Servier – Phlebolymphology

Abstract

Chronic venous disease (CVD) is a highly prevalent disorder with a broad spectrum of symptoms determined by disease stage and whether there is deep or superficial venous system compromise. The treatment goal for CVD is to slow and prevent disease progression and provide symptomatic relief. Available options range from conservative mechanical strategies such as leg elevation, compression stockings, and daily exercise programs to complex surgical deep valvular implants. The adequate treatment option is selected according to the disease phase, and clinicians can add further options as the disease severity progresses. Additionally, pharmacological treatment plays an essential role in CVD management, especially micronized purified flavonoid fraction (MPFF), a venoactive drug (VAD) with proven effectiveness and safety from early stages in C1 patients to complex C6 patients with severe ulcerations. Utilizing MPFF for CVD improves patients’ quality of life, symptoms severity, and ulceration healing. MPFF has been widely adopted by vascular practitioners and included in CVD management guidelines worldwide. Therefore, we reviewed several CVD management guidelines published by prestigious academic associations around the globe and summarized their recommendations about the use of MPFF and their level of evidence, providing clinicians with a straightforward and practical source document to include MPFF in daily practice.

Introduction

Chronic venous disease (CVD) is a highly prevalent disorder, with an overall worldwide reported prevalence of 83.6%.¹ The burden of CVD is increasing, associated with rising obesity and sedentarism,² with severe complications that affect quality of life (QOL) and represent a significant economic burden to health systems due to the loss of working days and elevated treatment costs. The spectrum of signs and symptoms associated with CVD has two major contributors, failure of either the deep or superficial venous system. The epidemiologic features of superficial venous disease (SVD) and deep venous disease (DVD) differ. Telangiectasias, a mild manifestation of SVD, might present in up to 80% of the general population,³ whereas varicosities have heterogeneous prevalence estimations, ranging from 1% to 60% in men and women.⁴ This wide range might be due to the variability in the number of patients who consult for spider veins or varicosities. Many individuals suffer from venous disease but never look for treatment.

On the other hand, DVD presents more severe conditions, including deep venous thrombosis (DVT) with its potential pulmonary embolism (PE); and post-thrombotic syndrome (PTS) in a chronic setting. DVT has an annual incidence of 0.1%, with one-third of these patients developing fatal PE.⁵ Additionally, up to 80% of DVT cases can progress over time to PTS,⁶ a chronic debilitating disease with limited effective treatment options and devastating consequences in QOL, including ulceration in up to 3% of patients older than 65 years of age.⁷ Given the broad spectrum of CVD and extensive clinical features, effective and easily accessible treatment must be offered to these patients. Available treatment options are directed to prevent the progression of the disease and provide symptomatic relief and vary from simple conservative strategies such as lower-limb elevation and compression stockings to more advanced and specialized techniques to restore valvular function in PTS.⁸

Although most of the current treatment options are directed to certain disease features (stage, deep vs superficial compromise), venoactive drug (VAD) therapy has demonstrated beneficial effects in all phases of CVD. Micronized purified flavonoid fraction (MPFF), an oral VAD composed of 90% diosmin and 10% active flavonoids, has shown efficacy in both early and advanced stages of CVD.^9,10 The benefit can be attributable to the drug mechanism of action, which reduces inflammatory response triggered by venous hypertension, specifically by preventing leukocyte rolling and adherence,¹¹ with a net effect of preventing and slowing disease progression.

Additionally, extensive studies^12-15 have demonstrated that MPFF can provide at least 50% symptomatic relief, reducing swelling, cramping, pain, and heaviness. Due to its effectiveness and broad adoption by patients and clinicians, MPFF has been included as a recommended CVD treatment option in many international management guidelines for CVD. This study aims to review and compare the recommendations about MPFF utilization from several international management guidelines for CVD and provide clinicians with a comprehensive and updated summary of MPFF utilization.

Methods

This review included the CVD clinical practice guidelines from the following academic societies: the European Society for Vascular Surgery, published in 2022; the European Venous Forum, published in 2018 and 2020; Latin American guidelines published in 2016; and the Society for Vascular Surgery and the American Venous Forum published in 2014. The document’s selection process aimed to include representation from the most prestigious academic societies worldwide, with different perspectives about the use of MPFF in Western vascular surgery practice. All the recommendations mentioning MPFF, with the corresponding level of evidence, were included in the document. Finally, the primary outcomes and benefits of MPFF therapy in different settings of CVD management were outlined.

Results

A summarized description of each guideline’s recommendations about MPFF utilization is included below:

Clinical practice guidelines of the European Society for Vascular Surgery: management of chronic venous disease of the lower limbs (2022)¹⁶

This document concludes that VADs in general have beneficial effects on objective measures of leg edema and symptoms and signs of CVD, such as pain, cramps, restless legs, sensation of swelling, paresthesia, and trophic disorders, on the basis of a large Cochrane review that included 53 trials.¹⁷ This guideline outlines that doubleblind, placebo-controlled, randomized clinical trials (RCTs) specifically involving MPFF demonstrated improvement in leg symptoms, such as pain, heaviness, feeling of swelling, cramps, paresthesia, edema, functional discomfort, QOL, and ankle circumference.¹⁸ Accordingly, the European Society for Vascular Surgery establishes that given its low cost and relatively low incidence and low severity of associated adverse events, VAD should be considered for treatment of symptomatology and edema in CVD.

Additionally, the guideline addresses the beneficial effects of utilizing MPFF for the treatment of venous leg ulceration (VLU). There is a 32% higher chance of healing at 6 months in patients treated with MPFF as adjuvant to compression therapy than with compression alone.¹⁹

• For patients with symptomatic CVD who are not undergoing interventional treatment, are awaiting intervention, or have persisting symptoms and/or edema after intervention, medical treatment with VADs should be considered to reduce venous symptoms and edema, on the basis of available evidence for each individual drug. Evidence was Class IIA (weight of evidence/ opinion is in favor of usefulness/efficacy), level A (data derived from multiple RCTs or meta-analyses).
• For patients with active VLU, MPFF, hydroxyethylrutosides, pentoxifylline, or sulodexide should be considered as an adjunct to compression and local wound care to improve ulcer healing. Evidence was Class IIA (weight of evidence/opinion is in favor of usefulness/efficacy), level A (data derived from multiple RCTs or metaanalyses).

Guidelines from the European Venous Forum, the International Union of Angiology, the Cardiovascular Disease Educational and Research Trust (UK), and Union Internationale de Phlébologie: management of CVDs of the lower limb (2018-2020)²⁰

In this document, the authors evaluated the effect of VAD on individual symptoms and signs through the assessment of several meta-analyses and systematic reviews.²⁰ Regarding the role of MPFF in signs and symptom improvement, this review concluded that pain, QOL, skin changes, functional discomfort, and feeling of swelling were reduced with the use of MPFF compared with placebo. These findings had a high level of evidence.^21-26

Additionally, the authors found beneficial effects of MPFF in leg redness, ankle circumference, and burning sensation, which were reduced; however, the level of evidence was moderate, thus more studies are needed to evaluate the real impact of MPFF on those symptoms.^26-28

• Pain was reduced with the use of MPFF compared with placebo. Level of evidence was high (Grade A; Level A evidence derives from 2 or more scientifically sound RCTs or systematic reviews and meta-analyses in which the results are clear-cut and are directly applicable to the target population).
• Heaviness was reduced with the use of MPFF compared with placebo. Level of evidence was high (Grade A; Level A evidence derives from 2 or more scientifically sound RCTs or systematic reviews and meta-analyses in which the results are clear-cut and are directly applicable to the target population).
• Ankle circumference was reduced with the use of MPFF compared with placebo. Level of evidence was moderate (Grade B; Level B evidence is provided by 1 well-conducted RCT or more than 1 RCT with less consistent results, limited power, or other methodological problems, which are directly applicable to the target population, as well as by RCTs extrapolated to the target population from a different group of patients).
• Skin changes were improved with the use of MPFF compared with placebo. Level of evidence was high (Grade A; Level A evidence derives from 2 or more scientifically sound RCTs or systematic reviews and meta-analyses in which the results are clear-cut and are directly applicable to the target population).
• Leg redness was reduced with the use of MPFF compared with placebo. Level of evidence was moderate (Grade B; Level B evidence is provided by 1 well-conducted RCT or more than 1 RCT with less consistent results, limited power, or other methodological problems, which are directly applicable to the target population as well as by RCTs extrapolated to the target population from a different group of patients).
• Functional discomfort was significantly reduced with the use of MPFF compared with placebo. Level of evidence was high (Grade A; Level A evidence derives from 2 or more scientifically sound RCTs or systematic reviews and meta-analyses in which the results are clear-cut and are directly applicable to the target population).
• Burning sensation was reduced with the use of MPFF compared with placebo. Level of evidence was moderate to low (Grade B/C; Level B evidence is provided by 1 well-conducted RCT or more than 1 RCT with less consistent results, limited power, or other methodological problems, which are directly applicable to the target population, as well as by RCTs extrapolated to the target population from a different group of patients; Level C evidence results from poorly designed trials, observational studies, or from small case series).
• Feeling of swelling was reduced with the use of MPFF compared with placebo. Level of evidence was high (Grade A; Level A evidence derives from 2 or more scientifically sound RCTs or systematic reviews and meta-analyses in which the results are clear-cut and are directly applicable to the target population).
• QOL was improved with the use of MPFF compared with placebo. Level of evidence was high (Grade A; Level A evidence derives from 2 or more scientifically sound RCTs or systematic reviews and meta-analyses in which the results are clear-cut and are directly applicable to the target population).

Clinical practice guidelines of the Latinoamerican Venous Forum – chronic venous insufficiency (2016)²⁹

This document was published in 2016, and to date, no updated versions are available. In these guidelines, the authors highlight the benefits of MPFF on inflammatory process, edema, venous tone, lymphatic drainage, and venous pain.30-32 One of the most significant effects is the additional chance of healing for chronic ulcers as adjuvant therapy.³³

• For venous ulcer treatment, we recommend MPFF as an adjuvant therapy based on the clearly superior benefits in comparison to risks. Evidence grade 1, level B (strong recommendation, moderate-quality evidence; derives from RCTs with important limitations [inconsistent results, methodologic flaws, indirect, or imprecise] or exceptionally strong evidence from observational studies).

Clinical practice guidelines of the Society for Vascular Surgery and the American Venous Forum30: management of venous leg ulcers (2014)³⁴

This document was published in 2014, and to date, no updated versions are available; however, it provides a clear perspective about the use of MPFF. The guideline highlights the demonstrated effect of MPFF on ulcer healing by protecting the microcirculation from damage induced by venous ambulatory hypertension. MPFF as an adjunct to compression therapy and local wound care showed a greater healing rate (32% in 6 months) and shortened time to ulcer healing.^35-39

• For long-standing or large venous leg ulcers, we recommend treatment with either pentoxifylline or MPFF used in combination with compression therapy. Evidence was Grade 1, Level B (strong recommendation, moderate-quality evidence; derives from RCTs with important limitations [inconsistent results, methodologic flaws, indirect, or imprecise] or exceptionally strong evidence from observational studies).

Discussion

In comparison of the guidelines mentioned above, the main prescription criteria were edema and trophic disorders, as well as subjective symptoms including pain, heaviness, cramps, restless legs, and the sensation of swelling. Significant benefits of treatment were demonstrated for these items.^35,40-47 When VADs were analyzed individually, MPFF subgroup analyses demonstrated significant treatment benefits for edema based on multiple studies and were effective for this range of symptoms.⁴¹ Since the American Venous Forum 2014 guidelines’ statement of recommendation for relief of symptoms associated with CVD in patients with CEAP classes C0s to C6s, MPFF has maintained a strong recommendation, on the basis of moderate evidence, as an adjuvant therapy for treatment of venous leg ulcers.⁴² Several reviews recommend combination of VADs and compression,^46,47 in addition to meta-analyses demonstrating efficacy of this combination to accelerate the healing of venous ulcers.^35,44,48,49

Conclusion

The role of VAD in the treatment of CVD has been studied in several meta-analyses and systematic reviews. Specifically, MPFF has been shown to significantly improve the signs and symptoms of CVD like pain, edema, and skin changes. In addition, improvement in QOL has been observed, as well as benefits in leg ulcer healing when MPFF is combined with compression therapy. After reviewing the current evidence, we suggest that MPFF is an effective treatment option for treating the main signs and symptoms of CVD and for the healing of ulcers when combined with compression.





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