title: Efficacy of Ruscus extract, HMC and vitamin C, constituents of Cyclo 3 fort®, on improving individual venous symptoms and edema: a systematic review and meta-analysis of randomized double-blind placebo-controlled trials.
abstract: BACKGROUND
  Venoactive drugs (VADs) are considered an important component of the medical (conservative) treatment of chronic venous disorders (CVDs). However, the efficacy of certain VADs on one or more individual leg symptoms may have not been extensively studied to justify a high level or grade of recommendation in guidelines on CVD. The aim of the present systematic review and meta-analysis was to study the effectiveness of VADs containing Ruscus across the spectrum of defined venous symptoms.
  
  
  METHODS
  On November 14 2016, a literature search of the databases MEDLINE and Scopus was performed, supplemented by hand searching, to identify randomized double-blind placebo-controlled trials on Ruscus extracts in patients with CVD.
  
  
  RESULTS
  The main outcome measures were the effects of Ruscus on individual symptoms and leg edema, which were expressed as risk ratio (RR) or standardized mean difference (SMD) with 95% confidence interval (CI). Trial quality of evidence was graded using the GRADE system. We identified 10 trials, mostly with low risk of bias, on 719 patients. On qualitative analysis, Ruscus significantly improved seven defined leg symptoms, including pain, heaviness, fatigue, feeling of swelling, cramps, itching and paresthesia compared to placebo. On quantitative analysis, Ruscus compared with placebo, assessed as a categorical variable, reduced leg pain (RR=0.35, P=0.01, number needed to treat [NNT] 5, with no heterogeneity), heaviness (RR=0.26, P<0.00001, NNT=2.4, with a small amount of heterogeneity), feeling of swelling (RR=0.53, P<0.0001, NNT=4, with considerable heterogeneity, minimized after sensitivity analysis), paresthesia (RR=0.27, P<0.0001, NNT=1.8), global symptoms (RR=0.54, P<0.00001, NNT=4.3) and the total number of venous symptoms (RR 0.41, P=0.002). Similarly, Ruscus compared to placebo, assessed as a continuous variable reduced pain (SMD=-0.80, 95% CI: -1.21 to -0.39), heaviness (SMD=-1.23, 95% CI: -1.60 to -0.86), fatigue (SMD -1.16, 95% CI: -1.71 to -0.61), feeling of swelling (SMD=-2.27, 95% CI: -3.83 to -0.70), and paresthesia (SMD=-0.86, 95% CI: -1.51 to -0.21). Regarding objective assessments of leg edema, the use of Ruscus compared with placebo reduced ankle circumference (SMD=-0.74, 95% CI: -1.01 to -0.47) and leg or foot volume (SMD=-0.61, 95% CI: -0.91 to -0.31). The existing evidence, where sufficient, was mostly of high quality.
  
  
  CONCLUSIONS
  Based on high quality evidence, Ruscus extracts are highly effective in reducing symptoms and edema of patients with CVD.
authors.affiliation: Department of Vascular Surgery, University Hospital of Patras, Patras, Greece - kakkos@upatras.gr.
authors.forename: Stavros K
authors.initials: SK
authors.lastname: Kakkos
authors.affiliation: Medical Evaluation, University Hospital of Dijon, Dijon, France.|Cen Biotech, Dijon, France.
authors.forename: François A
authors.initials: FA
authors.lastname: Allaert
mesh_terms: D001205:Ascorbic Acid / Q000627:therapeutic use*; D004487:Edema / Q000188:drug therapy*; D006801:Humans; D008517:Phytotherapy / Q000379:methods*; D010936:Plant Extracts / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D031443:Ruscus / Q000737:chemistry*; D014652:Vascular Diseases / Q000188:drug therapy*; D014680:Veins / Q000187:drug effects
chemical_list: D010936:Plant Extracts; C013343:cyclo 3; D001205:Ascorbic Acid