In chronic venous insufficiency, veins of the lower limbs are unable to transport blood towards the heart. It might be caused by genetic factors, may occur after trauma, or may result from a blood clot. Poor movement of blood up the legs may cause swelling and puffiness, feelings of heaviness, tingling, cramps, pain, varicose veins and changes in skin pigmentation. If severe insufficient blood circulation occurs, ulcers and skin wasting can develop. Drugs such as natural flavonoids extracted from plants and similar synthetic products may improve blood circulation. These drugs are known collectively as venoactive drugs or phlebotonics. This review examined evidence from randomised controlled clinical trials comparing these drugs versus inactive treatment (placebo), generally given over one to three months.
Study characteristics and key results
We identified three new studies for this update. In total, 69 studies met the eligibility criteria for this review. However, we could only use 56 studies (7690 participants; mean age 50 years) in further analysis.
We compared the results and summarised the evidence from the studies. After doing so, we assessed how certain the evidence was. To do this, we considered factors such as the way studies were conducted, study sizes, and consistency of findings across studies. Based on our assessments, we categorised the evidence as potentially being of very low, low, moderate or high certainty.
Moderate-certainty evidence from 13 studies (involving 1245 people) suggests that phlebotonics probably slightly reduce puffiness (oedema) compared with placebo. Moderate-certainty evidence suggests that there is little or no difference in quality of life for people taking phlebotonics when compared with placebo. Low-certainty evidence suggests there is little or no difference in the proportion of healed ulcers with phlebotonics, compared with placebo. Moderate-certainty evidence from 37 studies (involving 5789 people) suggests that phlebotonics probably produce more side effects, especially gastrointestinal disorders.
Certainty of the evidence
All evidence was of moderate or low certainty. Starting from an initial assumption of high certainty, we downgraded the certainty of evidence by one level for each outcome because of the high risk of bias, primarily due to selective outcome reporting and incomplete outcome data. For the outcome of ulcer healing, we downgraded by an additional level due to statistical imprecision (small number of events). With moderate-certainty evidence, we are moderately confident in the effect estimates for these outcomes. The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. With low-certainty evidence, our confidence in the effect estimate for that outcome is limited. The true effect may be substantially different from the estimate of the effect.
How-up-to date is this review?
The evidence in this Cochrane Review is current to November 2019.
There is moderate-certainty evidence that phlebotonics probably reduce oedema slightly, compared to placebo; moderate-certainty evidence of little or no difference in QoL; and low-certainty evidence that these drugs do not influence ulcer healing. Moderate-certainty evidence suggests that phlebotonics are probably associated with a higher risk of adverse events than placebo. Studies included in this systematic review provided only short-term safety data; therefore, the medium- and long-term safety of phlebotonics could not be estimated. Findings for specific groups of phlebotonics are limited due to small study numbers and heterogeneous results. Additional high-quality RCTs focusing on clinically important outcomes are needed to improve the evidence base.
Chronic venous insufficiency (CVI) is a condition in which veins are unable to transport blood unidirectionally towards the heart. CVI usually occurs 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 the second update of a review first published in 2005.
To assess the efficacy and safety of phlebotonics administered orally or topically for treatment of signs and symptoms of lower extremity CVI.
The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, and CINAHL databases and the World Health Organization International Clinical Trials Registry Platform and Clinicaltrials.gov trials register up to 12 November 2019. We searched the reference lists of the articles retrieved by electronic searches for additional citations. We also contacted authors of unpublished studies.
We included randomised, double-blind, placebo-controlled trials (RCTs) assessing the efficacy of phlebotonics (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.
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 standardized mean differences (SMDs), according to the outcome assessed. We calculated 95% confidence intervals (CIs) and percentage of heterogeneity (I2). Outcomes of interest were oedema, quality of life (QoL), assessment of CVI and adverse events. We used GRADE criteria to assess the certainty of the evidence.
We identified three new studies for this update. In total, 69 RCTs of oral phlebotonics were included, but only 56 studies (7690 participants, mean age 50 years) provided quantifiable data for the efficacy analysis. These studies used different phlebotonics (28 on rutosides, 11 on hidrosmine and diosmine, 10 on calcium dobesilate, two on Centella asiatica, two on aminaftone, two on French maritime pine bark extract and one on grape seed extract). No studies evaluating topical phlebotonics, chromocarbe, naftazone or disodium flavodate fulfilled the inclusion criteria.
Moderate-certainty evidence suggests that phlebotonics probably reduce oedema slightly in the lower legs, compared with placebo (RR 0.70, 95% CI 0.63 to 0.78; 13 studies; 1245 participants); and probably reduce ankle circumference (MD -4.27 mm, 95% CI -5.61 to -2.93 mm; 15 studies; 2010 participants). Moderate-certainty evidence shows that phlebotonics probably make little or no difference in QoL compared with placebo (SMD -0.06, 95% CI -0.22 to 0.10; five studies; 1639 participants); and similarly, may have little or no effect on ulcer healing (RR 0.94, 95% CI 0.79 to 1.13; six studies; 461 participants; low-certainty evidence). Thirty-seven studies reported on adverse events. Pooled data suggest that phlebotonics probably increase adverse events slightly, compared to placebo (RR 1.14, 95% CI 1.02 to 1.27; 37 studies; 5789 participants; moderate-certainty evidence). Gastrointestinal disorders were the most frequently reported adverse events. We downgraded our certainty in the evidence from 'high' to 'moderate' because of risk of bias concerns, and further to 'low' because of imprecision.