Diosmin and Other Venoactive Drugs: Mechanisms of Action, Current and Future Indications for Use

Venoactive drugs in the management of chronic venous disease: A critical appraisal of the evidence and comparison with international guidelines.

Evidence suggests that chronic venous disease (CVD) may be a cardiovascular disorder, as patients with CVD are prone to developing arterial (atherosclerosis) and venous (thromboembolism) diseases. This may be partly explained by shared risk factors. Thus, patients with CVD or cardiovascular disease require careful history-taking and physical assessment to identify coexisting pathologies and risk factors. This article summarises a symposium at the XIX World Congress of the International Union of Phlebology held in Istanbul, Turkey, in September 2022. Common pathophysiological features of CVD and cardiovascular disease are endothelial injury, hypercoagulability and systemic inflammation. In CVD, inflammation primarily affects the microcirculation, with changes in capillary permeability, vein wall and valve remodelling and increase in oxidative stress. Once patients develop symptoms/signs of CVD, they tend to reduce their physical activity, which may contribute to increased risk of cardiovascular disease. Data show that the presence of CVD is associated with an increased risk of cardiovascular disease, including peripheral arterial disease and heart failure (HF), and the risk of adverse cardiovascular events increases with CVD severity. In addition, patients with cardiovascular disease, particularly those with HF, are at increased risk of venous thromboembolism (VTE) and should be assessed for VTE risk if they are hospitalised with cardiovascular disease. Therefore, CVD management must include a multi-specialty approach to assess risk factors associated with both the venous and arterial systems. Ideally, treatment should focus on the resolution of endothelial inflammation to control both CVD and cardiovascular disease. International guidelines recommend various conservative treatments, including venoactive drugs (VADs), to improve the symptoms/signs of CVD. Micronized purified flavonoid fraction (MPFF) is a VAD, with high-quality evidence supporting its use in relieving symptoms/signs of CVD and improving quality of life. Moreover, in large-scale observational studies, MPFF has shown superior effectiveness in real-world populations compared with other VADs. Video Abstract. (MP4 97173 kb).

Chronic venous disease (CVD) can lead to considerable morbidity and impact health-related quality of life (HRQoL). The aim of this review was twofold: (i) to provide a deeper understanding of how CVD affects HRQoL (physical, psychological and social functioning), and (ii) to review the impact of evidence-based veno-active drugs (VADs) on HRQoL. For the effect of CVD on HRQoL, information was gathered during an Expert Consensus Meeting, during which data were presented from both the patient and physician perspective assessed with validated quality-of-life measures. For the impact of VADs on HRQoL, a systematic literature review was performed using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Electronic databases were searched for real world evidence or randomized-controlled trials (RCT) vs. placebo, reporting data on the influence of VADs on HRQoL in patients with CVD. CVD can negatively affect daily life in a number of areas related to pain, physical function and social activities. The impact of CVD on HRQoL begins early in the disease and for patients the emotional burden of the disease is as high as the physical burden. In contrast, physicians tend to overestimate the physical impact. The database search yielded 184 unique records, of which 19 studies reporting on VADs and HRQoL in patients with CVD met the inclusion criteria (13 observational and 6 RCTs). Micronized purified flavonoid fraction (MPFF) was the most represented agent, associated with 12/19 studies (2 RCTs and 10 observational). Of the 6 RCTs, only MPFF, aminaphthone and low-dose diosmin provided statistically significant evidence for improvement on HRQoL compared with placebo; for the other VADs improvements in HRQoL were not statistically different from placebo. MPFF was also associated with improvements in HRQoL in the observational studies, across all CEAP clinical classes, as monotherapy or in combination with other conservative therapy, and for all aspects of HRQoL: physical, psychological, and social. Real-world data for the other VADs were scarce. Ruscus extract, sulodexide and a semi-synthetic diosmin were each represented by a single observational study and these limited data were associated with statistically significant improvements compared with baseline in overall and subdomain scores across the range of CEAP clinical classes. CVD can impair patients' HRQoL significantly at all stages of the disease. MPFF has the greatest evidence base of clinical use in both RCT and real-world observational studies for effectiveness on HRQoL and is recognized by international guidelines. The complete video presentation of the work is available online at www.minervamedica.it (Supplementary Digital Material 1: Supplementary Video 1, 5 min, 194 MB).

Pharmacological Treatment of Primary Chronic Venous Disease: Rationale, Results and Unanswered Questions

To assess the clinical efficacy of sulodexide, including a comparison with venoactive drugs (VAD) (micronized purified flavonoid fraction, MPFF; hydroxy-ethyl-rutosides, HR; calcium dobesilate;Ruscus extract combined with hesperidin methyl chalcone and vitamin C, Ruscus+HMC+VitC; horse chestnut seed extract, HCSE) and pentoxifylline in patients with chronic venous disease. We performed a literature search in MEDLINE, Embase, and Cochrane Library for randomized controlled trials (RCTs) and observational studies. Proportion of patients with complete venous ulcer healing was the primary outcome and lower leg volume, foot volume, ankle circumference and symptoms were the secondary outcomes. Bayesian network meta-analysis (NMA) was perfomed with random effects models using only RCTs. A meta-analysis of observational studies was performed for sulodexide because no RCT could be included in NMA for symptoms or signs. Forty-five RCTs and eighteen observational studies were identified. Sulodexide was included only in a single NMA for the proportion of patients with complete ulcer healing and it showed to have the highest probability of being the best treatment (48%) compared with pentoxifylline (37%) and MPFF (16%). MPFF was the most effective treatment in reducing lower leg volume, CIVIQ-20 score and pain VAS scale while calcium dobesilate and Ruscus+HMC+VitC were the most effective in reducing foot volume and ankle circumference respectively.Meta-analyses of observational studies for sulodexide showed that it improves significantly the scoring of pain, feeling of swelling, heaviness and parasthesiae measured by Likert scales. Sulodexide is at least as effective as pentoxifylline and more effective than MPFF in improving the rate of ulcer healing in patients with CVD. VADs are effective in improving venous symptoms and signs, as was also shown by sulodexide in the meta-analysis of observational studies. The relative effectiveness of sulodexide and VADs needs to be evaluated by an RCT in order to better inform clinical practice.

Chronic venous disease (CVD) is a major global health issue, affecting millions of people and contributing to significant morbidity and economic strain. The condition's pathophysiology is complex, involving both mechanical and biochemical processes that lead to venous reflux, obstruction, and chronic inflammation. This review focuses on the role of venoactive compounds (VACs), also known as venoactive drugs in Europe and other parts of the world, in managing CVD. The aim was to review the scientific evidence and to define the role of VACs within the comprehensive treatment algorithm for CVD, alongside established and well adopted interventional therapies and noninterventional therapies such as compression. The review of the scientific evidence was done on VACs mechanism of action and efficacy in alleviating CVD symptoms, reducing swelling or venous edema, and improving healing of venous leg ulcers. Whenever available, systematic reviews, meta-analyses and randomized controlled trials were used. The quality of evidence assessment followed the GRADE methodology from A (high), B (moderate), to C (low to very low) quality. Venoactive drugs or compounds share similar effects, such as sealing the endothelial barrier, enhancing lymphatic drainage, reducing edema, improving venous tone, inhibiting leukocyte adhesion to vein walls/valves and inflammatory mediator release, lowering blood viscosity, and promoting red blood cell flexibility. Scientific evidence on the VACs effectiveness on CVD symptoms (pain, cramps, and heaviness) and swelling or edema have shown some variability. Micronized purified flavonoid fraction (MPFF) and Ruscus extract combined with hesperidin methyl chalcone and ascorbic acid had the highest, mostly level A, quality of evidence. In venous leg ulcers, micronized purified flavonoid fraction, sulodexide, and pentoxifylline were the most effective adjunctive treatments, with evidence level A. The existing scientific evidence provides a strong rationale for incorporating VACs into a comprehensive treatment plan for CVD, alongside established interventional therapies and noninterventional approaches like compression, to optimize patient outcomes and improve quality of life.

Chronic venous disease and diabetes mellitus are highly prevalent and debilitating conditions affecting millions of individuals globally. Although these conditions are typically considered as separate entities, they often co-exist which may be important in both understanding their pathophysiology and determining the best treatment strategy. Diabetes mellitus is twice as common in patients with chronic venous disease compared with the general population. Notably, a large proportion of patients with diabetes mellitus present with venous disorders, although this is often overlooked. The etiology of chronic venous disease is multifactorial, involving hemodynamic, genetic, and environmental factors which result in changes to the venous endothelium and structural wall as well as inflammation. Inflammation, endothelial dysfunction and hyperfiltration or leakage, are commonly observed in diabetes mellitus and cause various diabetic microvascular complications. Both diseases are also influenced by the increased expression of adhesion molecules, chemokines, and cytokines, and are characterized by the presence of vessel hypertension. Consequently, despite differences in etiology, the pathophysiology of both chronic venous disease and diabetic microangiopathy appears to be driven by endothelial dysfunction and inflammation. Treatment strategies should take the co-existence of chronic venous disease and diabetic microangiopathy into account. Compression therapy is recommended in inflammatory conditions that have an edema component as seen in both chronic venous disease and diabetes mellitus. Lifestyle changes like weight loss and exercise, will improve metabolic state and lower inflammation and should be promoted in these patients. Additionally, both patient populations may benefit from venoactive drugs.

Diabetic microvascular complications (DmVCs) and chronic venous disease (CVD) share common risk factors and pathophysiological features. However, they are often assessed and managed as separate conditions. The study objective was to map the available clinical evidence of venoactive drugs (VADs), beyond their demonstrated effects on sign and symptoms of CVD, in the management of patients with diabetic retinopathy (DR), diabetic nephropathy (DN) and diabetic peripheral neuropathy (DPN). We conducted a Scoping Review to map the clinical evidence on VADs recommended for treating CVD in the management of DR, DN and DPN to address VADs choices in clinics. PubMed and Cochrane Library databases were searched, studies in any language were included with no restriction on publication date. In total, 393 records were identified. Most included studies (N.=42) assessed clinical outcomes in DR (N.=33), followed by DN (N.=7) and DPN (N.=2). The median (range) publication date of the included studies was 2001 (1970-2022). Most studies were randomized trials (57%), followed by case series (17%), and case-control studies/systematic reviews (both 10%). Calcium dobesilate (CaD), was the most assessed VAD in DR (85%), DN (86%), and DPN (50%). CaD has shown significant improvements in DR and DN based on systematic-review data. Our findings suggest that VADs, in particular CaD, may represent a promising therapeutic option for the treatment of patients with both CVD and DmVC. Medical recommendations for VADs prescription should consider patients' microvascular status, evidence about VADs, as well as the multi-modal treatment approach.

Introduction: Hemorrhoids, more commonly known as piles, are swollen veins, similar to varicose veins in the lower rectum. Hemorrhoids can develop both inside and outside the rectum, and oftentimes, the cause of hemorrhoids remains unknown. This is an extremely common ailment faced by three out of four adults in their lifetime. Hemorrhoids can cause various kinds of complications, but the most common and serious ones are perianal thrombosis and incarcerated prolapsed internal hemorrhoids with subsequent thrombosis. They are accompanied by severe pain in the perianal region, and possible bleeding. Data on the coexistence of hemorrhoids with other conditions are sparse. Some data are consistent with a common pathophysiological link between straining at stool, constipation, and obstetrical events such as pregnancy and delivery. These events are also involved in the development of Chronic Vein Disease (CVD) or Chronic Vein Insufficiency (CVI). CVI is a condition that occurs when the venous walls or valves in the leg veins stop working properly, causing difficulty in blood returning to the heart from the legs. The present study was conducted with an aim to determine the frequency of complaints in hemorrhoidal patients and to assess the possible concomitance between hemorrhoidal disease and chronic venous disease. Methods: This was a multicenter, cross-sectional, observational study that enrolled patients spontaneously consulting for hemorrhoids in 17 different hospitals of different regions of Bangladesh from 1st June 2018 to 31st July 2018. Patients’ demographic and lifestyle characteristics were recorded, information on hemorrhoidal grade and signs of chronic venous disease was collected. Types of prescribed treatments were also recorded by the physicians. Results: A total of 499 patients were enrolled and analyzed. Reported frequencies of hemorrhoidal symptoms were: bleeding (80.8%), pain (66.3%), swelling (51.7%), prolapse (28.9%), itching (37.7%), soiling (12%), fecal incontinence (13.4%). 13.8% of the hemorrhoidal patients presented concomitant chronic venous disease. The Clinical-Etiological-Anatomical-Pathophysiological (CEAP) classification was used to classify the clinical signs and symptoms of the patients as C0—no visible or palpable signs of venous disease (6.2%), C1—telangiectasias or reticular veins (4.4%), C2—varicose veins (1.4%), C3—edema (2.6%), C4a—pigmentation or eczema (2%), C4b—lipodermatosclerosis or Atrophie Blanche (0.2%), C5 & C6—venous ulcer (0.6%). Commonly prescribed treatments were dietary fiber (89.8%), veno-active drugs (74.7%), topical treatments (63.7%), painkillers (11.2%), and surgical procedures (30.3%). Conclusion: The study provides small-scale data on patient profiles, risk factors, and commonly prescribed treatments in hemorrhoidal patients. The concomitance of chronic venous disease in 13.8% of the hemorrhoidal patients highlights the importance

Chronic venous insufficiency (CVI) and varicose veins are common conditions that cause symptoms such as heavy legs, swelling (oedema), skin discolouration, lipodermatosclerosis, venous ulcers, venous congestion, and reflux. To gather information for this review, the following keywords were used in PubMed: "varicose veins," "chronic venous insufficiency," "venoactive compounds (VAC)," and "venoactive drugs (VAD)," and a narrative review was then conducted to assess the efficacy of venoactive agents. Treatment includes venoactive medications, with the investigated substances being micronized purified flavonoid fraction (MPFF), a combination of Ruscus aculeatus, hesperidin methyl chalcone (HMC) and vitamin C, rutosides, hydroxyethylrutosides (HR), Ruscus aculeatus, pycnogenol, aescin, red vine leaf extract, calcium dobesilate, pentoxifylline, topical agents, and sulodexide. Venotonic medications have similar effects on the venous endothelium, lymphatic drainage, oedema, venous tone, leukocyte adhesion, inflammatory mediators, blood viscosity, and red blood cell behaviour. Study results concerning symptoms like pain, cramps, heaviness, and swelling show some variation; however, micronised purified flavonoid fractions (MPFF) and ruscus extract combined with hesperidin methyl chalcone and ascorbic acid demonstrated the highest quality of evidence, primarily at level A. For venous leg ulcers, MPFF, sulodexide, and pentoxifylline were effective adjunctive treatments, also supported by level A evidence. Additionally, the concept of venous active drugs (VAD) has been introduced to prevent deterioration of venous status, including arterial vascular changes, and although study quality varies, recent research tends to be more positive. In conclusion, the efficacy of venoactive compounds and drugs (VAC/VAD) in treating CVI and varicose veins has been confirmed by several studies, and recent research has achieved a level of evidence that supports recommendations in international guidelines; nonetheless, there is a clear need for further high-quality studies.

Objective: Chronic venous disease (CVeD) and arterial hypertension (HTA) are common circulatory system disorders associated with significant patient and healthcare burdens. Despite their high prevalence, patients presenting with both conditions are poorly studied resulting in a lack of evidence regarding optimal CVeD management in this specific group. This VeinStep sub-analysis evaluates the effectiveness of conservative treatments on CVeD symptoms and QoL in hypertensive patients. Design and method: VeinStep was an international, observational, prospective study, involving outpatients with symptomatic CVeD. Patients underwent a clinical examination to identify CVeD signs using CEAP classification. Main outcomes after 4 weeks were intensity of symptoms (VAS) and QoL using CIVIQ14. Changes over time were analyzed using a Wilcoxon test. Between-group comparisons for most prescribed venoactive drugs (VADs) used ranked ANCOVA with baseline value as covariate, adjusted on main baseline characteristics. Results: Among the 6084 patients analyzed in VeinStep, 1230 had HTA. They were more frequently men (28.9% vs 20.3%), older (Mean age±SD: 61.5±11.5 vs 47.9±13.0 yrs), obese (BMI>30 kg/m2: 43.9% vs 27.0%) and had more severe CEAP class (>=C4:26.6% vs 9.5%) than non-HTA patients. Most prescribed treatments involved VADs (97.2% of patients) mainly combined with compression and/or topicals: Micronized Purified Flavonoid Fraction (MPFF):77.5%, diosmin:17.7%, compression:59.1%, topicals:43.7%. VADs treatment resulted in significant decreases vs baseline in global symptoms intensity:- 2.39±1.78 (p<0.001) and in each symptom intensity (p<0.001) along with significant improvement in QoL: CIVIQ-14 score decreased by -10.49±8.21 (p<0.001). For MPFF- or diosmin-based therapy, global symptoms intensity decreased by -2.50±1.73 and -1.87±1.85, respectively (p<0.001 in favor of MPFF). MPFF-based therapy showed a higher beneficial effect on pain:-2.42±1.83 vs -1.77±1.69 (P=0.002); heaviness:-2.53±1.86 vs -1.79±1.75 (P<0.001); swelling:-2.46±1.92 vs - 1.76±2.03 (P<0.001); cramps:-2.15±1.96 vs -1.53±1.76 (P=0.002) and QoL:-10.94±8.02 vs - 9.07±8.87 (P=0.012) compared with diosmin-based therapy. Conclusions: This VeinStep sub-analysis offers valuable insights into the patient characteristics with both CVeD and HTA in real-life settings, guiding clinicians in selecting optimal treatments for improved outcomes. The findings suggest that VADs, particularly MPPF, significantly reduce CVeD symptoms and improve QoL in this population.

Venoactive drugs are widely used to improve the symptoms and signs of chronic venous disease. This study aimed to analyze the rate of adverse events after venoactive drug prescription and subsequent compliance and switching rates. Using the National Health Insurance Service database, individuals with at least one chronic venous disease code between January 2009 and December 2019 were identified, and 30% (2,216,780 individuals) of these were sampled. Finally, 1,551,212 patients were included, and we analyzed adverse events, compliance, and switching rates with 8 venoactive drugs, including Vitis vinifera extract, naftazone, micronized purified flavonoid fraction, Vitis vinifera leaf extract, diosmin, diobsilate calcium, bilberry fruit dried extract, and sulodexide. The most commonly prescribed venoactive drug was Vitis vinifera extract (72.2%), followed by sulodexide (9.3%), and Vitis vinifera leaf dry extract (8.2%). Adverse event rates were significantly lower in the naftazone and diosmin groups (P = 0.001 and P = 0.002, respectively) and significantly higher in the Vitis vinifera leaf dry extract group (P = 0.009). Drug adherence to sulodexide was the highest throughout the study period, followed by billberry extract and dobesilate (all P < 0.001). For most drugs, the drug switching rate was low (<5.0%). Vitis vinifera extract was the most commonly prescribed venoactive drug in Korea, and drug adherence to sulodexide was the highest among all venoactive drugs. The adverse event rates were significantly lower in the naftazone and diosmin groups.

A new formulation of low-dose diosmin (μsmin Plus) was safe and effective in relieving symptoms and improving quality of life (QoL) in patients with chronic venous disease (CVD). This study was a randomized, double-blind, placebo-controlled, multicenter, 8-week clinical trial to evaluate the safety of a commercially available dietary supplement (μsmin Plus) that is a diosmin preparation with enhanced bioavailability. The primary study outcomes of interest were mid-calf circumference change and QoL (pain score and Venous Clinical Severity Score), with secondary outcomes of CVD-related symptoms including pain, investigator/patient treatment satisfaction, and safety. Patients with C2-C4 disease were randomized to two matched groups: diosmin (37) or placebo (35). The study group had a statistically significant reduction in leg circumference at 4 or 8 weeks. Both groups had improvement in QoL scoring after 4 and 8 weeks compared with baseline with diosmin showing a significant improvement in Venous Clinical Severity Score. I am intrigued by this study. Pharmacological treatments, really supplements, have not been widely used in the US for prevention or resolution of symptoms of CVD. Venoactive drugs such as diosmin have been shown to have anti-inflammatory and antioxidant properties related to the inhibition of several chemical mediators of inflammation (cytokines, metalloproteases, histamine, serotonin, etc) and due to its specific phlebotonic action on the venous wall. Diosmin, a naturally occurring flavonoid found in citrus fruits, has a poor oral bioavailability that this new formulation attempts to overcome and has demonstrated several-fold higher bioavailability after oral ingestion in humans. I look forward to hearing more and seeing additional data before adding this routinely to my toolkit for venous patient care. If it is safe and can reduce leg swelling and improve QoL, then I am all for it!!

Our current understanding of the pathophysiology of chronic venous disease (CVD) suggests that veno-active drugs (VAD) can provide effective symptom relief. Few studies have conducted head-to-head comparisons of VAD and placebo while also assessing objective measures (such as water plethysmography findings and tibiotarsal joint range of motion) and patient-reported quality of life outcomes. To compare the effects of different VAD on limb volume reduction, tibiotarsal range of motion, and quality of life. 136 patients with CVD (CEAP grades 2-5) were randomly allocated into four groups to receive micronized diosmin + hesperidin, aminaphthone, coumarin + troxerutin, or placebo (starch). Patients were administered a questionnaire consisting of a quality of life (QoL) measure designed specifically for persons with CVD, and underwent tibiotarsal joint angle measurement and water plethysmography of the lower extremity before and 30 days after pharmacological intervention. Assessors were blind to the treatment groups. Nine patients dropped out of the trial. Data collected from the 127 remaining patients was considered for statistical analysis. There were no differences in tibiotarsal joint range of motion. Volume reductions ≥100 mL were more frequent in the diosmin + hesperidin group than in any other group. QoL scores were best in the aminaphthone group, and between-group differences were found on individual analysis of questionnaire items. Use of VAD was associated with significant improvements in QoL as compared with placebo. VAD may be effective for providing symptom relief in patients with CVD.

Background and AimThe CHORUS study (Chronic venous and HemORrhoidal diseases evalUation and Scientific research) was conducted to provide data on patients presenting with hemorrhoidal disease (HD) in clinical practice and to explore the frequency with which it coexists with chronic venous disease (CVD) and shared risk factors.MethodsThis international, noninterventional study enrolled adult patients attending a consultation for hemorrhoidal complaints. The questionnaire completed by physicians established the subjects' demographic and lifestyle characteristics and collected information on HD grade and symptoms and signs of CVD.ResultsA total of 5617 patients were analyzed. Symptoms commonly reported were bleeding (71.8%), pain (67.4%), swelling (55.0%), itching (44.1%), and prolapse (36.2%). Multivariate analysis revealed the variables with the strongest association with HD severity were older age, higher CVD CEAP (Clinical manifestations, Etiologic factors, Anatomic distribution of disease, and underlying Pathophysiology) class, constipation, and male gender (all P < 0.0001). Elevated BMI was a risk factor for HD recurrence. Among women, number of births had a significant association with both HD grade and recurrence. The presence of CVD, reported in approximately half the patients (51.2%), was strongly associated with advanced grade of HD (P < 0.0001). Treatments most commonly prescribed were venoactive drugs (94.3%), dietary fiber (71.4%), topical treatment (70.3%), analgesics (26.3%), and surgery (23.5%).ConclusionsCHORUS provides a snap shot of current profiles, risk factors, and treatments of patients with HD across the globe. The coexistence of HD and CVD in more than half the study population highlights the importance of examining for CVD among patients with a hemorrhoid diagnosis, particularly when shared risk factors are present.