaroxaban + Stockings Only | Number of Participants With Full Recanalization of the Popliteal Vein | 28 Participants |
Secondary
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
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Experimental: Rivaroxaban + Diosmin + Stockings | Number of Participants With Recurrent Symptomatic or Asymptomatic DVT | 1 Participants |
| Control: Rivaroxaban + Stockings Only | Number of Participants With Recurrent Symptomatic or Asymptomatic DVT | 6 Participants |
p-value: 0.049Log Rank
Secondary
Number of Participants With Symptomatic Pulmonary Embolism
detection of symptomatic pulmonary embolism verified with CT pulmonary angiogram
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Experimental: Rivaroxaban + Diosmin + Stockings | Number of Participants With Symptomatic Pulmonary Embolism | 0 Participants |
| Control: Rivaroxaban + Stockings Only | Number of Participants With Symptomatic Pulmonary Embolism | 0 Participants |
Secondary
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.
Time frame: 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Experimental: Rivaroxaban + Diosmin + Stockings | The Value of Chronic Lower Limb Venous Insufficiency Questionnaire - 20 Items | 22.1 CIVIQ-20 scores | Standard Deviation 3.3 |
| Control: Rivaroxaban + Stockings Only | The Value of Chronic Lower Limb Venous Insufficiency Questionnaire - 20 Items | 28.8 CIVIQ-20 scores | Standard Deviation 7.6 |
p-value: <0.0001Fisher Exact
Secondary
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)
Time frame: 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Experimental: Rivaroxaban + Diosmin + Stockings | The Value of Venous Clinical Severity Score | 1.2 VCSS score | Standard Deviation 1.1 |
| Control: Rivaroxaban + Stockings Only | The Value of Venous Clinical Severity Score | 4.4 VCSS score | Standard Deviation 2.1 |
p-value: <0.0001Fisher Exact