FormalPara Key Points

Chronic venous disease (CVD) is a condition arising from the microvessels and perpetuated by a vicious cycle of worsening venous flow and inflammation.

Micronised purified flavonoid fraction (MPFF) has been shown to reduce reflux in microvessels and larger veins, and to improve accompanying clinical symptoms and quality of life, in patients with early stage CVD.

Further, data from meta-analyses and individual clinical studies have demonstrated the efficacy of MPFF in patients at more advanced stages of CVD, in whom it increases the rate of ulcer healing when used alone or in combination with conventional therapy, compression and/or surgical intervention for CVD.

1 Introduction

Relatively little is known about the aetiology and pathophysiology of chronic venous disease (CVD), but emerging evidence indicates that it is a condition arising from the microvessels and perpetuated by a vicious cycle of worsening venous flow and inflammation (Fig. 1) [1].

Fig. 1
figure 1

Vicious cycle of microcirculatory disturbances, inflammation and remodelling in the pathophysiology of CVD [1]. CVD chronic venous disease

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The aim of this article is to describe research with micronised purified flavonoid fraction (MPFF), examining how it might affect the pathophysiological process in CVD development, and the clinical results of its pharmacological effects, with a focus on the most recent research.

2 Effects of MPFF on the Vasculature

2.1 Microvasculature

Researchers in Brazil have used an animal model of high pressure/low blood flow induced by ligature of the external right iliac vein to investigate the effects of MPFF on the structure and function of microvalves [2, 3]. Ligation of the iliac vein induces the development of venous hypertension, with a high pressure/low flow haemodynamic profile similar to the pathophysiology of CVD in humans. The most recent publication from this group reports results of a randomised study of MPFF, in which animals received MPFF 100 mg/kg/day for 2 days before and 5 days after ligation, drug vehicle plus ligation, or no treatment plus sham operation (without ligation) [3]. They found that in the absence of MPFF treatment, venular diameter increased in the first 4 hours post-ligation, then plateaued for about 5–7 days before decreasing again to baseline levels by Day 14. The increase in venular diameter was accompanied by an inflammatory response, with marked leukocyte adhesion on microvalves, which was maximal 3–5 days after ligation. MPFF significantly reduced venular diameter and leukocyte adhesion compared with vehicle treatment. In fact, the number of adherent leukocytes in the microvessels of MPFF-treated animals was similar to the number of adherent leukocytes in animals who had undergone the sham operation, without venous hypertension [3].

In comparison to animal models, CVD in humans is characterised by chronic microcirculatory hypertension due to reflux, venous obstruction or both [1]. The question of whether the vasoprotective effects of MPFF in animals may similarly occur in humans was investigated by Lugli and colleagues in a study of patients who met criteria for early CVD of stage C0s or C1s using the Clinical, Etiological, Anatomical and Pathophysiological (CEAP) categories [4] and who had lower limb symptoms [5]. These investigators had already found that patients at stage C0s, who experienced pain without any other identifiable signs of CVD, had detectable reflux in the valves of the down-stream tributaries of the saphenous vein, but no detectable changes in the saphenous vein or its first-generation tributaries [6]. In 30 patients with C0s (n = 3) or C1s (n = 27) who received MPFF 1000 mg/day, micro-vessel reflux decreased significantly compared with baseline at 6 months (p < 0.001), and these changes were accompanied by significant reductions in symptoms such as pain, cramps and heaviness (all p < 0.001 vs baseline) [5]. These data suggest that MPFF modifies symptoms by reducing reflux in the microvasculature.

2.2 Larger Veins

The effects of MPFF are not limited to the microvasculature. Researchers from Russia used the day orthostatic load (DOL) test to assess reflux in the great saphenous vein (GSV) in patients with symptoms of CVD [7]. Seventy-eight patients had a substantial difference between morning and evening reflux parameters on the DOL test, indicating situational (changing) reflux. Among these 78 patients, 46 met the criteria for C0s or C1s CVD (group 1) and 32 had C2 CVD (group 2). This group had undergone GSV-preserving phlebectomy but still had detectable situational reflux on DOL after surgery. The study also included ten C2 patients who had undergone phlebectomy but had persistent unchanging reflux on ultrasonography one month later (group 3). Three months of treatment with MPFF 1000 mg/day resolved the evening GSV reflux in 76.1 % of group 1 patients, and significantly reduced the evening GSV diameter and orthostatic gradient in this group. In group 2, MPFF treatment significantly reduced evening GSV diameter and orthostatic gradient in patients with resolved reflux but not in those with persistent reflux. Patients in group 3 did not have situational reflux so they did not undergo the DOL test after MPFF treatment, but treatment led to resolution of reflux in 40% of patients and reduction in reflux severity in 60%. Across all three groups of patients, treatment with MPFF was associated with a significant reduction in symptom intensity and significant improvement in quality of life (QoL), measured using the 20-item Chronic Venous Disease Quality of Life Questionnaire (CIVIQ-20) [7].

Similar beneficial changes in total venous reflux have been seen with MPFF in patients with more severe CVD. For example, Khorev and colleagues used air plethysmography to evaluate venous refilling time (VRT) in 35 patients with C2, C3 or C4 CVD [8]. Venous refilling time provides an assessment of vessel filling in the saphenous veins, deep veins, and microvessels, and VRT decreases with worsening CVD. Thirty days of treatment with MPFF 1000 mg/day significantly increased median VRT in these patients, and significant improvements were noted in all subgroups of patients—those with C2, C3 or C4 CVD [8].

These and earlier data, from animal models and studies in patients, indicate that MPFF has beneficial effects on a range of pathophysiological processes that contribute to the symptoms of CVD, including inflammation, micro-vessel permeability, valve and vessel wall remodelling and reflux in microvalves (Fig. 2) [2, 3, 5, 9,10,11,12,13]. While there is no direct evidence that treatment of CVD in the early stages can prevent progression, there is indirect epidemiological evidence that progression will be slower for patients who do not develop venous reflux of ≥0.5 seconds. For example, the Edinburgh Vein Study showed that venous reflux in superficial veins (± reflux in deep veins) was associated with a significantly increased risk of developing C2 disease (varicose veins) [14]. However, the risk of developing chronic venous insufficiency (C3–C6) CVD was similar in patients with or without reflux [14]. This suggests that reflux in large veins is only a small contributor to the progression of CVD, and that pathophysiological changes in the superficial venous circulation are more relevant to CVD progression.

Fig. 2
figure 2

Effects of MPFF on the pathophysiological processes that cause the signs and symptoms of CVD. CVD chronic venous disease, MPFF micronised purified flavonoid fraction

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3 MPFF Efficacy in All Classes of CVD

There is growing evidence that MPFF is effective in all CEAP classes of CVD, including in patients with C3 to C6 CVD.

3.1 C3 CVD

The Vein Act Prolonged-C3 (VAP-C3) study was a multicentre, prospective observational study conducted in 708 patients with C3 CVD [15]. Patients were treated according to their physician’s usual clinical practice and judgement, with compression and/or veno-active drug therapy, with or without surgery, and followed up for a median of 2.5 months. During follow-up visits, physicians recorded the nature and severity of patients’ CVD symptoms, characteristics and location of their oedema, oedema volume (using the disc model method) and QoL using the CIVIQ-14 [15]. Overall, 97.7% of patients received MPFF, as monotherapy or together with compression, topical treatment and/or surgical intervention. MPFF was associated with a significant reduction in ankle volume (p < 0.001), irrespective of additional treatments and averaging between 190 mL (when used as monotherapy) and 290 mL (when combined with compression, surgery and topical therapy). These changes were associated with a significant reduction in the severity of symptoms including heaviness, pain, and a sensation of leg swelling (p < 0.001), and a significant improvement in QoL (p < 0.001) [15].

These data confirm the results of previous meta-analyses of randomised, controlled trials (RCTs) [16, 17], one of which specifically examined the effect of different veno-active drugs on oedema [16]. This analysis evaluated the results of 10 placebo-controlled RCTs including 1010 CVD patients with oedema who received treatment with MPFF (4 studies), hydroxyethylrutoside (1 study), Ruscus extracts (4 studies) or diosmin (1 study). Ankle circumference decreased by a mean of 11 mm in the placebo group, 20 mm in the diosmin group (not significant vs placebo), 58 mm in both the hydroxyethylrutoside group and the Ruscus extracts group (both p < 0.0001 vs placebo), and 80 mm in the MPFF group (p < 0.00001 vs placebo). The magnitude of the mean change in ankle circumference was significantly greater with MPFF compared with hydroxyethylrutoside, Ruscus extracts or diosmin (all p < 0.0001) [16].

3.2 C4 CVD

MPFF has also been shown to improve the skin changes associated with CVD, which characterise the C4 CEAP class. Skin changes were one of the parameters evaluated in a 2018 meta-analysis of ten double-blind, placebo-controlled studies with MPFF (n = 1692) conducted by Kakkos and Nicolaides [17]. The effect of MPFF on skin was assessed in two studies, and there was a marked and significant reduction in the proportion of patients with CVD-related skin changes in the MPFF group versus the placebo group (relative risk 0.18 [95 % CI 0.07 to 0.46]; p = 0.0003), as well as a significant decrease in the severity of leg redness (p = 0.01). This analysis also showed a significant improvement in QoL with MPFF versus placebo (p = 0.01), as well as significant relief of symptoms such as pain, heaviness and cramps [17].

3.3 C6 CVD

Venous ulcers present a significant challenge in the management of CVD. A meta-analysis of five RCTs found that adding MPFF 1000 mg/day to conventional treatment significantly increased the rate of ulcer healing and reduced the time to ulcer healing compared with control (placebo or conventional treatment alone) [18]. Overall, there was a 32% increase in the rate of ulcer healing at 6 months with MPFF compared with control (p = 0.03) and ulcers healed an average of 5 weeks faster in the group receiving MPFF compared with control (p = 0.0034).

The weight of evidence in favour of MPFF as adjunctive treatment (along with compression and local care) for patients with venous ulcer is recognised in international guidelines. The evidence grading for MPFF in the healing of leg ulcers is grade A in the 2018 guidelines from the European Venous Forum, International Union of Angiology, Cardiovascular Disease Educational and Research Trust (UK) and the Union Internationale de Phlébologie [19], and level A, class IIa in the 2022 guidelines from the European Society for Vascular Surgery [20]. In the latter guidelines, MPFF is the only veno-active drug that is stated to improve QoL [20].

4 Conclusion

There is growing evidence that MPFF has a positive impact on the underlying pathophysiological processes in CVD, particularly in the microcirculation. Among the veno-active drugs, the role of MPFF for controlling the signs and symptoms in all stages of CVD from C0s to C6 is supported by various forms of evidence. The results of clinical trials and meta-analyses show that MPFF is a highly effective treatment for ameliorating oedema, preventing skin changes, and healing venous leg ulcers, when used alone or in combination with conventional therapy, compression and/or surgical intervention for CVD. As a result, MPFF is highly recommended in international guidelines of CVD management.