Evaluation of Elastic Venous Compression Device dispensation in pregnant and post-partum women using the French National Health Insurance Claims Database: The ProFIL retrospective cohort study.

OBJECTIVES: To describe the real-world use of Elastic Venous Compression Devices (EVCDs) during pregnancy and post-partum using data from a representative subset of the French National Health Insurance Claims Database (the Echantillon Généraliste des Bénéficiaires, EGB). STUDY DESIGN: Women aged 15-49 who were pregnant between 1st July 2017 and 15th June 2018 were identified in the EGB using pregnancy-specific acts (certain prenatal examinations or deliveries). Subgroups were defined by age, presence of Venous Thrombo-Embolism (VTE) risk factors, history of VTE, delivery type and time period. EVCD dispensations (format, prescriber, and date) were identified among those for "standard orthotics" using their unique reimbursement tariffs. Dispensation rates were computed for all subgroups, overall and by format and were compared. RESULTS: 15,528 pregnant women were included: 7,252 [46.7 %] deliveries (5,796 vaginal [79.9 %], 482 planned cesarean sections (C-sections) [6.7 %] and 974 unplanned C-Sections [13.4 %]), 2,734 (17.6 %) terminations and 5,542 (35.7 %) unknown outcomes. Overall, 4,919 (31.7 %) women were dispensed at least one EVCD. Ante-partum dispensation occurred in 43.1 % (n = 3,122) of women whose pregnancy led to a delivery. Dispensation rates were 17.3 % (n = 1,005), 46.7 % (n = 225) and 44.1 % (n = 430) after vaginal delivery, planned C-sections or unplanned C-sections, respectively. Overall, dispensation rates significantly increased with age, the presence of VTE risk factors, and a history of VTE (p < 0.01). EVCD dispensation was most frequent (17.0 %) during the 5th month of pregnancy. Among pregnant women who were dispensed at least one EVCD during ante- or post-partum, 69.0 % had one or two units of compression (27.1 % [one unit], 41.9 % [two units]). Stockings (48.6 %, n = 6,038) were dispensed significantly more frequently than socks (36.9 %, n = 4,586) and tights (14.5 %, n = 1,806) (p < 0.01). The main contributors to mechanical VTE prophylaxis were gynecologists (26.3 % of dispensations, n = 2,280), general practitioners (20.2 %, n = 1,749) and midwives (15.1 %, n = 1,314). CONCLUSIONS: Low observed dispensation rates highlight a discrepancy between the French National Authority for Health (Haute Autorité de Santé, HAS), recommending EVCDs use during pregnancy and after delivery, and the real-life use of EVCD. Prescription sensitization combined with targeted information campaigns for pregnant women would be beneficial to contribute to the prevention of VTE, a health problem for pregnant women.

25 mm Hg versus 35 mm Hg elastic compression stockings to prevent post-thrombotic syndrome after deep vein thrombosis (CELEST): a randomised, double-blind, non-inferiority trial.

BACKGROUND: The optimal strength of compression needed to prevent post-thrombotic syndrome (PTS) after a proximal deep vein thrombosis (DVT) is debated. We aimed to assess whether 25 mm Hg elastic compression stockings (ECS) are non-inferior to 35 mm Hg ECS in preventing PTS after a DVT. METHODS: In this multicentre, double-blind, non-inferiority, randomised controlled trial, we enrolled adults (≥18 years) with a first ipsilateral proximal DVT attending 46 French vascular medicine hospital departments or private practices. Participants were randomly allocated (1:1, stratified by centre, age, and sex; with varying block sizes of two and four) to wear 25 mm Hg or 35 mm Hg ECS for 2 years. The primary outcome was the cumulative rate of PTS 2 years after inclusion, defined by a Villalta scale (≥5). Efficacy was assessed by intention-to-treat and in eligible participants who had complete primary outcome data. A per-protocol analysis was also conducted among compliant patients as a secondary outcome measure. Safety was assessed in all participants who used ECS at least once, and for which we have at least some tolerance information during follow-up. The margin for non-inferiority was 12·5%. This study is registered with ClinicalTrials.gov, NCT01578122, and has been completed. FINDINGS: Between June 28, 2012, and July 21, 2017, we enrolled 341 eligible participants who consented to randomisation. 233 (68%) were men and median age was 59 years (IQR 45-70). Collection of ethnicity and race as a routine research variable is not authorised in France. Median follow-up was 735 days (IQR 721-760). 249 (73%) had complete data at 2 years. For the primary analysis, 40 (31%) of 129 participants with complete data in the 25 mm Hg ECS group and 40 (33%) of 120 in the 35 mm Hg group had PTS (absolute difference -2·3% [90% CI -12·1 to 7·4], pnon-inferiority=0·0062; relative risk 0·93, 95% CI 0·65 to 1·33). Results remained similar after imputation of missing data in patients we were authorised to do so: the cumulative proportion of PTS was 45 (29%) of 154 in the 25 mm Hg ECS group versus 52 (35%) of 148 in the 35 mm Hg ECS group (relative risk 0·83, 95% CI 0·60 to 1·16). Absolute difference was -5·9%, (90% CI -14·7 to 2·9), p=0·0003 for non-inferiority. Adherence was optimal (>80% and modified GIRERD score of 0-2) for 75 (51%) of 146 patients assigned to 25 mm Hg ECS and for 56 (42%) of 134 patients assigned to 35 mm Hg ECS (p=0·11). Regarding major adverse events related to ECS, there were no between-group differences in rates of deep vein thrombosis (0 vs 1 [0·6%]), ipsilateral leg ulcer (0 vs 1 [0·6%]), infection (0 vs 0), or death (0 vs 0) between the 169 patients evaluated in the 25 mm Hg ECS group and the 159 patients in the 35 mm Hg ECS group. Two (1%) of 328 patients who ever wore ESC developed ECS-related serious adverse events, one distal DVT and one leg ulcer (both in the 35 mm Hg ECS group). In the 25 mm Hg group, 6 patients died, 14 had a venous thromboembolic recurrence (proximal DVT or pulmonary embolism), and 7 had a major bleed. In the 35 mm Hg group, 5 patients died, 10 had a venous thromboembolic recurrence (proximal DVT or pulmonary embolism), and 6 had a major bleed. INTERPRETATION: Although we did not reach the prespecified sample size, our results suggest that 25 mm Hg ECS are non-inferior to 35 mm Hg ECS in preventing PTS. Larger more powerful studies are needed. FUNDING: Laboratoires Innothera, France.

Is There a Difference in the Clinical Efficacy of Diosmin and Micronized Purified Flavonoid Fraction for the Treatment of Chronic Venous Disorders? Review of Available Evidence.

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).

Comparative in vitro study on the local tolerance and efficacy of benzalkonium chloride, myristalkonium chloride and nonoxynol-9 as active principles in vaginal contraceptives.

BACKGROUND: Spermicides have been identified as a potentially attractive alternative to hormonal contraceptives and/or intrauterine devices. Thus, this study aimed evaluating the efficacy and local tolerance of benzalkonium chloride (BKC) and myristalkonium chloride (MKC) contained in Pharmatex® vaginal formulations and compare them with nonoxynol-9 (N-9), the most common active ingredient in topical vaginal contraceptives. METHODS: Human normozoospermic samples were assessed for motility, viability, acrosome status and penetration ability after exposure to control, N-9 or different BKC and MKC doses for 0 and 10 minutes. Local tolerance on HeLa cells was evaluated by the Trypan-blue and MTT assays. RESULTS: Exposure to BKC and MKC reduced acrosome integrity while promoting total immobilisation and complete loss of sperm viability (p < .001, n = 15). Both compounds also compromised sperm penetration ability upon exposure (p < .001, n = 15). N-9 induced the same outcomes (p < .001, n = 15); nevertheless, it was more toxic to HeLa cells than BKC and MKC (p < .05, n = 14). CONCLUSIONS: BKC and MKC present strong in vitro spermicidal activity at lower doses than N-9 and were better tolerated after immediate exposure than N-9. Available Pharmatex® galenic formulations were as effective as products based on N-9.

Anti-inflammatory and antiradical effects of a 2% diosmin cream in a human skin organ culture as model.

BACKGROUND: Diosmin, a naturally occurring flavonoid, is considered as a vascular-protective agent and is used orally to treat chronic venous insufficiency. It exhibits anti-inflammatory and free radical scavenging properties, but, like many other flavonoids, it is poorly absorbed in the small intestine. OBJECTIVE: Our aim was to investigate the skin protective effects of a diosmin-based cream, using skin organ culture as model. METHODS: Fragments of human skin explants, cultured ex vivo, were allocated to four treatment groups: no cream, no cream + stress, placebo cream + stress, and 2% diosmin cream + stress. Stress was induced by exposure to either substance P (anti-inflammatory effects' assessment) or UVB irradiation (free radical scavenging effects' assessment). Vascular dilation and the pro-inflammatory mediator IL-8 release were determined in the first model, whereas hydrogen peroxide level and the number of cyclobutane pyrimidine-positive cells were evaluated in the second model. RESULTS: In the substance P-induced inflammation model, 2% diosmin cream exhibited significant vasoconstrictive (proportion of dilated capillaries: -29%, capillary luminal area: -49% vs no cream + stress) and anti-inflammatory (IL-8 release: -36% vs no cream + stress) effects. In the UVB irradiation model, 2% diosmin cream significantly reduced hydrogen peroxide production and cyclobutane pyrimidine dimer formation (-45% and -36% vs no cream + stress, respectively). These effects were not observed with placebo cream. CONCLUSION: Diosmin administered topically may protect skin against the biological effects of various exogenous or endogenous stresses, such as those involved in chronic venous disease.