title: Phlebotonics for venous insufficiency.
abstract: BACKGROUND
  Chronic venous insufficiency (CVI) is a common condition caused by valvular dysfunction with or without associated obstruction, usually in the lower limbs. It might result in considerable discomfort with symptoms such as pain, itchiness and tiredness in the legs. Patients with CVI may also experience swelling and ulcers. Phlebotonics are a class of drugs often used to treat CVI. This is an update of a review first published in 2005.
  
  
  OBJECTIVE
  To assess the efficacy and safety of phlebotonics administered both orally and topically for treatment of signs and symptoms of lower extremity CVI.
  
  
  METHODS
  For this update, the Cochrane Vascular Trials Search Co-ordinator (TSC) searched the Specialised Register (August 2015), as well as the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 7). The reference lists of the articles retrieved by electronic searches were searched for additional citations. We also contacted pharmaceutical companies and searched the World Health Organization (WHO) International Clinical Trials Registry Platform Search Portal for ongoing studies (last searched in August 2015).
  
  
  METHODS
  Randomised, double-blind, placebo-controlled trials (RCTs) assessing the efficacy of rutosides, hidrosmine, diosmine, calcium dobesilate, chromocarbe, Centella asiatica, disodium flavodate, french maritime pine bark extract, grape seed extract and aminaftone in patients with CVI at any stage of the disease.
  
  
  METHODS
  Two review authors independently extracted data and assessed the quality of included RCTs. We estimated the effects of treatment by using risk ratios (RRs), mean differences (MDs) and standardised mean differences (SMDs), according to the outcome assessed. We calculated 95% confidence interval (CIs) and percentage of heterogeneity (I(2)). Additionally, we performed sensitivity analyses.
  
  
  RESULTS
  We included 66 RCTs of oral phlebotonics, but only 53 trials provided quantifiable data (involving 6013 participants; mean age 50 years) for the efficacy analysis: 28 for rutosides, 10 hidrosmine and diosmine, nine calcium dobesilate, two Centella asiatica, two aminaftone, two french maritime pine bark extract and one grape seed extract. No studies evaluating topical phlebotonics, chromocarbe, naftazone or disodium flavodate fulfilled the inclusion criteria.Moderate-quality evidence suggests that phlebotonics reduced oedema in the lower legs compared with placebo. Phlebotonics showed beneficial effects among participants including reduced oedema (RR 0.70, 95% CI 0.63 to 0.78; I(2) = 20%; 1245 participants) and ankle circumference (MD -4.27 mm, 95% CI -5.61 to -2.93 mm; I(2) = 47%; 2010 participants). Low-quality evidence reveals no difference in the proportion of ulcers cured with phlebotonics compared with placebo (RR 0.94, 95% CI 0.79 to 1.13; I(2) = 5%; 461 participants). In addition, phlebotonics showed greater efficacy for trophic disorders, cramps, restless legs, swelling and paraesthesia, when compared with placebo. We identified heterogeneity for the variables of pain, itching, heaviness, quality of life and global assessment by participants. For quality of life, it was not possible to pool the studies because heterogeneity was high. However, high-quality evidence suggests no differences in quality of life for calcium dobesilate compared with placebo (MD -0.60, 95% CI -2.15 to 0.95; I(2) = 40%; 617 participants), and low-quality evidence indicates that in the aminaftone group, quality of life was improved over that reported in the placebo group (MD -10.00, 95% CI -17.01 to - 2.99; 79 participants). Moderate-quality evidence shows that the phlebotonics group had greater risk of non-severe adverse events than the placebo group (RR 1.21, 95% CI 1.05 to 1.41; I(2) = 0; 3975 participants). Gastrointestinal disorders were the most frequently reported adverse events.
  
  
  CONCLUSIONS
  Moderate-quality evidence shows that phlebotonics may have beneficial effects on oedema and on some signs and symptoms related to CVI such as trophic disorders, cramps, restless legs, swelling and paraesthesia when compared with placebo but can produce more adverse effects. Phlebotonics showed no differences compared with placebo in ulcer healing. Additional high-quality RCTs focused on clinically important outcomes are needed to improve the evidence base.
authors.affiliation: Iberoamerican Cochrane Centre - Biomedical Research Institute Sant Pau (IIB Sant Pau), CIBER Epidemiología y Salud Pública (CIBERESP), Sant Antoni Maria Claret 167, Pavilion 18, Barcelona, Catalunya, Spain, 08025.
authors.forename: Maria José
authors.initials: MJ
authors.lastname: Martinez-Zapata
authors.forename: Robin W M
authors.initials: RW
authors.lastname: Vernooij
authors.forename: Sonia Maria
authors.initials: SM
authors.lastname: Uriona Tuma
authors.forename: Airton T
authors.initials: AT
authors.lastname: Stein
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Moreno
authors.forename: Emilio
authors.initials: E
authors.lastname: Vargas
authors.forename: Dolors
authors.initials: D
authors.lastname: Capellà
authors.forename: Xavier
authors.initials: X
authors.lastname: Bonfill Cosp
mesh_terms: D010129:4-Aminobenzoic Acid / Q000627:therapeutic use; D002123:Calcium Dobesilate / Q000627:therapeutic use; D028041:Centella; D002908:Chronic Disease; D004145:Diosmin / Q000031:analogs & derivatives / Q000627:therapeutic use; D004487:Edema / Q000188:drug therapy; D006401:Hematologic Agents / Q000627:therapeutic use*; D006801:Humans; D007871:Leg Ulcer / Q000188:drug therapy; D008517:Phytotherapy / Q000379:methods; D028223:Pinus; D010936:Plant Extracts / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D012431:Rutin / Q000627:therapeutic use; D014689:Venous Insufficiency / Q000188:drug therapy*; D062366:para-Aminobenzoates / Q000627:therapeutic use
chemical_list: D006401:Hematologic Agents; D010936:Plant Extracts; D062366:para-Aminobenzoates; C016217:aminaftone; C071047:hidrosmin; D002123:Calcium Dobesilate; D012431:Rutin; D004145:Diosmin; D010129:4-Aminobenzoic Acid