The medical management of VLU includes a careful assessment of the venous systems responsible to identify incompetent perforating and deep veins. Dressings and compression therapy are generally the primary therapeutic option, followed by surgery, if necessary, to remove incompetent veins [10, 11]. Intermittent pneumatic compression (IPC) has improved healing rates in some studies when used with standard compression , but it is not yet clear whether it is superior to standard compression and for which patients it is most beneficial. At present, IPC is recommended for patients with VLUs that have failed to heal with standard compression therapy or for patients who cannot tolerate compression stockings or bandages .
Many studies have aimed to determine the associations and effects of nutritional characteristics on VLU outcomes. Patients with VLU tend to be overweight or obese, which may mask nutritional deficiencies impacting on VLU healing and recurrence. Zinc intake was found to be below recommendations in a minority of VLU patients. Other nutritional characteristics of VLU patients included low levels of serum vitamin D, vitamin C and zinc as well as fatty acid imbalances . In a meta-analysis of 20 studies, vitamin D, folic acid and flavonoids were associated with some beneficial effects on ulcer healing . However, dietary supplements have not been shown to be efficient therapies for VLU, and further investigation into the role of micronutrient deficiencies in wound healing is needed.
Systemic treatment with venoactive drugs (VADs) in combination with compression can be highly effective in healing VLUs [10, 15]. Adjunct treatment with VAD can decrease the inflammation associated with venous hypertension, promote VLU healing and improve QoL. Micronized purified flavonoid fraction (MPFF; Daflon®) is the most widely prescribed VAD to treat CVD. The pharmacologic actions of MPFF include reductions in endothelial cell activation, serum concentrations of endothelial cell adhesion molecules and growth factors, leukocyte adhesion and activation, venous valve deterioration and reflux, proinflammatory mediator production and release, and capillary leakage [7, 10]. These properties result in clinical benefits that improve venous tone and the clinical signs and symptoms of CVD, edema, skin changes, VLU healing and QoL . Side effects of MPFF are infrequent and minor.
Evidence that MPFF treatment improves VLU healing comes from a meta-analysis of five randomized clinical trials (RCT) involving 723 VLU patients . Comparisons were made between patients receiving MPFF in addition to conventional treatment (compression and local care) and patients receiving conventional treatment only or with placebo, with a primary end point of complete ulcer healing after 6 months. Adjunct MPFF treatment led to an overall healing rate of 61.3% and was associated with a statistically significant increase of 32% in the chance that a VLU would be healed within 6 months over conventional treatment alone (47.6% healing rate; P = 0.03). Adjunct MPFF treatment also increased the chances of healing for VLUs that were > 5 cm2 (53%; P = 0.035) and for VLUs that had persisted between 6 and 12 months (44%; P = 0.021). Time to healing was also significantly shorter with MPFF treatment (16.1 weeks) than without (21.3 weeks; P = 0.003).
Such evidence has led to high-level recommendations for the use of MPFF therapy in VLU treatment across multiple international treatment guidelines since 2008 (Table 2). MPFF in addition to standard care is recommended for healing of venous ulcers (CEAP C6), for healing of venous ulcers due to post-thrombotic syndrome and for long-standing or large VLU.
Two other drugs, pentoxifylline and sulodexide, both of which are not VADs, have also been shown to improve VLU healing and are recommended in addition to compression therapy . Pentoxifylline, a methylated xanthine derivative, is a competitive non-selective phosphodiesterase inhibitor that has been shown to have antioxidant properties and to reduce inflammation. In addition, pentoxifylline reduces blood viscosity and decreases the potential for platelet aggregation and blood clot formation. Sulodexide, a combination of fast-moving heparin and dermatan sulfate, also has antithrombotic and profibrinolytic properties as well as antiinflammatory effects. In a 2012 Cochrane Review of 11 RCTs, pentoxifylline alone was more effective than placebo for complete ulcer healing or significant improvement [relative risk (RR) 1.70; 95% CI 1.30–2.24], while compression was more effective with pentoxifylline than with placebo (RR 1.56; 95% CI 1.14–2.13). In the 2016 Cochrane Review investigating sulodexide treatment, combined complete ulcer healing rates were 49.4% with conventional treatment plus sulodexide and 29.8% with conventional compression treatment alone for a relative risk ratio of RR 1.66 (95% CI 1.30–2.12) . Almost identical results were obtained from another analysis that included two additional studies .
In the current European CVD management guidelines (2018), high levels of evidence (grade A) are cited to recommend MPFF, pentoxifylline and sulodexide treatments in the healing of VLUs as an adjunct to compression therapy . MPFF, however, is the only VAD with such a recommendation.