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Flavonoids are oral venoactive drugs frequently prescribed to relieve the symptoms of chronic venous disorders (CVD). Among venoactive drugs, diosmin is a naturally occurring flavonoid glycoside that can be isolated from various plant sources; it can also be obtained after conversion of hesperidin extracted from citrus rinds. Micronized purified flavonoid fraction (MPFF) is a preparation that contains mainly diosmin and a small fraction of hesperidin. We performed a state-of-the-art literature review to collect and analyze well-conducted randomized clinical studies comparing diosmin - also called non-micronized or hemisynthetic diosmin - 600 mg a day and MPFF, 1000 mg a day. Three clinical studies met the criteria and were included for this literature review. These clinical studies showed a significant decrease of CVD symptom intensity (up to approximately 50%) and global patient satisfaction after one-to-six-month treatment with diosmin or MPFF, without statistical differences between these two forms of diosmin. Both treatments were well tolerated with few mild adverse drug reactions reported. Overall, based on this literature review, there is no clinical benefit to increase the dose of diosmin beyond 600 mg per day, to use the micronized form, or to add hesperidin, since clinical efficacy on venous symptomatology is achieved with 600 mg per day of pure non-micronized diosmin. This challenges the status of diosmin - 600 mg a day - in guidelines for the management of CVD, which is currently categorized 2C (weak recommendations for use and poor quality of evidence), while the most widely used and assessed preparation MPFF is rated 1B (strong recommendation for use and moderate quality of evidence)., Competing Interests: Michèle Cazaubon agreed to review this article in exchange to a compensation provided by Laboratoire Innotech International. Jean-Patrick Benigni is currently under contract with Laboratoire Innotech International as a consultant expert providing advices on compression therapy and chronic venous disorders. Violaine Jabbour and Christelle Gouhier-Kodas are employed by Laboratoire Innotech International. Marcio Steinbruch declares that he has no conflict of interest regarding this publication. The authors report no other conflicts of interest in this work., (© 2021 Cazaubon et al.)

Objectives: The purpose of this study was to investigate the prevalence of peripheral arterial disease (PAOD) and cardiovascular risk factors associated with the ankle-brachial index (ABI) in Senegalese patients aged 40 years and over., Methodology: We prospectively studied a random sample of Senegalese aged 40 years and older, residing in the city of St.-Louis, Senegal. The ABI was measured with a portable doppler (DIADOP 50) using 4 and 8Hz dual frequency probes. The standards were: normal ABI 0.9 to 1.3; peripheral artery obstructive disease (PAOD) ABI less than 0.9; incompressible artery ABI greater than 1.3. Cardiovascular risk factors were also studied., Results: Seven hundred and seventy-one subjects (mean age 57 ± 11.2 years, 559 women) were examined. Cardiovascular risk factors were: sedentary lifestyle (76.4%), hypertension (68%), obesity (32.1%), elevated LDL-cholesterolemia (27.8%), diabetes (18.3%) and tobacco smoking (6.9%). Ninety-three subjects (12.1%) had PAOD and 37 subjects (4.8%) had an incompressible artery. PAOD was significantly more common in sedentary subjects (P=0.008), in the elderly (P=0.0006) and in patients with a history of coronary artery disease (P=0.04). Smoking was not strongly associated with PAOD., Conclusion: PAOD is common in Senegalese and is associated with high prevalence of cardiovascular risk factors., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Aim: The aim of this study was to compare the change in functional signs of venous insufficiency and venous refilling time measured by mercury strain-gauge plethysmography under the effects of the combination of Ruscus aculeatus, hesperidin methylchalcone and ascorbic acid (Cyclo 3 Fort)., Methods: An open-label clinical trial conducted in 65 women presenting with CEAP class C2s and C3s assessment criteria. At D0 and D28, functional signs were measured on a visual analog scale (VAS), venous refilling time by mercury strain-gauge plethysmography and venous reflux by echo-Doppler method., Results: Under treatment, venous refilling time increased from 11.7±4 s to 13.8±4.4 s with Δ of 26% (P<0.0001) and the percentage of patients showing improvement of functional symptoms ≥30% was significantly correlated (P=0.04) with the percentage of patients presenting an improvement in venous refilling time ≥10%., Conclusion: Improvement in subjective functional signs under treatment with Cyclo 3 Fort was correlated with objective plethysmographic parameter improvement. There-fore, this study contributes to objectively document the benefit of prescribing this venoactive drug to active women with CEAP class C2s to C3s.

Aim: The advanced CEAP classification allows one to differentiate between isolated varicose veins (C2) and complicated varicose veins (C2, 3 - C2, 3, 4 - C2, 4 or C2, 3, 4, 5 etc) named (C2+)., Methods: The main objective of this study was to identify when using the advanced classification the prevalence of isolated varicose veins (C2) and complicated varicose veins (C2+) among patients consulting vascular specialists and to compare their symptomatic status and the data issued from the advanced CEAP including also the headings, Anatomy (A), Etiology (E) and Pathophysiology (P)., Results: 171 patients were evaluated, 100 in France and 71 in Italy. The prevalence of C2 and C2+ was the same in both countries: 64.4% in France and 63.3% in Italy. Also no difference was found in the prevalence of other descriptors: etiology, anatomy or pathophysiology. The time to complete the advanced form was less than 5 minutes for 65% of the investigators., Conclusion: The advanced CEAP is easy to use in daily pratice. We have the same prevalence of patients in France and in Italy, who consulted for isolated varicose veins or associated with other signs of chronic venous disorders.

Aim: In a recent epidemiological study on chronic venous disease (CVD) in French male patients, a correlation was found between obesity and disease severity. The objective of this study was to further analyze the relationship between age and/or obesity, and CVD severity as assessed by the CEAP C-class., Methods: Each physician taking part in this cross-sectional study included the first 3 adult male patients consulting for the first time and presenting at least one sign and one symptom of CVD. Patients' socio-demographic and clinical data were collected, and findings for obese (body mass index BMI: >30 kg/m(2)), overweight (25 60 years experienced trophic disorders, i.e., CEAP classes C4, C5, and C6)., Conclusions: This study does not show any relationship between the CEAP C-class and obesity in male patients. Obesity was thus probably not an aggravating factor in CVD but a simple reflection of ageing.

Aim: The aim of this study was to describe the employment conditions of women with chronic venous disorders of the lower limbs., Methods: Cross sectional study conducted by general practitioners who describe the first 3 women, between 18 and 65 years of age, who were employed and who presented with at least CEAP stage I venous disorders., Results: Occupations held by these women indicate significant departures from the general population with an over representation of industrial workers (18.6% vs 11.9%) and an under representation of intermediate professions (12.5% vs 26.6%), (P<0.001). At work, 78.2% (n=4,143) of the women remained standing for 6.2+/-2.4 hours per day and/or 52.3% (n=2,771) were seated for prolonged periods, 28.9% (n=1 503) were exposed to sources of high heat on the legs and 18.2% (n=947) wore garments that compressed the abdomen Conditions favorable to the ergonomic evolution of their workstation are limited: only 9.2% (n=397) thought it possible to reduce the time they spend standing; 10.1% (n=319) the time they spend sitting; 12.9% (n=189) their exposure to heat. Combating these factors appears difficult: 74.3% (n=3 883) state that they do not have sufficient breaks to rest their legs, 38.9% (n=2,053) that they do not have the opportunity to stretch their legs and 42.5% (n=1,395) that compression stockings would be permitted, but would be a hindrance in their work (85.6%, n=4,503). For 27% (n=1,424) of respondents, these problems significantly increase the arduousness of their work and 73.7% (n=3,870) think their working conditions have worsened their venous distress., Conclusions: Women who consult for venous problems are employed in work which are characterized by unavoidable conditions constituting undeniable venous risk factors for venous disease and occupational medicine does not pay enough attention to the ''ladies legs'' at work.

Aim: Chronic venous disease affects large numbers of men but there are fewer references to them than to women in the literature. The aim of our study was to determine the time lapse between the first symptom(s) and/or clinical signs of venous disease in the male and the first consultation with an angiologist to define the status of the veins within this population, and to demonstrate any possible links between the characteristics of the disorder in accordance with the CEAP international classification., Methods: The design was a cross-sectional descriptive survey. Each physician had to include the first 3 patients examined for the first time. Each male patient had to present at least 1 sign and 1 symptom of chronic venous disease. After randomization, 192 physicians included 561 patients: 494 have been analyzed., Results: The examined patients had a mean age of 49.3+/-13.7 years, mean height of 1.76+/-0.07 m, mean weight of 78.2+/-11.2 kg and a BMI of 25.3+/-3.3. The disorder had been developing for a mean 76.8+/-90.3 months prior to the specialist consultation. The longer the time span between the onset of the condition and the first consultation with a specialist, the more advanced was the condition as was also true with the increasing age of the patients. The following associations were observed: the incidence of trophic disorders increased with age (odds-ratio 1.47). The severity of the disease increased the greater the extent of obesity (odds-ratio 3.5)., Conclusion: The risk of trophic disorders was higher in shop workers, craftsmen (odds-ratio 3.7) and workers (odds-ratio 2.68) than in executives, in those working in a standing position (odds-ratio 1.5), in those whose father had the condition (odds-ratio 1.9), in the event of a popliteal reflux (odds-ratio 3.2) rather than affecting a saphenous trunk (small saphenous vein odds-ratio 2.5, great saphenous vein odds-ratio 1.9). Thirty-two percent of patients with trophic disorders had already worn elastic compression prior to the specialist consultation. After this consultation, the numbers for whom this was prescribed rose to 87%.

The study compared, by a prospective, randomized method, 6 treatment options: A: Sclerotherapy; B: High-dose sclerotherapy; C: Multiple ligations; D: Stab avulsion; E: Foam-sclerotherapy; F: Surgery (ligation) followed by sclerotherapy. Results were analyzed 10 years after inclusion and initial treatment. Endpoints of the study were variations in ambulatory venous pressure (AVP), refilling time (RT), presence of duplex-reflux, and number of recurrent or new incompetent venous sites. The number of patients, limbs, and treated venous segments were comparable in the 6 treatment groups, also comparable for age and sex distribution. The occurrence of new varicose veins at 5 years varied from 34% for group F (surgery + sclero) and ligation (C) to 44% for the foam + sclero group (E) and 48% for group A (dose 1 sclero). At 10 years the occurrence of new veins varied from 37% in F to 56% in A. At inclusion AVP was comparable in the different groups. At 10 years the decrease in AVP and the increase in RT (indicating decrease in reflux), was generally comparable in the different groups. Also at 10 years the number of new points of major incompetence was comparable in all treatment groups. These results indicate that, when correctly performed, all treatments may be similarly effective. "Standard," low-dose sclerotherapy appears to be less effective than high-dose sclero and foam-sclerotherapy which may obtain, in selected subjects, results comparable to surgery.

Background: The efficacy and cost of prostaglandin E1 (PGE1) in severe intermittent claudication was studied comparing a long-term protocol (LTP) with a short-term protocol (STP) in a randomised 40-week study., Methods: Phase 1 was a 2-week run-in phase (no treatment) for both protocols. In LTP, phase 2 was the main treatment phase. Treatment was performed with 2-hour infusions (60 micro g PGE1, 5 days each week for 4 weeks. In phase 3 (4-week interval period), PGE1 was administered twice a week (same dosage). In phase 4 (40 weeks), no PGE1 were used. In STP, phase 2 treatment was performed in two days by a 2-hour infusion (60 micro g PGE1 twice a day in 2 days). The same cycle was repeated every 4 weeks. A treadmill test was performed at inclusion, at the beginning of each phase and at the end of weeks 12, 16, 20 32 and 40. A progressive training plan (walking) and reduction in risk factors plan was used in both groups., Results: Out of the 1276 included patients 1165 completed the study (606 in LTP group; 559 in the STP). Drop-outs were 111. The two groups were comparable in distribution, risk factors and smoking. Intention-to-treat analysis indicated an increase in pain free walking distance (PFWD). The absolute and percent increase in pain-free walking distance (PFWD) was comparable in both LTP and STP groups with a significative increase in TWD at 4 weeks. At 20 and 40 weeks increase was up to 219% in the LTP and 460% in the STP group (p<0.02). Comparable results concerning PFWD were obtained in the two groups. Both treatments were well tolerated. No side effect was observed. Local effects were observed in 8.5% of the treated subjects in the LTP and 4% in the STP. The average cost of the LTP protocol was 8786 Euro. For STP the costs was 946 (10.8% of LTP). For both protocols the cost of the infusion was 24% of the total for the LTP and 35% in the STP. Therefore 75% of the cost is not drug-related., Conclusions: In conclusion between-group-analysis favours STP considering walking distance and costs. Results indicate good efficacy and tolerability of PGE1 treatment particularly STP.

Background: Possible intermediate circulating markers linking blood stasis to vein remodeling were explored in patients with varicose veins in the lower limbs., Methods and Results: Blood was sampled at rest (supine position) and after a stasis of 30 minutes both in the varicose vein (limbs hanging down) and in the brachial vein (arm hanging down) as a paired control. Several endothelial and leukocyte markers were measured in plasma with the use of ELISA kits. Angiotensin-converting enzyme activity was determined by use of a specific substrate. Matrix metalloproteinases (MMPs) 9 and 2 were evaluated with the use of gelatin zymography. No markers were significantly modified after 30 minutes of blood stasis in the brachial vein. After 30 minutes of blood stasis in the varicose vein, oxygen partial pressure decreased (P<0.01). Although thrombomodulin, von Willebrand factor, vascular endothelial growth factor, and MMP-2 were not modified in these conditions, the proteins released by proteolysis from the endothelial membrane intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and angiotensin-converting enzyme were increased (P<0.01). After blood stasis in varicose veins, the leukocyte markers lactoferrin, myeloperoxidase, and interleukin-8 were not modified, whereas L-selectin shed from leukocytes increased (P<0.05), and a major increase in pro-MMP-9, which is released from tertiary granules during polymorphonuclear activation, was observed (P=0.0001)., Conclusions: The marked increase in plasma pro-MMP-9 activity provides evidence of polymorphonuclear activation and granule release in the varicose vein in response to postural blood stasis. Similarly, detection in the plasma of membrane proteins shed from the endothelium or leukocytes provides evidence of pericellular proteolysis.

The aim of this study was to evaluate the prevalence and incidence of venous diseases and the role of concomitant/risk factors for varicose veins (VV) or chronic venous insufficiency (CVI). The study was based in San Valentino in Central Italy and was a real whole-population study. The study included 30,000 subjects in eight villages/towns evaluated with clinical assessment and duplex scanning. The global prevalence of VV was 7%; for CVI, the prevalence was 0.86% with 0.48% of ulcers. Incidence (new cases per year) was 0.22% for VV and 0.18% for CVI; 34% of patients with venous disease had never been seen or evaluated. The distribution of VV and CVI in comparison with duplex-detected incompetence (DI) indicates that 12% of subjects had only VV (no DI), 2% had DI but no VV, 7.5% had DI associated with VV, 2% apparent CVI without DI, 3% DI only (without CVI), and 1.6% both CVI and DI. VV associated with DI are rapidly progressive and CVI associated with DI often progresses to ulceration (22% in 6 years). VV without significant DI (3%) and venous dilatation without DI tend to remain at the same stage without progression for a lengthy time. New cases per year appear to have a greater increase in the working population (particularly CVI) possibly as a consequence of trauma during the working period. In older age (>80 years), the incidence of CVI tends to decrease. Ulcers increase in number with age. Only 22% of ulcers can be defined as venous (due to venous hypertension, increased ambulatory venous pressure, shorter refilling time, obstruction and DI). Medical advice for VV or CVI is requested in 164 subjects of 1,000 in the population. In 39 of 1,000, there is a problem but no medical advice is requested and in only 61 of 1,000, the venous problem is real. In VV in 78% of limbs, there is only reflux, in 8% only obstruction, and in 14% both. In CVI, 58% of limbs have reflux, 23% obstruction, and 19% both. In conclusion, VV and CVI are more common with increasing age. The increase with age is linear. There was no important difference between males and females. These results are the basis for future real, whole population studies to evaluate VV and CVI.

The efficacy, safety, and cost of pentoxifylline (PXF) in the treatment of severe intermittent claudication were studied comparing PXF and placebo in a randomized 40-week study. A treadmill test was performed at inclusion and at the end of weeks 20 and 40. A progressive training plan and the control of risk factors (with antiplatelet treatment) were used in both groups. Of the 200 included patients, 178 completed the study: 88 in the PXF group and 90 in the placebo group. There were 22 dropouts. The two groups were comparable for age, sex distribution, and for the presence of risk factors and smoking. There was a significant increase in pain-free walking distance (PFWD) in both groups. The absolute and percent increase in PFWD was significantly greater in the PXF group (p<0.05). At 20 weeks, the increase was 360.5% in the PXF vs 252% in the placebo group. At 40 weeks, the increase was 386% in the PXF and 369% in the placebo group (p<0.02). Total walking distance (TWD) increased at 20 weeks (up to 254%) and up to 329% at 40 weeks. In the placebo groups the increase was 158% at 20 weeks and 183% at 40 weeks. The excess increase produced by PXF treatment was 30% at 20 weeks and 38% at 40 weeks (p<0.02). Unwanted effects treatment was well tolerated. No serious drug-related side effects were observed. In summary, between-group analysis favors PXF considering walking distance and costs. Results indicate good efficacy and tolerability.

Infusional, cyclic PGE1 treatment is effective in patients with intermittent claudication and critical limb ischemia (CLI). One of the problems related to chronic PGE1 treatment in vascular diseases due to atherosclerosis is to evaluate the variations of clinical conditions due to treatment in order to establish the number of cycles per year or per period (in severe vascular disease reevaluation of patients should be more frequent) needed to achieve clinical improvement. In a preliminary pilot study a group of 150 patients (mean age 67+/-12 years) with intermittent claudication (walking range from 0 to 500 m) and a group of 100 patients with CLI (45% with rest pain, and 55% gangrene; mean age 68 +/-11 years) the number of PGE1 cycles according to the short-term protocol (STP) needed to produce significant clinical improvement was preliminarily evaluated. Considering these preliminary observations, the investigators established a research plan useful to produce nomograms indicating the number of cycles of PGE1-STP per year needed to improve the clinical condition (both in intermittent claudication and CLI). A significant clinical improvement was arbitrarily defined as the increase of at least 35% in walking distance (on treadmill) and/or the disappearance of signs and symptoms of critical ischemia in 6 months of treatment in at least 75% of the treated patients. With consideration of the results obtained with the preliminary nomograms a larger validation of the nomograms is now advisable. A cost-effectiveness analysis is also useful to define the efficacy of treatment on the basis of its costs. The publication of this report in two angiological journals (Angeiologie and Angiology) will open the research on nomograms to all centers willing to collaborate to the study. The data are being collected in the ORACL.E database and will be analyzed within 12 months after the publication of this report.

The efficacy, safety, and cost of prostaglandin E1 (PGE1) in the treatment of severe intermittent claudication was studied by comparing a long-term treatment protocol (LTP) with a short-term treatment protocol (STP) in a randomized 20-week study. The study included 109 patients (96 completed the study) with an average total walking distance of 65.5 +/- 8 m (range 20-109). Phase 1 was a 2-week run-in phase (no treatment) for both protocols. In LTP, phase 2 was the main treatment phase. In the LTP, treatment was performed with 2-hour infusions (60 microg PGE1, 5 days each week for 4 weeks). In phase 3 (4-week interval period) PGE1 was administered twice a week (same dosage). In phase 4 (monitoring lasting 3 months, from week 9 to 20) no drugs were used. In STP, phase 2 treatment was performed in 2 days by a 2-hour infusion (1st day: morning 20 microg, afternoon 40 microg; 2nd day morning and afternoon 60 microg). The reduced dosage was used only at the first cycle (week 0) to evaluate reduced tolerability or side effects. Full dosage (60 microg b.i.d.) was used for all other cycles. The same cycle was repeated at the beginning of weeks 4, 8, and 12. The observation period was between weeks 12 and 20. A treadmill test was performed at inclusion, at the beginning of each phase, and at the end of the 20th week. A similar progressive physical training plan (based on walking) and a reduction in risk factors levels plan was used in both groups. Intention-to-treat analysis indicated an increase in walking distance, which improved at 4 weeks (101.5% in STP vs 78.3% in LTP), at 8 weeks (260.9% STP vs 107.3% LTP), and at 20 weeks (351% STP vs 242% LTP). Comparable increases in pain-free walking distance were observed in the two groups. No serious drug-related side effects were observed. Local, mild adverse reactions were seen in 7% of the treated subjects in the LTP and 5% in the STP. Average cost of LTP was approximately 6,588 ECU; for STP the average cost was approximately 1,881 ECU. The cost to achieve an improvement in walking distance of 1 m was 35.6 ECU with the LTP and 9.45 ECU with the STP (26% of the LTP cost; p<0.02). For an average 100% increase in walking distance the LTP cost was 1,937 ECU vs 550 ECU with STP (p<0.02). The cost of PGE1 (including infusion and operative costs) was 25% of the total cost for LTP (24.9% for STP). In summary, between-group-analysis favors STP, in terms of walking distance and costs. Results indicate good efficacy and tolerability of PGE1 treatment. With STP less time is spent in infusion and more can be spent in the exercise program. STP reduces costs, speeds up rehabilitation, and may be used in a larger number of nonspecialized units available to follow the protocol.