Phlebotonics for venous insufficiency
Maria José Martinez-Zapata, Robin W M Vernooij, Sonia Maria Uriona Tuma, Airton T Stein, Rosa M Moreno, Emilio Vargas, Dolors Capellà, Xavier Bonfill Cosp, Maria José Martinez-Zapata, Robin W M Vernooij, Sonia Maria Uriona Tuma, Airton T Stein, Rosa M Moreno, Emilio Vargas, Dolors Capellà, Xavier Bonfill Cosp
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.
Objectives: To assess the efficacy and safety of phlebotonics administered both orally and topically for treatment of signs and symptoms of lower extremity CVI.
Search 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).
Selection criteria: 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.
Data collection and analysis: 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.
Main 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.
Authors' 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.
Conflict of interest statement
Dr D Capellà, Dr X Bonfill Cosp, Dr RM Moreno and Dr E Vargas were part of an advisory group of the Safety Committee of the Spanish Drug Agency, whose objective was to assess the efficacy and safety of phlebotonics during 2002. Dr MJ Martínez assisted with technical work for this group.
Dr RM Moreno, Dr X Bonfill Cosp and Dr MJ Martínez‐Zapata were authors of a published double‐blind, placebo‐controlled clinical trial (Martinez‐Zapata 2008) that is included in this review. This study was sponsored by Laboratorios Dr Esteve, which markets calcium dobesilate (Doxium). Laboratorios Dr Esteve signed a written commitment to fully respect the researchers' independence and to allow dissemination of results, whatever they could be. Furthermore, Dr RM Moreno, Dr X Bonfill Cosp and Dr MJ Martínez‐Zapata were researchers in the included clinical trial DOBESILATO500/2, which was prematurely interrupted because of lack of funding.
Dr MJ Martínez‐Zapata: none known. Dr RWM Vernooij: none known. Dr SM Uriona Tuma: none known. Dr AT Stein: none known. Dr RM Moreno: none known. Dr E Vargas: none known. Dr D Capellà: chair of the Independent Drug Monitoring Committee of the clinical trial "Neurodegeneration as an early event in the pathogenesis of diabetic retinopathy: a multicentric, prospective, phase II‐III, randomised controlled trial to assess the efficacy of neuroprotective drugs administered topically to prevent or arrest diabetic retinopathy", carried out by the European Consortium for the Early Treatment of Diabetic Retinopathy (EUROCONDOR) with support from the European Commission, FP7‐HEALTH‐2011‐GA No. 278040 and sponsored by BCN Peptides. Dr X Bonfill Cosp: none known.
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Source: PubMed