Use of Micronized Purified Flavonoid Fraction Together with Rivaroxaban Improves Clinical and Ultrasound Outcomes in Femoropopliteal Venous Thrombosis: Results of a Pilot Clinical Trial

This pilot, single-center, open-label comparative clinical trial with blinded outcome assessment recruited patients over 18 years of age with a first episode of clinically provoked or unprovoked DVT in the femoropopliteal vascular segment with possible involvement of the calf veins and the common femoral vein. DVT location was confirmed by duplex ultrasound scan (DUS). All procedures performed in studies involving human participants were in accordance with local ethics committee of the Clinical Hospital No. 1 of the Presidents Administration of Russian Federation and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study. At the authors’ institution it is not obligatory to register pilot and unfunded studies; therefore this trial is not registered.

Exclusion criteria were suspected or confirmed pulmonary embolism; bilateral DVT location; extension of the thrombosis into the iliac veins above the inguinal fold; contraindications to therapy with anticoagulants or MPFF; verified malignant tumor at the time of DVT manifestation; known severe thrombophilia (deficiency of protein C, protein S, antithrombin III, antiphospholipid syndrome); use of parenteral anticoagulants for 7 days or more from the time of DVT verification; inability to use compression stockings; any intervention for DVT (inferior vena cava filter implantation, thrombectomy, or catheter-guided thrombolysis); continued use of other drugs affecting the hemostatic system (except acetylsalicylic acid at a dose of up to 100 mg per day); and poor compliance.

The study was carried out at the facilities of the Clinical Hospital No. 1 of the Presidents Administration of the Russian Federation in 2017–2018. In accordance with the internal protocol of the institution, all patients with suspected DVT entering the emergency department were assessed using a two-level Wells score and a D-dimer evaluation [32]. In patients with a high clinical probability of DVT or a combination of low clinical probability for DVT with an increased level of D-dimer, anticoagulant therapy was initiated with low molecular weight heparin (LMWH), followed by DUS. Patients with diagnosed femoropopliteal venous thrombosis were assessed for fulfillment of the inclusion and exclusion criteria. After signing informed consent, patients were randomly allocated to one of two groups based on the number on the patient’s medical record form: those whose last digit was even were assigned to the MPFF group, and those whose last digit was odd were assigned to the control group; if the last digit was zero, the penultimate digit was used. In the case of premature completion of recruitment to either group, all eligible patients were intentionally allocated to the second group.

During the period from hospital admission to treatment allocation, all patients received therapeutic doses of LMWH (enoxaparin 1 mg/kg twice daily). After randomization, patients in both groups were switched to the oral anticoagulant rivaroxaban at a dosage of 15 mg twice daily for up to 3 weeks from the administration of the first dose of LMWH. Thereafter they received a dosage of 20 mg once daily for up to 6 months. The first dose of rivaroxaban was administered instead of LMWH at the time of the next scheduled injection. In addition, during the first 3 days following the DVT diagnosis, patients in both groups applied individualized medical compression in the form of thigh-high stockings with a pressure of 23–32 mmHg (class 2 compression according to RAL-GZ 387 standard). Matching the size of the stocking to the diameter of the limb was controlled 3 weeks and 3 months after the start of treatment. Patients were advised to wear the stockings 24 h a day for the first week and then during the day for the next 6 months. In the MPFF group, patients received MPFF 500 mg twice daily for 6 months in addition to standard treatment. The first dose of MPFF was administered immediately after treatment allocation and in parallel with the switch to the oral form of the anticoagulant.

Patients were followed for 6 months with clinical and ultrasound evaluation every 2 months. At baseline, in addition to standard clinical data, the affected lower limb was evaluated for the presence of pre-existing CVD, and if confirmed, the clinical class according to the CEAP (Clinical, Etiological, Anatomical, and Pathological) classification was determined. CEAP clinical classes C1 (telangiectases), C2 (varicose veins), C4 (skin pigmentation, eczema, lipodermatosclerosis or athrophie blanche), C5 (healed venous ulcer), and C6 (active venous ulcer) were confirmed objectively on the basis of the presence of corresponding signs of the disease. CEAP clinical class C3 (presence of leg edema) was confirmed on the basis of the patient’s medical history (complaints of edema of the lower limb or need for compression therapy prior to the manifestation of thrombosis), as at the time of physical examination all patients had swelling due to acute deep vein occlusion. CEAP class was also determined after 6 months of treatment. CVD severity was assessed using the Venous Clinical Severity Score (VCSS) [33]. The VCSS includes 10 clinical descriptors (pain, varicose veins, venous edema, skin pigmentation, inflammation, induration, number of active ulcers, duration of active ulceration, size of ulcer, and compressive therapy use), scored from 0 to 3 (total possible score, 30). Quality of life was assessed using the Chronic Venous Disease quality of life Questionnaire (CIVIQ-20), a validated, 20-item, self-reported scale that captures the key dimensions of quality of life specifically impaired by CVD in the following four domains: physical, psychological, social, and pain [34]. The presence and severity of PTS was assessed using the Villalta score, which is based on the sum of severity ratings of five venous symptoms and six clinical signs (Table 1) [35]. The final judgement about the presence of PTS and the severity of CVD was made by an independent expert who was blinded to the patient’s allocation to MPFF or control group.

DUS was performed using the MyLab30 device (Esaote, Italy) with a linear ultrasound transducer LA532 in the frequency range 5–13 MHz. The common femoral vein (CFV) and femoral vein (FV) were assessed in the supine position, popliteal vein (PV) in the prone position, and calf veins in a sitting position. At each examination, all accessible venous segments were subject to evaluation.

The criteria for DVT were incompressibility of the vein during compression by the transducer and absence of blood flow in the vein on the color mapping mode. To assess the prevalence of thrombotic occlusion, a modified Marder score was used. This allocates points to each of the deep and superficial venous segments of the lower limb that are occluded. If all the veins of one leg are occluded the total score is 34 (Table 2) [36]. When performing the dynamic DUS, the degree of recanalization of the CFV, FV, and PV was calculated on the basis of their compressibility. This was achieved by measuring the veins’ diameters without compression and at maximum compression with the transducer at the narrowest point of each venous segment. The degree of recanalization was calculated with the following formula: [d (no compression) − d (maximal compression)]/d (no compression) × 100%. All measurements were repeated three times, and an average value was used for calculations. All ultrasound studies were performed by a specialist blinded to the patient’s allocation to the MPFF or control group.

The primary study endpoint was the presence of PTS signs at 6 months, determined by a blinded expert. For the diagnosis of PTS, the Villalta score was used. The criteria for a PTS diagnosis were a Villalta score of ≥ 5; severe PTS was defined as a score of ≥ 15 or the presence of an active venous ulcer.

The secondary study endpoints included severe PTS; symptomatic or asymptomatic recurrence of DVT; symptomatic pulmonary embolism; change in CEAP clinical class; CVD severity assessed by VCSS, quality of life assessed by CIVIQ-20; complete recanalization of vessels; change in degree of recanalization for the CFV, FV, and PV; change in thrombus extension by the Marder score; and the occurrence of bleeding and/or other adverse events associated with therapy.

Symptomatic recurrence of DVT was defined as an increase in edema, pain, or hyperemia of the affected lower limb, or the occurrence of the same signs on the intact leg. The asymptomatic recurrence of DVT was defined as the occurrence of signs of total occlusion in a previously recanalized venous segment. A complete recanalization was the clearance of thrombotic masses by 80% or more in the venous lumen (residual vein occlusion less than 20%).

Bleeding related to anticoagulant therapy was classified as major (according to the International Society on Thrombosis and Hemostasis criteria) [37], clinically relevant non-major (any episode not fulfilling the criteria of major bleeding, but resulting in withdrawal of anticoagulant therapy and/or requiring a specific medical intervention and/or leading to an unscheduled visit to the doctor), or minor (any episode not fulfilling the criteria of major or clinically relevant non-major bleeding).

Patients’ general health status was assessed at each follow-up visit with an emphasis on identifying possible adverse events of therapy.