Quality of life of patients with chronic venous disease: systematic review and expert panel report

Chronic venous disease (CVD) significantly reduces quality of life, limits physical activity in patients, and is a predictor of serious cardiovascular damage. Prevention and control of venous diseases are especially important in patients with hereditary predisposition, obesity, and a sedentary lifestyle. The choice of treatment depends on the stage of the disease, the anatomical features of the veins, and the general condition of the patient. This review presents the results of a systematic analysis of the literature, highlighting current trends and criteria for the selection of therapy for lower limb venous dysfunction. Keywords: chronic venous disease, venous insufficiency, varicose veins, micronized purified flavonoid fraction.

CVD is frequently observed in clinical practice. According to the results of a global study, the prevalence of CVD among adults who visit a general practitioner is 83.6% [1]. A recent large-scale study of this issue has shown that there are clear indications for active treatment of CVD in approximately a quarter of the adult working population [2, 3]. The situation is unlikely to change in the near future, as rising obesity rates and increased life expectancy worldwide contribute to high CVD prevalence. Although the CEAP classification only defines the clinical stage of the disease without assessing its severity, it should be noted that chronic venous insufficiency (CVD) progresses annually, with approximately 4% of patients progressing from one CEAP stage to the next [4, 5].

The impact of CVD treatment on patients’ quality of life

The systematic literature review conducted by J.H. Ulloa et al. is important for studying the impact of venoactive drugs (VADs) on the quality of life (QoL) of patients with CVD. The Embase and PubMed databases, which are among the most authoritative sources of scientific information, were selected to search for relevant studies. The search covered articles published between January 2000 and December 2022, ensuring the high relevance of the results. The key criteria for inclusion in the review were existing studies using real-world data or randomized controlled trials (RCTs) comparing ARBs with placebo, as well as specific studies of the impact of these drugs on QoL in patients with CKD. Excluding studies involving patients who underwent surgery allowed us to focus only on cases in which the effect of drug treatment was directly evaluated. From 184 publications, the researchers selected 19 original articles demonstrating the effects of VAP on the quality of life of people with COPD.

QOL is a multi-component indicator that includes at least three major components affected by the disease and/or its treatment: physical, psychological, and social [6]. Physical functioning is usually defined as the ability to perform everyday tasks and takes into account the physical symptoms caused by the disease. Psychological functioning encompasses a person’s emotional state, as well as their level of anxiety or depression. Social functioning refers to the patient’s interactions with other people and their social relationships. Chronic diseases can impair various aspects of daily life in all areas, beginning to affect QoL in the early stages. A systematic review has shown that the emotional burden of the disease has at least as much impact on patients as the physical burden. However, doctors often overestimate the physical impact of the disease. In order to minimize the negative impact of COPD on QoL, more attention should be paid to early detection of the disease and its timely and proper treatment. First and foremost, the choice of drugs for the treatment of COPD should be based on the largest evidence base of their clinical use, recognized by international guidelines and systematic reviews.

Scientific research on the effectiveness of venoactive drugs

Among the VAPs with the highest quantity and quality of evidence, micronized purified flavonoid fraction (MPFF) occupies a special place in the review – 12 studies, including two RCTs. Most observational and open-label studies evaluating the effectiveness of VAP in improving QoL in patients with COPD were conducted using MPFF and involved more than 12,000 patients. The choice of this particular drug for comparison with placebo is important because it has shown positive results in improving QoL indicators. The largest prospective open-label studies investigated the efficacy of MOFF, administered at a dose of 500 mg twice daily to patients with symptomatic CVD across a wide range of CEAP clinical classes, including C0.

The international RELIEF study (Reflux Evaluation and Improvement of Quality of Life with Micronized Flavonoids) assessed QoL in clinical classes C0-C4 according to CEAP, who received MOFF treatment for 6 months depending on the presence or absence of venous reflux [7]. QOL was assessed using the CIVIQ-20 questionnaire for CVD. At the beginning of the study, patients with venous reflux had significantly worse QOL scores than patients without reflux on all CIVIQ-20 scales (psychological, pain, physical, and social). Both groups achieved an improvement in QoL while taking MOFF, but better results were observed in patients without reflux. MOF contributed to improved QoL by reducing the intensity of CVD symptoms: pain, heaviness in the legs, swelling, and cramps, which is important for patients at different stages of the disease [7].

The international VEIN STEP study provided large-scale data on the effectiveness of conservative therapy for C0-C6 clinical classes of CVD according to CEAP in real-world clinical practice [8]. Most patients were prescribed VAP alone or in combination with compression therapy and local treatment. Although the study was not specifically designed to evaluate the effectiveness of MOFF, it was the most commonly used VAP, prescribed to 75.5% of patients. QOL was assessed using the CIVIQ-14 questionnaire. At week 4 of follow-up, improvements were observed in all indicators (pain, physical, and psychological) regardless of whether VAP was prescribed alone or in combination. In a pooled analysis of data for the three countries with the largest number of participants, the effectiveness of MOFF (n=998), VAP excluding MOFF (n=249), and diosmin (n=183) on quality of life was compared [9]. The median total symptom intensity (Q1, Q3) decreased by -2.25 (-3.5, -1.0), -2.00 (-3.0, -1.0), and -2.00 (-3.0, -0.5) for the three treatments, respectively. The most significant reduction was observed with MOFF compared to other VAPs and diosmin (p<0.001 for both comparisons). The reduction in the intensity of individual symptoms (pain, heaviness, cramps, and swelling) was also significantly more pronounced with MOFF. Improvements in CIVIQ-14 scores and reductions in the total venous clinical severity score (VCSS) were significantly greater in patients receiving MOFF compared to other VAPs and diosmin. Improvements in CIVIQ-14 scores and reductions in total venous clinical severity scores (VCSS) were significantly greater in patients receiving MOFF compared with other VAPs and diosmin [9].

In a large observational study conducted in France, QoL was assessed in patients with C1-C3 clinical classes of CVD who underwent sclerotherapy in combination with MOFF for 2 months [10]. All indicators determining quality of life were significantly improved.

The DELTA study involved 522 patients who took 500 mg of MOFF twice daily for 2 months. Most patients (89.4%) had clinical classes C1-C4, but all classes were represented in the study cohort. After 2 months of treatment, QoL scores improved 1.3 times (p<0.0001). Improvements were also observed in the physical subdomain (1.3 times), psychological subdomain (1.2 times), social subdomain (1.3 times), and pain syndrome subdomain (1.4 times) (all p<0.0001) [11].

The administration of MOFF at a dose of 1000 mg once daily in patients with C0s clinical class CKD for 2 months showed a significant improvement in QoL by 1.2 times [12]. Similar results were obtained in patients with early symptoms of C0-C1s class CKD when taking MOFF at a dose of 1000 mg for 3 months [13, 14].

A study conducted in India to assess the real effectiveness of long-term use of MOFF at a dose of 1000 mg/day (500 mg twice a day) in patients with clinical class C0-C3 showed an improvement in QoL by 21.7% in terms of physical indicators, 25.9% in social terms, and 19.2% in psychological terms [15].

In a study on the treatment of edema in CVD in patients with CEAP class C3, 97.7% of whom received MOFF alone or in combination with other conservative treatments and, in some cases, surgery, the dosage regimen ranged from 1000 mg in tablets once a day (77.9% of patients), 500 mg in tablets twice a day (4.8%) to 1000 mg in the form of an oral suspension once a day (15%). The duration of treatment was also variable, at the discretion of the physicians. Regardless of whether MOFF was used alone or in combination with other treatments, its use was associated with a significant improvement in QoL as measured by the CIVIQ-14 questionnaire compared to baseline [16].

Long-term (6 months) use of MOFF in combination with other conservative therapies (compression and topical treatment) in patients with clinical class C4a (pigmentation, eczema) or C4b (lipodermatosclerosis, white atrophy) according to CEAP showed an improvement in QoL compared to baseline: pain intensity decreased by 26.4%, physical discomfort by 21.5%, and psychological distress by 19.3% [17].

The place of MOFF in international institutions

Major international guidelines, such as those of the European Venous Forum (EVF), the International Union of Angiologists (IUA), the International Union of Phlebologists (UIP), and the European Society for Vascular Surgery (ESVS) specifically indicate MOFF among VAPs that improve QoL [18, 19]. In a global scientific analysis in 2023, MOFF was the only VAP associated with a significant improvement in QoL related to CVD [8, 20].

A systematic review and meta-analysis by Kakkos and Nicolaides based on seven double-blind placebo-controlled studies (n=1692) demonstrated an improvement in QoL indicators with MOF use compared to placebo [21].

Based on a meta-analysis by Kakkos and Nicolaides and other studies, the MOFF has been given a level of evidence A in international guidelines. Pharmacological treatments for CHD should be selected from those with the strongest evidence base for clinical use according to RCTs and observational studies with large sample sizes of patients at all stages of the disease. Treatment should be effective for the symptoms and signs of COPD while improving QOL [22].

Summarizing the above, the authors of the review point out that quality of life can deteriorate at all stages of the disease, so more attention should be paid to early detection and proper treatment of COPD, even with minimal symptoms. For treatment, drugs should be chosen that have the strongest evidence base for clinical use, recognized by international guidelines and systematic reviews. Among modern VAPs, which are the standard of care for venous diseases, MOFF is associated with the largest number and quality of RCT and observational studies demonstrating a significant positive impact on QoL. MOFF improves quality of life by reducing symptoms such as pain, heaviness in the legs, swelling, and cramps in patients with CVD at various stages (C0-C4 according to CEAP). The effectiveness of MOFF in combination treatment regimens has also been confirmed, making it a universal tool for improving QoL in various treatment options (compression therapy, topical agents).

Based on materials from: Ulloa J.H. et al. International Journal of Angiology 2023 Dec;42(6):465-476.

Prepared by Tatyana Nesterova

Editor’s note

On the Ukrainian market, MOFF is represented, in particular, by the drug Normoven 1000 (manufactured by JSC “Kyiv Vitamin Plant”), one tablet of which contains 1000 mg of MOFF in the form of diosmin and hesperidin (the name hesperidin refers to a mixture of flavonoids: hesperidin, isorhamnetin, linarin, diosmetin) in a ratio of 9:1. The recommended dose of the drug is 1 tablet per day in the morning with food.

 

Normoven 1000 has a venotonic and angioprotective effect, reduces vein distensibility and venostasis, improves microcirculation, reduces capillary permeability and increases their resistance, and also improves lymphatic drainage by increasing lymphatic outflow. The ability to obtain the required daily dose of MOFF through a single dose promotes compliance with the prescribed treatment.