Abstract: 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; I2 = 20%; 1245 participants) and ankle circumference (MD -4.27 mm, 95% CI -5.61 to -2.93 mm; I2 = 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; I2 = 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; I2 = 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; I2 = 0; 3975 participants). Gastrointestinal disorders were the most frequently reported adverse events. 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.

Plain-language summary: In total, 66 studies (53 with quantifiable data, including 6013 participants; mean age 50 years) met the eligibility criteria for this review (current until August 2015). Moderate-quality evidence from 13 studies (involving 1245 people) suggests that phlebotonics reduce puffiness (oedema) compared with placebo. Low quality evidence suggests there is no difference in the proportion of healed ulcers with phlebotonics compared with placebo. For quality of life, it was not possible to combine all studies because of differences between the studies. However, individual phlebotonic treatments shows high quality evidence there is no difference in quality of life for the phlebotonic calcium dobesilate. Low-quality evidence revealed improvement of quality of life for aminaftone when compared to placebo. Furthermore evidence suggests phlebotonics have beneficial effects on trophic disorders, cramps, restless legs, swelling and tingling. However, the relevance of these findings to the overall clinical state remains unclear. Moderate-quality evidence from 33 studies (involving 3975 people) shows that phlebotonics produce more side effects, especially gastrointestinal disorders. Quality of the evidence The quality of evidence was downgraded because of selective reporting for the outcome ulcer healing, for incomplete outcome data for the outcomes ulcer healing, oedema and adverse events and for unclear randomisation and imprecision of the overall results for the outcome quality of life.