- Email: [email protected]
Pharmacologic treatment to improve venous leg ulcer healing
Pharmacologic treatment to improve venous leg ulcer healing Joseph D. Raffetto, MD,a,b,c Robert T. Eberhardt, MD,d,e Steven M. Dean, DO,f Daniela Ligi, PhD,g and Ferdinando Mannello, PhD,g Boston, Mass; Columbus, Ohio; and Urbino, Italy Pharmacologic treatment for venous leg ulcers (VLUs) is an adjuvant treatment to compression therapy. It encompasses a variety of plant-derived and synthetic compounds with properties that alter venous microcirculation, endothelial function, and leukocyte activity to promote VLU healing. These compounds are often referred to as venotonics or venoactive drugs but have also been referred to as edema-protective agents,
phlebotonics, vasoprotectors, phlebotropics, and venotropics. The exact mechanism of their ability to heal VLUs is not known; however, clinical trials support their efficacy. This evidence-based review assesses randomized clinical trials and meta-analyses with the objective of determining the effectiveness of venotonics to promote VLU healing. (J Vasc Surg: Venous and Lym Dis 2015;-:1-4.)
A number of pharmacologic agents have been used in the treatment of varied manifestations of chronic venous disease including venous leg ulcers (VLUs; Table). The most common classes of pharmacologic agents are the g-benzopyrones, which include flavonoids such as diosmin, micronized purified flavonoid fraction (MPFF, originates from Citrus spp [Daflon 500]; Servier, Suresnes, France), oxerutin, rutin, troxerutin, and rutosides; and saponins, such as horse chestnut seed extract (Aesculus hippocastanum, aescin, escin, b-escin) and ruscus extract.1-6 Diosmin has been suggested to decrease venous tissue inflammatory response, to increase lymph drainage, and to inhibit venous catechol-O-methyltransferase, which reduces the metabolism of norepinephrine and prolongs its venoconstrictor effects.7,8 MPFF is an edema-protecting agent that decreases the inflammatory cascade and leukocyte-endothelial cell interactions.9 MPFF 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 molecules.10 Some of the suggested mechanisms of the
venotonic action of escin include increasing endothelial cell permeability to calcium and release of vasoconstrictor prostanoids (such as prostaglandin F2a) and sensitization of the vein wall to the contractile effects of serotonin and histamine.3,11,12 Other drugs that have proved helpful in healing of VLU in randomized clinical trials (RCTs) are pentoxifylline and glycosaminoglycans (sulodexide [SDX] and mesoglycan). Other compounds tried in VLU treatment are calcium dobesilate, stanozolol, and maritime pine tree extract (Pycnogenol); however, these lack corroborative RCT evidence as well as effectiveness in VLU healing.13-15 In this evidence-based summary, only pharmacologic compounds that have been evaluated in RCTs and demonstrated effectiveness in healing of VLU as an adjuvant to compression therapy are reviewed. There are no recommended limits on the duration of treatment for the majority of venoactive drugs or the long-term effects of venotonic therapy; however, we include in each section the duration of drug treatment based on the trial protocol. In clinical practice, these drugs are likely to be used longer and to be titrated to effect as long as side effects are absent or minimized. It is also not known what the possible positive or negative effects are in the long-term use of these drugs. In addition, it is not advised to take venotonic drugs during pregnancy or while breastfeeding.6
From the Boston VA Health Care System, Vascular Surgery,a the Brigham and Women’s Hospital,b the Harvard Medical School,c the Cardiovascular Medicine, Boston Medical Center,d and the Boston University School of Medicine,e Boston; the Division of Cardiovascular Medicine, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbusf; and the Department of Biomolecular Sciences, Section of Clinical Biochemistry and Cell Biology, University “Carlo Bo”, Urbino.g Author conflict of interest: none. Correspondence: Joseph D. Raffetto, MD, VA Boston Health Care System, Surgery 112, 1400 VFW Pkwy, West Roxbury, MA 02132 (e-mail: [email protected]). The editors and reviewers of this article have no relevant financial relationships to disclose per the Journal policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. 2213-333X Published by Elsevier Inc. on behalf of the Society for Vascular Surgery. http://dx.doi.org/10.1016/j.jvsv.2015.10.002
FLAVONOIDS Flavonoids have been studied as an adjuvant to compression therapy in healing of VLU. Five RCTs were selected in a meta-analysis on the basis of inclusion criteria of VLU 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.10 The meta-analysis included a total of 723 patients who used MPFF (Daflon 500, 1000 mg/d) and compression. The treatment duration for Daflon 500 was between 2 months and 6 months. 1
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Table. Pharmacologic agents for the treatment of venous leg ulcer (VLU) RCTs of effectiveness in VLUa Venotonic agents MPFF (Daflon), diosmin Rutosides, hydroxyrutosides (Venoruton, Paroven) Horse chestnut seed extract, ruscus extract Maritime pine bark extract (Pycnogenol), grape seed extract, Ginkgo biloba, Centella asiatica Calcium dobesilate, benzarone, naftazone Hemorheologic agent Pentoxifylline Fibrinolytic agents SDX Mesoglycan Anabolic steroids (stanozolol, oxandrolone) Danazol Defibrotide
Yes10 No No No No Yes18-21 Yes14,26-28 Yes29 No No No
MPFF, Micronized purified flavonoid fraction; RCTs, randomized clinical trials; SDX, sulodexide. a Superscript numbers are references that support effectiveness in VLU healing.
Although no contraindications are listed from the manufacturer, trials excluded patients with renal or hepatic insufficiency. Two trials had placebo in addition to compression, whereas the other three trials evaluated compression plus MPFF vs compression alone. Ulcer characteristics included a mean VLU area of 10.4 cm2, mean duration of 19.6 months, average number of ulcerations at inclusion of 1.6, and average duration of VLU disease of 13.5 years. The primary end point of VLU healing at 6 months was evaluated in four trials (616 patients) and was 61.3% in the MPFF plus compression group vs 47.7% in the compression group, with a relative risk reduction (RRR) of 32% (95% confidence interval [CI], 3%-70%) in favor of MPFF. When all five trials (N ¼ 723 patients) were assessed (one trial evaluated healing at 2 months), the probability for ulcer healing in the MPFF group compared with the controls was 44% (95% CI, 7%-94%; P ¼ .015). Ulcer area and duration were also assessed in subset analysis. Ulcers between 5 and 10 cm2 (n ¼ 146) had a 40% better chance of healing with MPFF (RRR, 40%; 95% CI, 6%-87%; P ¼ .019). No heterogeneity was found in the subgroup. With regard to ulcer duration, for VLUs present between 6 and 12 months (n ¼ 136), the RRR of healing with MPFF was 44% (95% CI, 6%-97%), and the studies were homogeneous. Finally, in patients with VLU disease of <5 years, the chance of healing their ulcer at month 6 was better in the MPFF group (RRR, 36%; 95% CI, 12%-67%).10 The main side effects of flavonoids are gastrointestinal disturbances, which can occur in 10% of patients.14 Although MPFF Daflon 500 in not approved by the Food and Drug Administration (FDA) in the United States, a recently FDA-approved diosmin-based drug called Vasculera is indicated for patients with chronic venous insufficiency. Vasculera is considered a medical food and not a drug, and it is generally recognized as safe under a food safety distinction at the FDA. It has a proprietary alka4-complex that provides an alkaline environment; it is
indicated for venous edema, skin changes, and VLU. Currently, 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 healing of VLU with compression therapy. RUTOSIDES Rutosides are flavonoids that originate from a variety of plant species (Sophora japonica L, Eucalyptus spp, Fagopyrum esculentum Moench). Several small RCTs have evaluated rutosides in the treatment of VLU. In an RCT of 55 patients treated with 1000 mg of rutoside vs placebo in addition to compression, healing of VLU was seen in 52% of the active treatment group compared with 28% of the placebo group at 12 weeks (P ¼ .087). In another RCT of 107 patients treated with rutoside 500 mg twice daily with compression vs compression alone, VLU healing at 6 weeks was found in 18% vs 23% (not significant), respectively.14 On the basis of these small trials, rutosides do not appear to improve VLU healing. HORSE CHESTNUT SEED EXTRACT Horse chestnut seed extract is known to have benefit in reducing symptoms of pain, pruritus, and edema in patients with chronic venous insufficiency.16 There are few studies that have evaluated the effect of horse chestnut seed extract and VLU healing. In a small placebo-controlled, blinded RCT of 57 patients randomized to horse chestnut seed extract with compression vs placebo with compression, there was no difference in VLU healing at 12 weeks of follow-up.17 PENTOXIFYLLINE Pentoxifylline 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
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deformability, reduced blood viscosity, and decreased platelet aggregation and thrombus formation. Pentoxifylline has been evaluated in 11 placebo-controlled RCTs, of which seven trials used compression therapy. Three important trials are discussed in a Cochrane review and summarized here. Patients with VLU were assessed in a three-arm multicenter double-blind placebo-controlled RCT of pentoxifylline 400 mg (n ¼ 41) or 800 mg (n ¼ 43) or placebo (n ¼ 45) three times per day in addition to compression bandaging. Patients were treated for up to 24 weeks, and the primary outcome was time to complete healing of all VLUs. Baseline characteristics were similar among the groups. Pentoxifylline accelerated complete healing of VLU over placebo. However, only patients receiving 800 mg of pentoxifylline three times per day healed significantly faster than with placebo (P ¼ .043). Gastrointestinal side effects were more common in the pentoxifylline groups.18 In another study consisting of VLU patients randomized to pentoxifylline 400 mg three times a day (n ¼ 82) vs placebo (n ¼ 78) along with compression, complete VLU healing at 6 months was assessed. Complete VLU healing was 67% in the pentoxifylline group and 30.7% in the placebo group (P < .02).19 Finally, another double-blind RCT comparing patients receiving pentoxifylline 400 mg three times a day (n ¼ 101) vs placebo (n ¼ 99), in addition to compression, assessed for the primary efficacy variable of complete healing of all ulcers on the reference leg by 24 weeks. Pentoxifylline healed 64% of VLUs, whereas placebo healed 53%; however, this did not reach statistical significance.20 In summary, the Cochrane review of all seven RCTs assessing pentoxifylline with compression combined the results from 659 participants using a random-effects model and found that VLU patients receiving pentoxifylline with compression were more likely to heal than those receiving placebo and compression (relative risk, 1.56; 95% CI, 1.14-2.13).21 Pentoxifylline is supported by other meta-analyses of RCTs and has clear benefit in healing of VLU. The drug metabolism is urinary; however, pentoxifylline has not been tested in patients with renal or hepatic impairment. The drug is FDA approved for intermittent claudication but used clinically for VLU and is available in the United States.14 GLYCOSAMINOGLYCANS SDX. SDX, a sulfated polysaccharide complex extracted from porcine intestinal mucosa, is composed of two glycosaminoglycans (80% of fast-moving heparin fraction and 20% of dermatan sulfate component) and is biologically active by both parenteral and oral routes.22 Several preclinical studies highlight SDX as an endothelial cell-protecting agent. The main properties are linked to (1) extensive absorption by the vascular endothelium, with an antithrombotic action similar to heparins but associated with lesser alterations of the blood clotting mechanisms; (2) prevention and restoration of integrity and permeability of endothelial cells; (3) regulation of endothelial-blood cell interactions; and (4) inhibition of microvascular inflammatory and proliferative changes.23-25 Four RCTs
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evaluating SDX with compression vs placebo with compression or compression alone, involving 488 VLU patients, demonstrated that oral SDX is more effective at increasing healing rates at 1 to 3 months.14 In one of the larger RCTs, patients were treated up to 70 days, and patients with renal or liver disease were excluded.26 SDX improved VLU healing ranging between 52% and 70% compared with placebo or compression alone, which healed only 32% to 35% of VLUs.26-28 Potential side effects of SDX include cutaneous rash, diarrhea, headache, and abdominal pain, which can occur in up to 19% of patients.14 SDX is not available or FDA approved in the United States. Mesoglycan. Mesoglycan, also a glycosaminoglycan mixture (composed by 52% heparan sulfate, 35% dermatan sulfate, 8% slow-moving heparin, and about 5% chondroitin sulfate),29,30 was evaluated in a multicenter doubleblind placebo-controlled RCT involving 18 outpatient Italian medical centers. There were 92 VLU patients in the mesoglycan group and 91 in the placebo group, with all patients undergoing weekly compression change; 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, there was healing of VLUs in 97% of the mesoglycan group and in 82% of the placebo group (P < .05), with the relative risk for healing favoring mesoglycan (1.43; 95% CI, 1.01-2.04; P < .05).29 Mesoglycan is not available or FDA approved in the United States. CONCLUSIONS Several pharmacologic drugs can be used in combination with compression therapy in healing of VLU. This evidence-based summary supports drugs that have a benefit in 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 pharmacologic venotonic drugs in VLUs that have a duration between 6 and 12 months, for VLUs that are between 5 and 10 cm2, and with VLU disease duration of <5 years. The last subset recommendation is especially relevant for MPFF and diosmin-based drugs. 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.31 Future studies will be required to assess various pharmacologic venotonic agents in patients with VLUs and to assess quality of life, longer follow-up, recurrence rates, and cost-effectiveness. AUTHOR CONTRIBUTIONS Conception and design: JR, RE, SD, FM Analysis and interpretation: JR, RE, SD, DL, FM Data collection: JR Writing the article: JR, RE, SD, DL, FM
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Critical revision of the article: JR, RE, SD, DL, FM Final approval of the article: JR, RE, SD, DL, FM Statistical analysis: Not applicable Obtained funding: Not applicable Overall responsibility: JR REFERENCES 1. Frick RW. Three treatments for chronic venous insufficiency: escin, hydroxyethylrutoside, and Daflon. Angiology 2000;51:197-205. 2. Coleridge Smith PD. From skin disorders to venous leg ulcers: pathophysiology and efficacy of Daflon 500 mg in ulcer healing. Angiology 2003;54(Suppl 1):S45-50. 3. Sirtori CR. Aescin: pharmacology, pharmacokinetics and therapeutic profile. Pharmacol Res 2001;44:183-93. 4. Ramelet AA, Boisseau MR, Allegra C, Nicolaides A, Jaeger K, Carpentier P, et al. Veno-active drugs in the management of chronic venous disease. An international consensus statement: current medical position, prospective views and final resolution. Clin Hemorheol Microcirc 2005;33:309-19. 5. Gohel MS, Davies AH. Pharmacological agents in the treatment of venous disease: an update of the available evidence. Curr Vasc Pharmacol 2009;7:303-8. 6. Gohel MA, Davies AH. Pharmacological treatment in patients with C4, C5 and C6 venous disease. Phlebology 2010;25(Suppl 1):35-41. 7. Boudet C, Peyrin L. Comparative effect of tropolone and diosmin on venous COMT and sympathetic activity in rat. Arch Int Pharmacodyn Ther 1986;283:312-20. 8. Araujo D, Viana F, Osswald W. Diosmin therapy alters the in vitro metabolism of noradrenaline by the varicose human saphenous vein. Pharmacol Res 1991;24:253-6. 9. Katsenis K. Micronized purified flavonoid fraction (MPFF): a review of its pharmacological effects, therapeutic efficacy and benefits in the management of chronic venous insufficiency. Curr Vasc Pharmacol 2005;3:1-9. 10. Coleridge-Smith P, Lok C, Ramelet AA. Venous leg ulcer: a metaanalysis of adjunctive therapy with micronized purified flavonoid fraction. Eur J Vasc Endovasc Surg 2005;30:198-208. 11. Berti F, Omini C, Longiave D. The mode of action of aescin and the release of prostaglandins. Prostaglandins 1977;14:241-9. 12. Carrasco OF, Vidrio H. Endothelium protectant and contractile effects of the antivaricose principle escin in rat aorta. Vascul Pharmacol 2007;47:68-73. 13. Kaur C, Sarkar R, Kanwar AJ, Attri AK, Dabra AK, Kochhar S. An open trial of calcium dobesilate in patients with venous ulcers and stasis dermatitis. Int J Dermatol 2003;42:147-52. 14. Nelson EA. Venous leg ulcers. BMJ Clin Evid 2011;2011. 15. Belcaro G, Cesarone MR, Errichi BM, Ledda A, Di Renzo A, Stuard S, et al. Venous ulcers: microcirculatory improvement and faster healing with local use of Pycnogenol. Angiology 2005;56:699-705.
16. Pittler MH, Ernst E. Horse chestnut seed extract for chronic venous insufficiency. Cochrane Database Syst Rev 2012;11:CD003230. 17. Leach MJ, Pincombe J, Foster G. Clinical efficacy of horsechestnut seed extract in the treatment of venous ulceration. J Wound Care 2006;15:159-67. 18. Falanga V, Fujitani RM, Diaz C, Hunter G, Jorizzo J, Lawrence PF, et al. Systemic treatment of venous leg ulcers with high doses of pentoxifylline: efficacy in a randomized, placebo-controlled trial. Wound Repair Regen 1999;7:208-13. 19. Belcaro G, Cesarone MR, Nicolaides AN, De Sanctis MT, Incandela L, Geroulakos G. Treatment of venous ulcers with pentoxifylline: a 6month randomized, double-blind, placebo controlled trial. Angiology 2002;53(Suppl 1):S45-7. 20. Dale JJ, Ruckley CV, Harper DR, Gibson B, Nelson EA, Prescott RJ. Randomised, double blind placebo controlled trial of pentoxifylline in the treatment of venous leg ulcers. BMJ 1999;319:875-8. 21. Jull AB, Arroll B, Parag V, Waters J. Pentoxifylline for treating venous leg ulcers. Cochrane Database Syst Rev 2012;12:CD001733. 22. Andreozzi GM. Sulodexide in the treatment of chronic venous disease. Am J Cardiovasc Drugs 2012;12:73-81. 23. Coccheri S, Mannello F. Development and use of sulodexide in vascular diseases: implications for treatment. Drug Des Devel Ther 2013;8:49-65. 24. Mannello F, Ligi D, Raffetto JD. Glycosaminoglycan sulodexide modulates inflammatory pathways in chronic venous disease. Int Angiol 2014;33:236-42. 25. Mannello F, Ligi D, Canale M, Raffetto JD. Sulodexide downregulates the release of cytokines, chemokines, and leukocyte colony stimulating factors from human macrophages: role of glycosaminoglycans in inflammatory pathways of chronic venous disease. Curr Vasc Pharmacol 2014;12:173-85. 26. Coccheri S, Scondotto G, Agnelli G, Aloisi D, Palazzini E, Zamboni V. Randomised, double blind, multicentre, placebo controlled study of sulodexide in the treatment of venous leg ulcers. Thromb Haemost 2002;87:947-52. 27. Scondotto G, Aloisi D, Ferrari P, Martini L. Treatment of venous leg ulcers with sulodexide. Angiology 1999;50:883-9. 28. Kucharzewski M, Franek A, Koziolek H. Treatment of venous leg ulcers with sulodexide. Phlebologie 2003;32:115-20. 29. Arosio E, Ferrari G, Santoro F, Gianese F, Coccheri S. A placebocontrolled, double blind study of mesoglycan in the treatment of chronic venous ulcers. Eur J Vasc Endovasc Surg 2001;22:365-72. 30. Zou YX, Feng X, Jing ZP. Efficacy and safety of sulodexide in the treatment of venous ulcers of leg. Pharm Care Res 2007;7:22-4. 31. O’Donnell TF Jr, Passman MA, Marston WA, Ennis WJ, Dalsing M, Kistner RL, et al; Society for Vascular Surgery; American Venous Forum. Management of venous leg ulcers: clinical practice guidelines of the Society for Vascular Surgery and the American Venous Forum. J Vasc Surg 2014;60(Suppl):3S-59S. Submitted Jun 12, 2015; accepted Oct 11, 2015.
phlebotonics, vasoprotectors, phlebotropics, and venotropics. The exact mechanism of their ability to heal VLUs is not known; however, clinical trials support their efficacy. This evidence-based review assesses randomized clinical trials and meta-analyses with the objective of determining the effectiveness of venotonics to promote VLU healing. (J Vasc Surg: Venous and Lym Dis 2015;-:1-4.)
A number of pharmacologic agents have been used in the treatment of varied manifestations of chronic venous disease including venous leg ulcers (VLUs; Table). The most common classes of pharmacologic agents are the g-benzopyrones, which include flavonoids such as diosmin, micronized purified flavonoid fraction (MPFF, originates from Citrus spp [Daflon 500]; Servier, Suresnes, France), oxerutin, rutin, troxerutin, and rutosides; and saponins, such as horse chestnut seed extract (Aesculus hippocastanum, aescin, escin, b-escin) and ruscus extract.1-6 Diosmin has been suggested to decrease venous tissue inflammatory response, to increase lymph drainage, and to inhibit venous catechol-O-methyltransferase, which reduces the metabolism of norepinephrine and prolongs its venoconstrictor effects.7,8 MPFF is an edema-protecting agent that decreases the inflammatory cascade and leukocyte-endothelial cell interactions.9 MPFF 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 molecules.10 Some of the suggested mechanisms of the
venotonic action of escin include increasing endothelial cell permeability to calcium and release of vasoconstrictor prostanoids (such as prostaglandin F2a) and sensitization of the vein wall to the contractile effects of serotonin and histamine.3,11,12 Other drugs that have proved helpful in healing of VLU in randomized clinical trials (RCTs) are pentoxifylline and glycosaminoglycans (sulodexide [SDX] and mesoglycan). Other compounds tried in VLU treatment are calcium dobesilate, stanozolol, and maritime pine tree extract (Pycnogenol); however, these lack corroborative RCT evidence as well as effectiveness in VLU healing.13-15 In this evidence-based summary, only pharmacologic compounds that have been evaluated in RCTs and demonstrated effectiveness in healing of VLU as an adjuvant to compression therapy are reviewed. There are no recommended limits on the duration of treatment for the majority of venoactive drugs or the long-term effects of venotonic therapy; however, we include in each section the duration of drug treatment based on the trial protocol. In clinical practice, these drugs are likely to be used longer and to be titrated to effect as long as side effects are absent or minimized. It is also not known what the possible positive or negative effects are in the long-term use of these drugs. In addition, it is not advised to take venotonic drugs during pregnancy or while breastfeeding.6
From the Boston VA Health Care System, Vascular Surgery,a the Brigham and Women’s Hospital,b the Harvard Medical School,c the Cardiovascular Medicine, Boston Medical Center,d and the Boston University School of Medicine,e Boston; the Division of Cardiovascular Medicine, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbusf; and the Department of Biomolecular Sciences, Section of Clinical Biochemistry and Cell Biology, University “Carlo Bo”, Urbino.g Author conflict of interest: none. Correspondence: Joseph D. Raffetto, MD, VA Boston Health Care System, Surgery 112, 1400 VFW Pkwy, West Roxbury, MA 02132 (e-mail: [email protected]). The editors and reviewers of this article have no relevant financial relationships to disclose per the Journal policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. 2213-333X Published by Elsevier Inc. on behalf of the Society for Vascular Surgery. http://dx.doi.org/10.1016/j.jvsv.2015.10.002
FLAVONOIDS Flavonoids have been studied as an adjuvant to compression therapy in healing of VLU. Five RCTs were selected in a meta-analysis on the basis of inclusion criteria of VLU 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.10 The meta-analysis included a total of 723 patients who used MPFF (Daflon 500, 1000 mg/d) and compression. The treatment duration for Daflon 500 was between 2 months and 6 months. 1
2 Raffetto et al
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Table. Pharmacologic agents for the treatment of venous leg ulcer (VLU) RCTs of effectiveness in VLUa Venotonic agents MPFF (Daflon), diosmin Rutosides, hydroxyrutosides (Venoruton, Paroven) Horse chestnut seed extract, ruscus extract Maritime pine bark extract (Pycnogenol), grape seed extract, Ginkgo biloba, Centella asiatica Calcium dobesilate, benzarone, naftazone Hemorheologic agent Pentoxifylline Fibrinolytic agents SDX Mesoglycan Anabolic steroids (stanozolol, oxandrolone) Danazol Defibrotide
Yes10 No No No No Yes18-21 Yes14,26-28 Yes29 No No No
MPFF, Micronized purified flavonoid fraction; RCTs, randomized clinical trials; SDX, sulodexide. a Superscript numbers are references that support effectiveness in VLU healing.
Although no contraindications are listed from the manufacturer, trials excluded patients with renal or hepatic insufficiency. Two trials had placebo in addition to compression, whereas the other three trials evaluated compression plus MPFF vs compression alone. Ulcer characteristics included a mean VLU area of 10.4 cm2, mean duration of 19.6 months, average number of ulcerations at inclusion of 1.6, and average duration of VLU disease of 13.5 years. The primary end point of VLU healing at 6 months was evaluated in four trials (616 patients) and was 61.3% in the MPFF plus compression group vs 47.7% in the compression group, with a relative risk reduction (RRR) of 32% (95% confidence interval [CI], 3%-70%) in favor of MPFF. When all five trials (N ¼ 723 patients) were assessed (one trial evaluated healing at 2 months), the probability for ulcer healing in the MPFF group compared with the controls was 44% (95% CI, 7%-94%; P ¼ .015). Ulcer area and duration were also assessed in subset analysis. Ulcers between 5 and 10 cm2 (n ¼ 146) had a 40% better chance of healing with MPFF (RRR, 40%; 95% CI, 6%-87%; P ¼ .019). No heterogeneity was found in the subgroup. With regard to ulcer duration, for VLUs present between 6 and 12 months (n ¼ 136), the RRR of healing with MPFF was 44% (95% CI, 6%-97%), and the studies were homogeneous. Finally, in patients with VLU disease of <5 years, the chance of healing their ulcer at month 6 was better in the MPFF group (RRR, 36%; 95% CI, 12%-67%).10 The main side effects of flavonoids are gastrointestinal disturbances, which can occur in 10% of patients.14 Although MPFF Daflon 500 in not approved by the Food and Drug Administration (FDA) in the United States, a recently FDA-approved diosmin-based drug called Vasculera is indicated for patients with chronic venous insufficiency. Vasculera is considered a medical food and not a drug, and it is generally recognized as safe under a food safety distinction at the FDA. It has a proprietary alka4-complex that provides an alkaline environment; it is
indicated for venous edema, skin changes, and VLU. Currently, 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 healing of VLU with compression therapy. RUTOSIDES Rutosides are flavonoids that originate from a variety of plant species (Sophora japonica L, Eucalyptus spp, Fagopyrum esculentum Moench). Several small RCTs have evaluated rutosides in the treatment of VLU. In an RCT of 55 patients treated with 1000 mg of rutoside vs placebo in addition to compression, healing of VLU was seen in 52% of the active treatment group compared with 28% of the placebo group at 12 weeks (P ¼ .087). In another RCT of 107 patients treated with rutoside 500 mg twice daily with compression vs compression alone, VLU healing at 6 weeks was found in 18% vs 23% (not significant), respectively.14 On the basis of these small trials, rutosides do not appear to improve VLU healing. HORSE CHESTNUT SEED EXTRACT Horse chestnut seed extract is known to have benefit in reducing symptoms of pain, pruritus, and edema in patients with chronic venous insufficiency.16 There are few studies that have evaluated the effect of horse chestnut seed extract and VLU healing. In a small placebo-controlled, blinded RCT of 57 patients randomized to horse chestnut seed extract with compression vs placebo with compression, there was no difference in VLU healing at 12 weeks of follow-up.17 PENTOXIFYLLINE Pentoxifylline 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
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deformability, reduced blood viscosity, and decreased platelet aggregation and thrombus formation. Pentoxifylline has been evaluated in 11 placebo-controlled RCTs, of which seven trials used compression therapy. Three important trials are discussed in a Cochrane review and summarized here. Patients with VLU were assessed in a three-arm multicenter double-blind placebo-controlled RCT of pentoxifylline 400 mg (n ¼ 41) or 800 mg (n ¼ 43) or placebo (n ¼ 45) three times per day in addition to compression bandaging. Patients were treated for up to 24 weeks, and the primary outcome was time to complete healing of all VLUs. Baseline characteristics were similar among the groups. Pentoxifylline accelerated complete healing of VLU over placebo. However, only patients receiving 800 mg of pentoxifylline three times per day healed significantly faster than with placebo (P ¼ .043). Gastrointestinal side effects were more common in the pentoxifylline groups.18 In another study consisting of VLU patients randomized to pentoxifylline 400 mg three times a day (n ¼ 82) vs placebo (n ¼ 78) along with compression, complete VLU healing at 6 months was assessed. Complete VLU healing was 67% in the pentoxifylline group and 30.7% in the placebo group (P < .02).19 Finally, another double-blind RCT comparing patients receiving pentoxifylline 400 mg three times a day (n ¼ 101) vs placebo (n ¼ 99), in addition to compression, assessed for the primary efficacy variable of complete healing of all ulcers on the reference leg by 24 weeks. Pentoxifylline healed 64% of VLUs, whereas placebo healed 53%; however, this did not reach statistical significance.20 In summary, the Cochrane review of all seven RCTs assessing pentoxifylline with compression combined the results from 659 participants using a random-effects model and found that VLU patients receiving pentoxifylline with compression were more likely to heal than those receiving placebo and compression (relative risk, 1.56; 95% CI, 1.14-2.13).21 Pentoxifylline is supported by other meta-analyses of RCTs and has clear benefit in healing of VLU. The drug metabolism is urinary; however, pentoxifylline has not been tested in patients with renal or hepatic impairment. The drug is FDA approved for intermittent claudication but used clinically for VLU and is available in the United States.14 GLYCOSAMINOGLYCANS SDX. SDX, a sulfated polysaccharide complex extracted from porcine intestinal mucosa, is composed of two glycosaminoglycans (80% of fast-moving heparin fraction and 20% of dermatan sulfate component) and is biologically active by both parenteral and oral routes.22 Several preclinical studies highlight SDX as an endothelial cell-protecting agent. The main properties are linked to (1) extensive absorption by the vascular endothelium, with an antithrombotic action similar to heparins but associated with lesser alterations of the blood clotting mechanisms; (2) prevention and restoration of integrity and permeability of endothelial cells; (3) regulation of endothelial-blood cell interactions; and (4) inhibition of microvascular inflammatory and proliferative changes.23-25 Four RCTs
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evaluating SDX with compression vs placebo with compression or compression alone, involving 488 VLU patients, demonstrated that oral SDX is more effective at increasing healing rates at 1 to 3 months.14 In one of the larger RCTs, patients were treated up to 70 days, and patients with renal or liver disease were excluded.26 SDX improved VLU healing ranging between 52% and 70% compared with placebo or compression alone, which healed only 32% to 35% of VLUs.26-28 Potential side effects of SDX include cutaneous rash, diarrhea, headache, and abdominal pain, which can occur in up to 19% of patients.14 SDX is not available or FDA approved in the United States. Mesoglycan. Mesoglycan, also a glycosaminoglycan mixture (composed by 52% heparan sulfate, 35% dermatan sulfate, 8% slow-moving heparin, and about 5% chondroitin sulfate),29,30 was evaluated in a multicenter doubleblind placebo-controlled RCT involving 18 outpatient Italian medical centers. There were 92 VLU patients in the mesoglycan group and 91 in the placebo group, with all patients undergoing weekly compression change; 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, there was healing of VLUs in 97% of the mesoglycan group and in 82% of the placebo group (P < .05), with the relative risk for healing favoring mesoglycan (1.43; 95% CI, 1.01-2.04; P < .05).29 Mesoglycan is not available or FDA approved in the United States. CONCLUSIONS Several pharmacologic drugs can be used in combination with compression therapy in healing of VLU. This evidence-based summary supports drugs that have a benefit in 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 pharmacologic venotonic drugs in VLUs that have a duration between 6 and 12 months, for VLUs that are between 5 and 10 cm2, and with VLU disease duration of <5 years. The last subset recommendation is especially relevant for MPFF and diosmin-based drugs. 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.31 Future studies will be required to assess various pharmacologic venotonic agents in patients with VLUs and to assess quality of life, longer follow-up, recurrence rates, and cost-effectiveness. AUTHOR CONTRIBUTIONS Conception and design: JR, RE, SD, FM Analysis and interpretation: JR, RE, SD, DL, FM Data collection: JR Writing the article: JR, RE, SD, DL, FM
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Critical revision of the article: JR, RE, SD, DL, FM Final approval of the article: JR, RE, SD, DL, FM Statistical analysis: Not applicable Obtained funding: Not applicable Overall responsibility: JR REFERENCES 1. Frick RW. Three treatments for chronic venous insufficiency: escin, hydroxyethylrutoside, and Daflon. Angiology 2000;51:197-205. 2. Coleridge Smith PD. From skin disorders to venous leg ulcers: pathophysiology and efficacy of Daflon 500 mg in ulcer healing. Angiology 2003;54(Suppl 1):S45-50. 3. Sirtori CR. Aescin: pharmacology, pharmacokinetics and therapeutic profile. Pharmacol Res 2001;44:183-93. 4. Ramelet AA, Boisseau MR, Allegra C, Nicolaides A, Jaeger K, Carpentier P, et al. Veno-active drugs in the management of chronic venous disease. An international consensus statement: current medical position, prospective views and final resolution. Clin Hemorheol Microcirc 2005;33:309-19. 5. Gohel MS, Davies AH. Pharmacological agents in the treatment of venous disease: an update of the available evidence. Curr Vasc Pharmacol 2009;7:303-8. 6. Gohel MA, Davies AH. Pharmacological treatment in patients with C4, C5 and C6 venous disease. Phlebology 2010;25(Suppl 1):35-41. 7. Boudet C, Peyrin L. Comparative effect of tropolone and diosmin on venous COMT and sympathetic activity in rat. Arch Int Pharmacodyn Ther 1986;283:312-20. 8. Araujo D, Viana F, Osswald W. Diosmin therapy alters the in vitro metabolism of noradrenaline by the varicose human saphenous vein. Pharmacol Res 1991;24:253-6. 9. Katsenis K. Micronized purified flavonoid fraction (MPFF): a review of its pharmacological effects, therapeutic efficacy and benefits in the management of chronic venous insufficiency. Curr Vasc Pharmacol 2005;3:1-9. 10. Coleridge-Smith P, Lok C, Ramelet AA. Venous leg ulcer: a metaanalysis of adjunctive therapy with micronized purified flavonoid fraction. Eur J Vasc Endovasc Surg 2005;30:198-208. 11. Berti F, Omini C, Longiave D. The mode of action of aescin and the release of prostaglandins. Prostaglandins 1977;14:241-9. 12. Carrasco OF, Vidrio H. Endothelium protectant and contractile effects of the antivaricose principle escin in rat aorta. Vascul Pharmacol 2007;47:68-73. 13. Kaur C, Sarkar R, Kanwar AJ, Attri AK, Dabra AK, Kochhar S. An open trial of calcium dobesilate in patients with venous ulcers and stasis dermatitis. Int J Dermatol 2003;42:147-52. 14. Nelson EA. Venous leg ulcers. BMJ Clin Evid 2011;2011. 15. Belcaro G, Cesarone MR, Errichi BM, Ledda A, Di Renzo A, Stuard S, et al. Venous ulcers: microcirculatory improvement and faster healing with local use of Pycnogenol. Angiology 2005;56:699-705.
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