A Literature Review of Pharmacological Agents to Improve Venous Leg Ulcer Healing

Compression therapy is the gold standard treatment for venous leg ulcers (VLUs); however, with adjunctive pharmacological therapies and poor patient adherence using compressive dressings, clinicians are looking to find the advantage in treating VLUs. This literature review focuses on the efficacy of pharmacological agents, quality of life using agents in addition to compression therapy, and cost effectiveness to indicate the best outcomes for pharmacological treatment of VLUs. The following available venotonic, hemorheologic, and fibrinolytic agents were reviewed for oral management in treating VLUs: pentoxifylline, flavonoids (diosmin, hidrosmin, rutosides, and micronized purified flavonoid fraction, Vasculera), Red-Vine-Leaf-Extract AS 195, Ruscus, Ginkgo biloba, Centella asiatica, Pycnogenol (French maritime pine bark), escin/horse chestnut extract, nutritional supplements (ie, zinc and magnesium, glycosaminoglycans [sulodexide], mesoglycans), Axaven, cilostazol, fibrinolytic enhancers (stanozolol and defibrotide), calcium dobesilate, aspirin, antibiotics (antimicrobials, doxycycline, levamisole), diuretics, cinnarizine, naftazone, and benzarone. Venous leg ulcer pharmacological treatment options were searched in the English language from February 2020 to March 2020 using numerous databases and sites, such as PubMed. Drugs used adjunctively with compression therapy that facilitate healing in long-standing or large VLUs include micronized purified flavonoid fraction, pentoxifylline, sulodexide, and mesoglycan. 

RE: A literature review of pharmacological agents to improve venous leg ulcer healing by M. Mark Melin, MD, FACS, RPVI, FACCWS; and Steven M. Dean, DO, FSVM, RPVI in the November 2020 issue of Wounds.

Venous leg ulcers (VLUs), or varicose ulcers, are the final stage of chronic venous insufficiency (CVI) and are the most common type of leg ulcer.¹ The development of VLUs on distal legs and ankles can occur after minor trauma or spontaneously. The ulcers are often painful and exudative, healing is often long-drawn-out, and recurrence is common. This cycle of healing and recurrence has a considerable impact on the health and quality of life of individuals, health care, and socioeconomic costs.¹ Venous leg ulcers are a common and costly problem worldwide; prevalence of VLUs is estimated to be between 1.65% to 1.74% in the western world and is more common in adults aged 65 years and older.¹ In addition, the recurrence rates within 3 months of healing are reported to be about 70%.² Venous leg ulcers can cultivate physical, financial, and psychological implications, such as pain and disability,³ depression,^4,5 social isolation,⁵ and decreased quality of life.⁶ Venous leg ulcers account for approximately 2% to 3% of total health care expenditure in developed countries.⁷ The main treatment for a VLU is a firm compression dressing. Compression assists by reducing venous hypertension, thus reducing peripheral edema and enhancing venous return. However, studies show compression only has moderate effects on healing, with up to 50% of VLUs remaining unhealed after 2 years of compression therapy.¹ Adherence may be the principal cause of these poor results, but presence of inflammation in people with CVI may be another factor. Pharmacological treatment that suppresses inflammation and reduces the frequency of VLUs would be an invaluable intervention to complement compression treatments.

The objective of this review is to provide pharmaceutical options for treatments of VLUs based on the current literature.

From February 2020 through March 2020, the following databases and sites were searched: the Cochrane Wounds Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), Ovid MEDLINE, Ovid MEDLINE In-Process & Other Non-Indexed Citations, PubMed, Ovid EMBASE, and EBSCO CINAHL. Additional searches were made in trial registers and reference lists of relevant publications for published or ongoing trials. There were no language or publication date restrictions.

Selection criteria
The criteria included randomized controlled trials (RCTs) that compared the drug of interest with placebo or no drug intervention (in the presence or absence of compression therapy) for treating people with VLUs. The main outcomes were time to complete ulcer healing, rate of change in the area of the ulcer, proportion of ulcers healed in the trial period, pain, mortality, adverse events, and ulcer recurrence.

Data collection and analysis
All authors collectively selected studies for inclusion, extracted data, assessed the risk of bias of each included trial, and assessed the overall quality of evidence for the main outcomes (Table). 

Current treatment for VLUs
Patients should have venous insufficiency testing, as a venous reflux ultrasound could potentially display pathologic valves and reflux in real time. Ulcer characteristics, depth, area, base, and ulcer edges should be monitored over time, because the changing nature of an ulcer can insinuate advancement of disease or healing. Bacteriological swabs and antibiotics should only be used in cases of proven clinical infection, and a biopsy may be considered in cases of atypical or nonhealing ulceration.⁸ Simple dressings, meticulous wound care, and judicious sharp debridement should be undertaken by experienced practitioners and, in particular, podiatrists. All patients with VLUs should have an ankle-brachial index (ABI) performed prior to the instigation of treatment to exclude arterial disease. In the presence of an abnormal ABI, patients should have cardiovascular risk factors addressed, in addition to receiving a referral to a vascular surgeon.⁸ Compression therapy should be instigated and undertaken by an appropriately trained professional. According to the Scottish Intercollegiate Guidelines Network,⁸ patients with chronic, nonhealing VLUs and concomitant superficial venous reflux should be referred for consideration for surgery to prevent recurrence. 

Pentoxifylline
Pentoxifylline (Trental; sanofi-aventis) is a xanthine derivative with a variety of beneficial anti-inflammatory and hemorheologic properties, including inhibition of tumor necrosis factor A and leukotriene synthesis, with improved red blood cell deformability, reduced blood viscosity, and decreased platelet aggregation and thrombus formation.⁹ Pentoxifylline increases microcirculatory blood flow, oxygenation of ischemic tissues, and red and white cell filterability as well as decreases whole blood viscosity, platelet aggregation, and fibrinogen levels.^10–12  

In a factorial, randomized trial of pentoxifylline or placebo, compression for venous ulcers and pentoxifylline increased the proportion healing compared with placebo.¹³ In a Cochrane review, 3 significant trials were discussed and summarized.^14–16 Patients with VLUs were assessed in a 3-arm multicenter double-blind placebo-controlled RCT of pentoxifylline 400 mg, 800 mg, or placebo 3 times daily in addition to compression bandaging.¹⁴ Patients were treated for up to 24 weeks, and the primary outcome was time to complete healing of all VLUs. This study found that high doses of pentoxifylline had 2 important effects on the complete healing of leg ulcers. Not only did a significantly greater proportion of patients become ulcer free on pentoxifylline than on placebo but also complete healing occurred at least 4 weeks earlier in the majority of pentoxifylline cases by comparison with placebo.¹⁴ In 1999, a double-blind RCT comparing patients receiving pentoxifylline 400 mg 3 times daily versus placebo, in addition to compression, assessed for the primary efficacy variable of complete healing of all ulcers on the reference leg by 24 weeks.¹⁵ The pentoxifylline group had 64% of VLUs healed, whereas the placebo group only had 53%; however, this did not reach clinical significance.¹⁵ In another randomized study, patients with VLUs took pentoxifylline 400 mg 3 times daily or placebo along with compression, with complete VLU healing assessed at 6 months.¹⁶ Complete VLU healing was 67% in the pentoxifylline group and 30.7% in the placebo group (P < .02).¹⁶ Gastrointestinal side effects were common in the pentoxifylline groups.¹⁷ In summary, the Cochrane review¹⁷ of 7 RCTs assessing pentoxifylline with compression combined the results of 659 participants using a random-effects model. The review found that patients with VLUs receiving pentoxifylline with compression were more likely to heal than those receiving placebo and compression. This finding suggests pentoxifylline should be considered for use in people unable to tolerate compression bandaging or those who do not want to use compression.¹⁷ 

Pentoxifylline is supported by other meta-analyses of RCTs¹⁷ and has documented benefits in the healing of VLUs. The drug metabolism is urinary; however, pentoxifylline has not been tested in patients with renal or hepatic impairment.¹⁷ The drug is approved by the United States Federal Drug Administration for intermittent claudication but is clinically used for VLUs.¹⁸ Pentoxifylline is contraindicated in patients with severe hemorrhages, acute myocardial infarction, angina, or liver and kidney disease.^18,19 

Glycosaminoglycans: sulodexide 
Sulodexide (SDX), a sulfated polysaccharide complex extracted from porcine intestinal mucosa, is composed of 2 glycosaminoglycans (80% of fast-moving heparin fraction and 20% of dermatan sulfate component) and is biologically active by both parenteral and oral routes.²⁰ Several preclinical reports^21-23 highlight SDX as an endothelial cell-protecting agent. The main properties are linked to extensive absorption by the vascular endothelium, with an antithrombotic action similar to heparins, but associated with lesser alterations of the blood clotting mechanisms; prevention and restoration of integrity and permeability of endothelial cells; regulation of endothelial-blood cell interactions; and, lastly, inhibition of microvascular inflammatory and proliferative changes.^21-23 

Four RCTs evaluating SDX with compression, placebo with compression, and compression alone, involving 488 patients with VLUs, demonstrated that oral SDX is more effective at increasing healing rates at 1 to 3 months.²⁴ In one of the larger RCTs, patients were treated for up to 70 days, and improved VLU healing ranged between 52% and 70% compared with placebo or compression alone, which healed only 32% to 35% of VLUs.^25-27 In an open-label, observational, non-parallel trial of 50 VLUs treated with SDX, all of the VLUs were healed by week 12.²⁸ All ulcers in the control group were healed at week 21. Lipodermatosclerosis improved in both groups, but it decreased faster in the SDX group. No adverse effects attributed to the medications were seen in either group. González ochoa²⁸ found the combined administration of SDX and diosmin-hesperidin micronized purified flavonoids was effective in accelerating ulcer healing, controlling pain, and improving lipodermatosclerosis. Potential side effects of SDX include cutaneous rash, diarrhea, headache, and abdominal pain, which can occur in up to 19% of patients.²⁴ A total of 53 patients were treated with compression therapy, surgery, and SDX (600 lipoprotein lipase-releasing units/day intramuscularly) for 15 days, followed by SDX 250 lipase-releasing units twice daily for 6 months as adjunctive treatment alongside a control group of compression therapy and surgery. The results showed SDX treatment was able to reduce tissue expression of matrix metalloproteinases (MMPs), improving the clinical conditions in patients with mixed ulcers.²⁹ These findings demonstrate the efficacy of SDX in patients with mixed arterial and venous chronic ulcers of the lower limbs.²⁹ 

Glycosaminoglycans: mesoglycans
The exact mechanism of mesoglycan, a glycosaminoglycan mixture (composed of 52% heparan sulfate, 35% dermatan sulfate, 8% slow-moving heparin, and about 5% chondroitin sulfate), is unknown.¹⁹ However, it has a profibrinolytic action and microrheologic and macrorheologic benefits.³⁰ It also has been reported to be advantageous in treating venous disorders.³⁰ Mesoglycans also have properties that inhibit neutrophil adhesion and activation, and enhancement in the process of wound healing.³¹ Mesoglycan was evaluated in a multicenter, double-blind placebo-controlled RCT involving 18 outpatient Italian medical centers.³² There were 92 patients with VLUs in the mesoglycan group and 91 in the placebo group, with all patients undergoing weekly compression changes; the primary end point was a healed ulcer. Mesoglycan was administered intramuscularly for 21 days and then orally for 21 weeks. Patients with renal insufficiency were excluded. At 24 weeks, the complete healing rate of VLUs was 97% in the mesoglycan group and 82% in the placebo group (P < .05), with the relative risk for healing favoring mesoglycan.³² Mesoglycan has proven efficacy in reducing plasma fractional breakdown rate levels and the risk of recurrences in patients with cerebral arterial disease, with a good safety profile.³³ These antithrombotic and profibrinolytic activities, although not indicated in the treatment of acute arterial or venous thrombosis due to the low anticoagulant effect, suggest that mesoglycan may be useful in the management of vascular diseases when combined with antithrombotic medications.³³ The protective effect of mesoglycan in patients with venous thrombosis and the absence of side effects help support the use of vascular glycosaminoglycans in patients with CVI and persistent venous ulcers.³³ This is in association with compression therapy, local wound care, and following the standard course of oral anticoagulation treatment.³³ 

Glycosaminoglycans: nutraceutical
A nutraceutical (Axaven) on both clinical and molecular parameters in patients with chronic venous ulcers (CVUs). During the study period, 44 patients with CVUs received standard treatment (compression therapy and surgical correction of superficial venous incompetence) and this nutraceutical once daily for 8 months as adjunctive treatment; the control group received compression therapy alone. Serra et al³⁴ found the administration of the nutraceutical in patients with CVUs was able to decrease inflammatory cytokines, MMPs, and neutrophil gelatinase-associated lipocalin, inducing an improvement of both symptoms with an increase in the speed of wound healing.

Glycosaminoglycans: defibrotide
Defibrotide is an antithrombotic and profibrinolytic drug.¹⁹ It is approved for the treatment of adult and pediatric patients with hepatic veno-occlusive disease, also known as sinusoidal obstruction syndrome, with renal or pulmonary dysfunction following hematopoietic stem cell transplantation.³⁵ Defibrotide has multiple and complex mechanisms of action, including anti-inflammatory, anti-atherosclerotic, anti-ischemic, and antithrombotic properties.^35-37  Studies with defibrotide also have demonstrated increased plasmin activity, promotion of fibrinolysis via upregulation of tissue plasminogen activator and inhibition of tissue factor pathway, reduced circulating levels of plasminogen activator inhibitor-1, and increased concentration of endogenous prostaglandins, which modulate thrombomodulin, platelets, and fibrinolysis.^35,37–39  Defibrotide also may be involved in the modulation of endothelial and leukocyte cellular interactions, which play a significant role in ischemic and reperfusion events due to alteration of endothelial cell membrane permeability, lipid peroxidation, free radical production, and recruitment of leukocyte adhesion to endothelial cells.⁴⁰

Treatment with defibrotide is generally well tolerated. According to Jazz Pharmaceuticals, the most common adverse reactions were hypotension (37%), diarrhea (24%), vomiting (18%), nausea (16%), and epistaxis (14%).³⁵ Coadministration of defibrotide with systemic anticoagulant or fibrinolytic therapy is contraindicated.⁴¹ In a crossover trial involving 32 patients, defibrotide 400 mg 3 times daily along with compression was found to be more efficacious in healing VLUs compared with placebo.⁴² 

Flavonoids
The principle for the use of venoactive drugs in CVI associated with VLUs is to improve capillary permeability and venous tone. Flavonoids have venotonic properties and act on leukocytes and endothelium, which result in decreased inflammation and permeability.⁴³ This is all made possible by decreasing leucocyte adhesion, free radical formation, and venous wall permeability; increasing venous tone; and protecting cells from effects of hypoxia.⁴⁴ A meta-analysis of randomized prospective studies using micronized purified flavonoid fraction (MPFF) as an adjunctive therapy found that VLUs healed more rapidly.⁴⁵ 

A number of pharmacologic agents have been used in the treatment of varied manifestations of chronic venous disease (CVD), including VLUs. The most common classes of pharmacologic agents are the g-benzopyrones, which include flavonols (kaempferol, diosmetin, diosmin, hidrosmin, quercetin, rutin [rutoside, oxerutin, troxerutin]), MPFF, flavanes (or flavonones), hesperitin, hesperidin and its derivatives, Pycnogenol, and procyanidolic oligomers.⁴⁶ 

Flavonoids: diosmin, hidrosmin, and MPFF
Diosmin originates from Citrus spp, which has been proposed to reduce venous tissue inflammatory responses, increase lymph drainage, and inhibit venous catechol-O-methyltransferase. In turn, this reduces the metabolism of norepinephrine and prolongs its venoconstrictor effects.^47,48 The half-life of diosmin is 8 to 12 hours, with its elimination being renal (65%) and biliary (35%).⁴⁶ Possible drug-drug interactions with diosmin include: chlorzoxazone, diclofenac, and metronidazole.⁴⁹ 

A total of 54 RCTs⁵⁰ of oral phlebotonic trials provided quantifiable data (involving 6013 participants; mean age, 50 years) for the efficacy analysis: 28 for rutosides, 10 hidrosmine and diosmine, 9 calcium dobesilate, 2 Centella asiatica, 2 aminaftone, 2 French maritime pine bark extract, and 1 grape seed extract. Moderate-quality evidence suggests that, when compared with placebo, phlebotonics reduced edema in the lower legs and on signs and symptoms related to CVI, such as trophic disorders, cramps, restless legs, swelling, and paraesthesia.⁵⁰ Phlebotonics showed no differences compared with placebo in ulcer healing.⁵⁰ 

Micronized purified flavonoid fraction (Daflon 500 mg/day, 1000 mg/day) is an edema protecting agent that decreases the inflammatory cascade and leukocyte-endothelial cell interactions.⁵¹ It also protects the microcirculation by inhibiting leukocyte activation on endothelial cells by reducing expression of endothelial intercellular adhesion molecule 1 and vascular cell adhesion molecule as well as the surface expression of endothelial and leukocyte selectin adhesion. Micronized purified flavonoid fraction consists of 90% diosmin and 10% supplementary flavonoids, including hesperidin.¹⁹ It is free of any known major side-effects.^45,51

Double-blind clinical trials have demonstrated a significant improvement in the quality of life of patients with CVI.^45,52-54 However, the number of patients registered in these trials was small. One study only demonstrated a benefit on night cramps.⁵² A meta-analysis of 5 clinical trials found that MPFF accelerated the healing of leg ulcers.⁴⁵ Unfortunately, the most rigorously conducted study was not published and yielded negative results.⁵³ Therefore, this indication is not considered in the latest guidelines.⁵⁴ 

Coleridge-Smith et al⁴⁵ identified 5 RCTs in a meta-analysis on the basis of inclusion criteria of VLUs of at least 3 months in duration, primary or secondary venous disease, confirmed venous disease by duplex ultrasound, and minimum of 30 mm Hg of compression, with the primary end point of meta-analysis documented VLU healing at 6 months. The meta-analysis included a total of 723 patients who used MPFF (Daflon 500 mg/day, 1000 mg/day) and compression. The treatment duration for Daflon 500 mg daily was between 2 months and 6 months. No benefit regarding healing was seen in VLUs of less than 6 months duration.⁴⁵ Larger ulcers of 6 to 12 months duration were found to benefit more from MPFF treatment. These ulcers tend to heal more slowly and hence the role of an adjunctive therapy is required more in such ulcers.^45,55 Another meta-analysis found a 37% increase in probability in healing VLUs with MPFF treatment.⁵⁶  Micronized purified flavonoid fraction also has value in reducing other clinical symptoms like pain, edema, and cramps as noted in a large study featuring 5000 patients.⁵⁷ Hence, MPFF has utility in treating venous ulcers of more than 6 months duration. Nair¹⁹ referenced RCTs exhibiting no benefit for ulcers with a duration less than 6 months as well. However, benefits were noted with ulcers greater than 6 months duration and treating symptoms.¹⁹ 

In a literature review by Bush et al,⁵⁸ 10 papers were selected out of 250 abstracts. Although their recommendation for the clinical use of MPFF reported beneficial outcomes without serious side effects, no specific reference to ulcer duration was made. Diosmiplex is the only available prescription formulation of MPFF currently available in the United States. The Working Group for CVD approved with the International European Society for Vascular Surgery in 2015 that MPFF can be used alone or in adjunctive therapy with compression for treatment of CVDs.⁵⁸ 

Flavonoids: red vine leaf extract AS 195
When orally administered, red vine leaf extract has been shown to have a protective effect on the venous intima.⁵⁹ It also acts as an anti-inflammatory, with prothrombotic inhibitory properties.⁵⁹ This venoactive drug has been reviewed and advocated for decades. Specifically, Antistax has shown a statistically and clinically significant improvement over placebo in patient-reported symptoms.⁵⁹ It is well-tolerated, safe, and does not have cross-medication interactions.⁵⁹ Although this drug has been on the market for years, there is still a lack of evidence in the treatment of VLUs.⁵⁹ 

Flavonoids: Vasculera
Vasculera (diosmin-based drug) is indicated for patients with chronic venous insufficiency. Vasculera is considered a medical food and not a drug.⁹ It has a proprietary alka4-complex that provides an alkaline environment; it is indicated for venous edema and VLUs.⁹ Vasculara has been indicated to reduce inflammation, improve vascular tone, and decrease tissue acidosis. It also has been shown to be effective in the treatment of postphlebitic syndrome and may reduce thrombotic complications.⁶⁰ Recent data have demonstrated decreased post sclerotherapy inflammation in rabbits.⁶⁰ In anecdotal reports, medical providers have had good results with prescribing Vasculara to patients when taken prior to a procedure and in the postoperative period. However, evidence for this practice is lacking. Vasculara is a generally safe product with very limited side effects and thus could be applied to a large patient population if clear benefit were documented.⁶⁰ To the authors’ knowledge, Vasculera has not been tested for VLU healing in RCTs, but given its similarity to diosmin-based flavonoids, it may yield a similar salutary benefit. Future trials are necessary to assess its efficacy in VLU healing with compression therapy.

Flavonoids: rutosides
Rutosides are indicated as an antiedematous agent in venous disorders and in proctology (hemorrhoids) and ophthalmology (retinopathy). Oxerutine is absorbed via topical application, and its action on cutaneous capillary fragility has been established.⁶¹ Studies have provided evidence of its influence on disturbances of capillary permeability, effects on erythrocyte deformation and aggregation, antiedematous actions, and inhibition of prostaglandin synthesis. Its diffusion and accumulation in the venous wall have been demonstrated.^62-67 Rutosides are flavonoids that originate from a variety of plant species (Sophora japonica L., Eucalyptus spp, Fagopyrum esculentum). Several small RCTs have evaluated rutosides in the treatment of VLUs. In an RCT of 55 patients treated with 1000 mg of rutoside and compression versus placebo with compression, at 12 weeks, healing of VLUs was seen in 52% of the active treatment group compared with 28% of the placebo group.⁶⁷ In another RCT of 107 patients treated with rutoside 500 mg twice daily with compression compared with compression alone, VLU healing at 6 weeks was found not to be significant at 18% versus 23%, respectively.⁶⁸ Rutosides do not appear to improve VLU healing.⁶⁸ Oxerutins and hydroxyethylrutosides are flavonoids that originate from a variety of plant species. They also have demonstrated hemodynamic and quality-of-life benefits in CVI.^57,69 However, high-quality evidence is lacking in cases of healing VLUs for oxerutins and rutosides. The same is the case with other flavonoids, such as catechins and epicatechins.⁵³ 

Flavonoids: ruscus
Extracts of ruscus (butcher’s broom) contain saponins and flavonoids. The exact composition of these extracts is not well understood. Venotonic and antiedematous actions have been well demonstrated in open and RCTs and are associated with a reduction of symptoms and improvement in quality of life for patients with CVD.^70-75 

Flavonoids: other plant extracts
Extracts of Ginkgo biloba contain terpenes and flavonoids.^76,77 Antagonists of platelet-activating factor, they have an action on platelet aggregation, blood viscosity, and edema. Extracts of Centella asiatica are believed to enhance collagen synthesis in connective tissue.^78-80 

Many other plants are used successfully in the treatment of symptoms of CVD. All of them contain flavonoids, among other active substances, including procyanidolic oligomers (anthocyanins in bilberry extracts, proanthocyanidins in white grape seeds, red vine [Vitis vinifera], and maritime pine [Pycnogenol]).^81-91 

Flavonoids: Pycnogenol (French maritime pine bark)
Pycnogenol is an herbal drug that has a higher safety profile and lower degree of sensitivity (adverse effects) compared with synthetic drugs, such as diosmin/hesperidin.⁹¹ The cost of a 1-month supply of Pycnogenol is equivalent to that of diosmin/hesperidin. Pycnogenol is easily accessible and may be prepared by a compounding pharmacy at lower costs.⁹¹ A longitudinal, prospective, RCT including 30 patients with venous ulcers indicated that the pine bark may be used as a novel adjunct to the many existing protocols for the management of patients with VLUs.⁹² The results suggested Pycnogenol had an adjuvant effect on the healing of venous ulcers equivalent to that of diosmin/hesperidin.⁹² 

Flavonoids: escin/horse chestnut extract
Horse chestnut seed extract is an herbal supplement that is extracted from the seeds of Aesculus hippocastanum L. and has the active component, escin. Escin inhibits the activity of hyaluronidase and the accumulation of leucocytes in patients with CVI. Horse chestnut seed extract is known to have benefits in reducing symptoms of pain, pruritus, and edema in patients with CVI. A meta-analysis demonstrated benefits of escin in reducing symptoms and edema in CVI, but no evidence, to the authors’ knowledge, exists to demonstrate efficacy in healing VLUs.⁹³ 

Flavonoids: cilostazol 
Cilostazol is a vasodilator and a phosphodiesterase-3 inhibitor. It has properties that inhibit platelets by increasing the levels of protein kinase A.¹⁹ This drug also has been used in the treatment of intermittent claudication.¹⁹ Currently, there is no good-quality evidence for recommending cilostazol in routine therapy of VLUs.⁹⁴

Fibrinolytic enhancers: stanozolol
Stanozolol, an anabolic steroid, has fibrinolytic activity, and reduces the level of tissue plasminogen activator inhibitor.^95,96 In vitro studies have demonstrated procollagenase synthesis enhancement in fibroblasts.⁹⁷ Studies have demonstrated the efficacy of clearing of fibrosis on therapy of lipodermatosclerosis by stanozolol in combination with compression.^98,99 However, studies have revealed undesirable outcomes on healing venous ulcers.^100,101 

In 1986, Layer et al¹⁰² compared the effects of oral stanozolol with placebo on the total healing time of venous ulcers; 75 patients were entered into the study, and, after 28 months of treatment, 65% in the stanozolol group had healed compared with 61.5% in the placebo group. No improvement was seen in the healing of VLUs when treated with oral stanozolol.¹⁰² Evidence does not support the use of stanozolol routinely in the treatment of VLUs. 

Fibrinolytic enhancers: oxandrolone
A case study presented oxandrolone as a therapeutic option for patients with stanozolol-responsive lipodermatosclerosis in whom hepatic toxicity develops.¹⁰³ The study focused on a patient with lipodermatosclerosis and hepatotoxicity who was treated with oxandrolone. Oxandrolone has shown to be beneficial in patients requiring anabolic support and promote beneficial clinical outcomes in catabolic conditions, including severe burn injury, trauma after major surgery, HIV-related muscle wasting, neuromuscular disorders, alcoholic hepatitis, and chronic disease or muscle wasting of unclear etiology.¹⁰⁴

Fibrinolytic enhancers: calcium dobesilate 
Calcium dobesilate decreases capillary permeability and blood viscosity and improves lymphatic drainage.¹⁰⁵ The antiedematous effect persists for about 2 months after treatment has stopped. Its effectiveness is enhanced by concomitant administration of rutosides.^105–111 A meta-analysis including more than 500 patients failed to show any edema-reducing symptoms or quality of life improvements in patients taking calcium dobesilate in comparison with placebo.¹¹² 

A randomized, double-blind, placebo-controlled trial assessed 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. A Cochrane review showed high-quality evidence suggesting no differences in quality of life for calcium dobesilate compared with placebo.⁵⁰ Another meta-analysis identified 3 RCTs, which demonstrated improvement in pain and other symptoms, more so with severe than mild disease.¹⁰⁷ 

Fibrinolytic enhancers: aspirin
Aspirin reduces prostaglandin-2 and thromboxane A2, which are involved in platelet aggregation as well as inhibiting the enzyme cyclooxygenase, thereby obstructing the synthesis of several potent stimulators of inflammation.¹¹³ In vivo studies suggest 300 mg of aspirin suppresses inflammatory markers, which may promote ulcer healing.¹¹⁴ Altered hemodynamics associated with venous hypertension cause dilation of the capillaries, thus resulting in edema. Vessel wall prostanoids linked to dilation may not be inhibited by low-dose aspirin but seemed to be inhibited by higher anti-inflammatory doses.¹¹⁵ 

Layton et al¹¹⁶ conducted 2 small RCTs in the United Kingdom. They found an oral daily administration of 300 mg of aspirin with compression decreased time-to-ulcer healing compared with placebo over a 4-month period¹¹⁶; 38% of the participants in the aspirin group reported complete healing compared with 0% in the placebo group. A reduction in wound size occurred in 52% of the aspirin group compared with 26% of the placebo group. However, this sample size was small, with 20 patients.¹¹⁶ The study identified potential benefits of taking aspirin as an adjunct to compression, however, neither the mechanism by which aspirin improved healing nor its effects on recurrence were investigated. 

In 2012, del Río Solá et al¹¹⁷ completed an RCT in which 51 patients were given daily administration of aspirin in addition to compression bandage over a 5-month period. They found there was little difference observed between the 2 groups, but the average time to healing was shorter in the treated group (12 weeks in the treated group vs. 22 weeks in the compression-only group). The average time for recurrence was longer in the aspirin group at 39 days compared with nearly 16 days in the compression-only group.¹¹⁷ The study by Layton et al¹¹⁶ is too small of a sample size and low quality to draw any definitive conclusions regarding the benefits and maltreatments of aspirin on the healing and recurrence of VLUs. The study done by del Río Solá et al¹¹⁷ provides limited data on 51 patients comparing aspirin and compression with a control group. No information was reported regarding the placebo in the control group. 

In 2017, Jull et al conducted the largest trial to study aspirin for VLUs in New Zealand.¹¹⁸ This study included 251 participants who were randomized to receive 150 mg of daily oral aspirin or placebo for up to 24 weeks adjunctively with compression therapy. The average time to healing was 77 days for the aspirin group and 69 days for the placebo group. The quality of life and adverse effects were similar between the 2 groups. Based on their findings, the researchers concluded that low-dose aspirin treatment for up to 24 weeks did not increase the time to healing, percentage of participants with healed ulcers, or change in ulcer area or health-related quality of life when used as an adjuvant to compression in people with VLUs.¹¹⁸

In 2018, Tilbrook et al¹¹⁹ reported that there was no evidence that aspirin was efficacious in hastening the healing of chronic VLUs after 27 randomized participants took either 300  mg of daily oral aspirin or placebo. 

A randomized double-blind, multicenter, placebo-controlled, clinical study protocol targeting the inflammatory process with aspirin was performed by Weller et al.¹²⁰ This protocol study can help determine whether 300 mg of oral doses of aspirin improve time to healing. This study included 268 patients treated with compression therapy and a placebo/aspirin for 24 weeks. The primary outcome was 12 weeks to healing, and the secondary outcomes were recurrence, wound pain, quality of life, and wellbeing. This study investigated the efficacy and safety of aspirin as an adjunct to compression therapy with a large cohort. The study was anticipated to be completed in December 2018; however, it has yet to be published.¹²⁰ 

To the authors’ knowledge, to date, the impact of aspirin on VLUs and evidence for its effectiveness on ulcer healing and recurrence in high-quality RCTs is lacking. Aspirin may not be effective in the treatment of VLUs unless dosage is increased more than 300 mg. However, if aspirin is proven to be an effective treatment, aspirin therapy as an adjunct to compression could make it an affordable preventive agent for people with VLUs.

Antibiotics: antimicrobials
A Cochrane review evaluated 5 RCTs (232 study patients) involving oral systemic antimicrobial therapy. No routine use of systemic antibiotics in the treatment of VLUs when there is no evidence of infection was concluded.¹²¹ 

Antibiotics: doxycycline
Doxycycline is known as an antibiotic; however, it is also known to inhibit proinflammatory cytokines. The pathogenesis of VLUs involve these proinflammatory cytokines, such as tumor necrosis factor-alpha and matrix metalloproteinases, and thus is therapeutic for VLUs.^122,123 A pilot study of oral doxycycline in combination with compression in 20 patients with VLUs concluded that doxycycline 100 mg twice daily had a median ulcer area reduction of 48%.¹²⁴ Doxycycline 100 mg also had a greater suppression of MMPs as opposed to doxycycline 20 mg daily.¹²⁴ Further studies are required to evaluate the therapeutic utility of doxycycline in healing of VLUs. There is no strong evidence to support routine antibiotic use in VLU therapy at this point in time.¹⁹ 

Antibiotics: levamisole
Levamisole is a drug used for roundworm infestation. It is ostensible to have an antibacterial action in wounds. An RCT of 59 patients analyzed the effect of levamisole in treating VLUs.¹²⁵ All ulcers in the treatment group had healed at 20 weeks as opposed to 76% healing in the placebo group.¹²⁵ Further studies are needed.

Antibiotics: cinnarizine 
Cinnarizine was developed as an antihistamine in the 1960s; however, it soon demonstrated that it had many other pharmacological activities.¹²⁶ It has been found to be a potent antagonist of vasoconstriction and has been used therapeutically to improve both peripheral and cerebral blood flow.^126,127 A study with a better design was carried out in 1970, in which 53 patients with leg ulcers were randomly assigned to either treatment with cinnarizine (50 mg 3x/day) or placebo.¹²⁸ Various defined concomitant therapies also were used. In total, 44 patients completed the trial; the time to healing in the cinnarizine group was found to be significantly shorter than in the placebo group (P = .023).¹²⁹ 

In 4 double-blind, placebo-controlled studies of patients with venous insufficiency, flunarizine, similar to cinnarizine with selective calcium entry blocker with calmodulin binding properties and histamine H1 blocking activity, was statistically significantly superior to placebo in improving symptomatology, reducing the circumference of swollen lower legs and ankles, and increasing the speed of healing of venous ulcers. No side effects were noted.¹³⁰ Further studies are warranted.

Antibiotics: naftazone
A venoconstrictor effect and lowering of serum beta-glucuronidase levels have been demonstrated following the administration of 30 mg per day of naftazone. This substance might act on both vessel wall permeability and abnormalities of endothelial cells seen in CVD.¹³¹ In a double-blind, placebo-controlled study, naftazone was more effective than placebo for the clinical improvement of women with primary uncomplicated symptomatic varicose veins.¹³² 

Antibiotics: benzarone
Several cases of severe hepatitis have been reported. Photosensitization may occur during treatment. Therefore, this drug should no longer be used.¹²⁸ 

Nutritional supplements
Nutritional supplements contain vegetal derivatives, mostly polyphenols, and antioxidants to relieve the symptoms of CVD.¹³¹ Dihydroergotamine and dihydroergocristine (rye ergot extract) are no longer used in CVD treatment.¹³³ 

Zinc and magnesium
Zinc is an essential trace metal that is necessary for some enzymes and hormones to function.¹⁹ Of the micronutrients, the crucial factors in wound healing are zinc and magnesium. Zinc is a cofactor for RNA and DNA polymerase, and, consequently, its deficiency diminishes wound strength and epithelialization. There is a lack of evidence in the treatment of VLUs, and its mechanism in healing VLUs is unknown. The alleged benefits include an anti-inflammatory effect on monocytes and macrophages. Research also has noted that people with zinc deficiency may show delayed wound healing as well as an increased possibility of wound infection.¹³⁴ A Cochrane review determined the effect of zinc sulfate orally in 183 patients across 6 RCTs; 4 of the 6 trials concerned venous ulcers. Compared with the placebo, zinc did not show any significant difference in the healing of VLUs.¹³⁵ 

Zinc is a component of Unna boots used for venous stasis ulcers. However, to the authors’ knowledge, there is no support that supplementation in patients improves wound healing.¹³⁶ Magnesium functions as a cofactor in enzymes required for protein and collagen synthesis. In addition, it is used in specific topical wound healing applications. As with zinc, its consumption as a supplement in the general clinical population lacks proven benefit.¹¹³ 

Diuretics
Use of low-dose diuretic (hydrochlorothiazide 25 mg–50 mg daily or furosemide 40  mg up to 3 times daily) for up to 1 week can be considered as initial treatment for patients with massive edema.¹³⁷ Patients should be monitored for volume depletion and electrolyte imbalance.¹³⁷

Chronic VLU healing remains a complex clinical problem and requires the intervention of skilled, but costly, multidisciplinary wound care teams. Recurrence is often an ongoing issue for people who experience venous ulcers. Additionally, with the number of people with VLUs expected to rise significantly in the coming decades, development of new, safe ways of healing and reducing recurrence are high priorities in health care research.¹ 

Pentoxifylline and MPFF are recommended adjuncts to compression therapy, but there are barriers to use, including frequency of dosing regimens, off-label use, cost, and the quality of evidence. Using the venous clinical severity score and CEAP classification can prove beneficial for wound care physicians. Daflon, flavonoid derivatives, and pentoxifylline have demonstrated clinical benefits in patients with C4 to C6 venous disease.¹³⁸ After evaluating the current literature, pharmacotherapy should be approached as a viable treatment option in the modern management of patients with CVI or VLUs. Earlier use of these agents when identified in C1 to C3 prophylactically or therapeutically could potentially mitigate symptoms and severity of the disease. Further studies are necessary to see how the discussed pharmacological agents may help physicians and allied professionals in managing VLUs as well as with symptoms of venous disease.

A study by Finlayson et al¹³⁹ identified 4 key risk factors for recurrence of venous ulcers: age, history of deep vein thrombosis, history of multiple previous leg ulcers, and total duration of the previous ulcer. Based on their cyclooxygenase proportion-hazards regression analysis, they found significant protective factors included elevating legs for 30 minutes a day and higher levels of physical activity and self-efficacy.¹³⁹

Perhaps with a holistic approach, compression therapy, pharmaceutical therapy, higher levels of patient efficacy, and physical activity, VLUs may be able to be treated efficiently and without recurrence. It takes a team approach. As a health care cohort, it takes a transdisciplinary approach to heal VLUs. That being said, the provider is cautioned to determine possible adverse effects of these drugs and assiduously weigh the risk-benefit ratio and act judiciously.

The limitations involved in this review revolve around the lack of homogeneity in high-quality data regarding VLUs. 

Several pharmacological drugs can be used in combination with compression therapy and healing values.This evidence-based summary supports drugs that have a benefit and facilitating healing, including MPFF, pentoxifylline, SDX, and mesoglycan. diosmin and pentoxifylline are available in the United States; SDX and mesoglycan are mainly used in Europe and South America. The evidence suggests use of pharmacological venotonic drugs in VLUs that have a duration between 6 and 12 months, for VLUs that are between 5 cm² and 10 cm², and with a VLU disease duration of less than 5 years. In the recently published Society for Vascular Surgery/ American Venous Forum VLU guidelines, pentoxifylline and MPFF pharmacologic drugs along with compression therapy are recommended for long-standing or large VLUs.¹⁴⁰The authors are basing their assessment on the current evidence evaluated, in which future studies are warranted.

Note: The authors would like to thank Barry University School of Podiatric Medicine for their continued support of medical research. Thank you to Brandon Kitchens, DPM, MBA, for his extensive research and tackling a topic that has not been reviewed in nearly a decade. A special thanks to Robert Snyder, DPM, MSc, MBA, CWSP, and Cherison Cuffy, DPM, CWSP, for their expertise in wound care management. 

Authors: Brandon P. Kitchens, DPM, MBA; Robert J. Snyder, DPM, MSc, MBA, CWSP; and Cherison A. Cuffy, DPM, CWSP

Affiliation: Barry University School of Podiatric Medicine, Miami Shores, FL

Correspondence: Brandon Kitchens, DPM, MBA, Barry University School of Podiatric Medicine, Podiatry, 11300 NE 2nd Avenue, Miami Shores, FL 33161; bpkitchens86@gmail.com

Disclosure: The authors disclose no financial or other conflicts of interest.