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Phlebology OnlineFirst, published on June 1, 2015 as doi:10.1177/0268355515587194
Original Article
Pharmacological adjuncts for chronic venous ulcer healing: a systematic review
Phlebology 0(0) 1–10 ! The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0268355515587194 phl.sagepub.com
Lavanya Varatharajan, Ankur Thapar, Tristan Lane, Alex B Munster and Alun Huw Davies
Abstract Background: The aim of this study was to systematically review the current evidence and determine whether there is a clinical benefit for using pharmacological agents as adjunctive treatment for chronic venous ulcers. Method: A systematic review of the MEDLINE and EMBASE (from 1 January 1947 through 15 August 2013) and Cochrane databases (from inception through 15 August 2013) was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Inclusion criteria were all randomised controlled trials investigating pharmacological adjuncts for the treatment of venous ulcers with a minimum sample size of 20 patients for each treatment arm. Results: Ten relevant articles were identified; one pilot randomised controlled trial and four Cochrane reviews were included. Pentoxifylline, aspirin, sulodexide, mesoglycan, flavonoids, thromboxane A2 antagonist (ifetroban), zinc, prostaglandin and prostacyclin analogues were the drugs reviewed. Pentoxifylline was found to be more effective than placebo in terms of complete ulcer healing or in causing a significant improvement (greater than 60% reduction in ulcer size) (RR 1.70, 95% CI 1.30 to 2.24). Aspirin and flavonoids show potential to be effective adjuncts but methodological shortcomings and issues with bias limit the validity of results from trials involving each of these drugs, respectively. There was no significant difference between placebo and Ifetroban and likewise pooled results from trials investigating sulodexide and zinc showed no benefit in comparison to placebo. Conclusion: Many systemic pharmacological agents have been investigated as adjuncts to venous ulcer healing; however, pentoxifylline (400 mg, three times a day) is currently the only drug that has promising evidence to support its use. Other compounds are in early stage research.
Keywords Chronic venous ulcers, pharmacological adjuncts, pentoxifylline, aspirin
Introduction Chronic venous ulceration is defined as ‘a break in the skin below the knee that has not healed within two weeks’.1 It affects 1% of the adult population with an estimated economic burden in the UK of £300 million per year.2,3 These costs are amplified for ulcers refractory to treatment with approximately 1 to 2% of the NHS budget being spent on ulcers.4 The currently accepted theory is that venous hypertension results in venous valve deterioration, remodelling of the vessel wall and microcirculatory dysfunction via a common mechanism involving leukocyte–endothelium interaction.5,6 The persistently elevated venous pressure is thought to also cause tissue oedema by capillary transudation of fluid, promoting the deposition of protein molecules within the subcutaneous tissue, which impedes tissue oxygenation causing hypoxia of the overlying skin, culminating in ulceration.7
Although current management with four-layer compression bandaging results in approximately four months to heal 55% and one year to heal 78% of venous ulcers,8,9 its use is limited by a number of factors. Firstly, not all patients are candidates for compression due to concurrent arterial disease. Secondly, compliance remains an issue both because of difficulty in arranging nursing care and the discomfort when compression is applied or in hot weather.10 Finally, venous ulcer healing is slow and requires repetitive dressing changes.11,12 Based on 2001 prices, the cost
Academic Section of Vascular Surgery, Imperial College London, UK Corresponding author: Lavanya Varatharajan, Vascular Surgery Research Office, Charing Cross Hospital, 4 North, London W6 8RF, UK. Email: [email protected]
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of treating one ulcer was estimated to be £1,298–£1,526 per year in a trial conducted within a specialist leg ulcer clinic,13 compared to a median of £6,804 in 2012.11 Approximately 20,000 venous leg ulcers will not heal despite being treated with high compression therapy in the UK and the annual cost of treating these ulcers is estimated to be around £30 million (E46 million).14 Recent recommendations by the Scottish Intercollegiate Guidelines Network (SIGN) suggest that venous ulcers should be treated with cleansing and debridement if required, simple non-adherent dressings and routine use of high compression multicomponent bandaging. Consideration is given to systemic therapy with pentoxifylline 400 mg three times daily for up to six months.15 With such a high social and economic cost, any simple, safe pharmacological agent which could reduce time to healing by even a month would be useful. The aim of this study was to systematically review the current evidence and determine whether there is a clinical benefit for using pharmacological agents as an adjunctive treatment for chronic venous ulcers.
Methods The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines16 were used to conduct this systematic review. The MEDLINE and EMBASE databases were searched from 1 January 1947 to 15 August 2013 by two independent reviewers (LV, AM) to identify relevant randomised controlled trials (RCTs). The keyword search string used for both databases was ‘ulcer AND venous OR vein AND drug OR pharma* OR adjunct OR therapy OR aspirin OR pentoxifylline OR sucralfate OR oxerutins OR sulodexide OR mesoglycan OR iloprost OR prostaglandin OR flavonoids OR antibiotics OR rutosides OR stanozolol OR thromboxane alpha 2 antagonist OR zinc OR calcium dobesilate’. Additionally, the Cochrane Database of Systematic Reviews was searched from inception to 15 August 2013 with the combined term ‘venous ulcer’. All systematic reviews pertaining to the pharmacological management of venous ulcers were manually examined to identify further RCTs not retrieved by the initial electronic searches. Inclusion criteria were all RCTs investigating oral pharmacological adjuncts for the treatment of venous ulcers with a minimum sample size of 20 patients for each treatment arm. Exclusion criteria were duplicate publications, editorials, narrative reviews, case reports, abstracts, non-English language articles and studies where full text was not available (including from the author). No limits or filters were applied on publication status or date. The Cochrane Review Manager Version 5.2 was used for data analysis.17
Results Description of studies Ten relevant articles were identified: one pilot randomised controlled trial and three Cochrane reviews (Figure 1). Studies were excluded at the full-text stage for the following reasons: non-venous leg ulcers, narrative reviews, duplicate publications, trials that were not RCTs, RCTs unrelated to research question, RCTs investigating topical agents, antibiotics and antiseptics as adjuncts, RCTs with insufficient number of study participants and RCTs investigating the effect of drugs on ulcer recurrence. The pilot study investigating aspirin as adjunctive treatment for venous ulcers was excluded due to the small sample size in each group from which no reliable conclusions can be made regarding the effect of aspirin on venous ulceration healing.18,19
Methodological quality Two review authors independently assessed the risk of bias of the included studies using the guide by the Cochrane Handbook for Systematic Reviews of Interventions.20 Six specific domains are addressed: sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting and other bias. A risk of bias table was created for each eligible study. Any uncertainties regarding bias were discussed amongst all review authors to reach a consensus (Figures 2 to 4).
Pentoxifylline Pentoxifylline, a haemorrheological agent, is thought to alter the microcirculation by promoting leukocyte migration, reducing platelet aggregation and fibrinogen levels and decreasing plasma viscosity.21 The most recent Cochrane review assessing the efficacy of pentoxifylline for treating venous leg ulcers identified 12 randomised trials involving a total of 864 participants.22 Eleven trials compared pentoxifylline with placebo23–32 or no treatment33 and one trial compared pentoxifylline with the anticoagulant defibrotide.34 Despite the quality of the trials being variable (Figure 3) and the heterogeneity in sample populations,10 pentoxifylline was found to be more effective than placebo in terms of complete ulcer healing or in causing a significant improvement (greater than 60% reduction in ulcer size) (RR 1.70, 95% CI 1.30 to 2.24). Additionally, pentoxifylline plus compression was more effective than placebo plus compression (RR 1.56, 95% CI 1.14 to 2.13) and pentoxifylline in the absence of compression appeared to be more effective than no treatment at all (RR 2.25, 95% CI 1.49 to 3.39). The main
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Figure 1. PRISMA diagram of search on MEDLINE and EMBASE using search term string: ‘ulcer AND venous OR vein AND drug OR pharma* OR adjunct OR therapy OR aspirin OR pentoxifylline OR sucralfate OR oxerutins OR sulodexide OR mesoglycan OR iloprost OR prostaglandin OR flavonoids OR antibiotics OR rutosides OR stanozolol OR thromboxane alpha 2 antagonist OR zinc OR calcium dobesilate’.
side effects reported were gastrointestinal disturbances such as nausea, indigestion and diarrhoea (Table 1).22
Aspirin The use of acetylsalicylic acid as an adjunct for the treatment of venous ulcers has been evaluated in one pilot study and one randomised controlled trial to date. The rationale behind these studies is attributed to the irreversible cyclooxygenase-mediated reduction in thromboxane A2 implicated in platelet aggregation.35 Ibbotson et al. investigated the effect of aspirin on haemostatic activity in 20 patients with venous ulcers
and proposed that aspirin could modify abnormalities in haemostatic factors found in patients with venous ulcers. Additionally, an increased rate of ulcer healing occurred in the aspirin-treated group at two and four months.19 Similar findings were reported in a recent randomised controlled trial, which included 51 patients treated with 300 mg aspirin daily versus standardised compression therapy. They found that there was a 46% reduction in healing time in patients receiving aspirin (p ¼ 0.032) and concluded that the use of daily aspirin shortens healing time. There were shortcomings, in the lack of placebo and information regarding blinding included in this study (Figure 2).36 Interestingly, in
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Figure 2. Risk of bias graph: review authors’ judgements about each methodological quality item for each included study.
multivariate analysis, aspirin was not an independent predictor for healing, with only ulcer size at baseline showing an effect. This is an important stratification variable for future randomised trials. Subsequent to these findings, the National Institute for Health Research (NIHR) has recently called for a randomised controlled pilot study for the use of adjunctive aspirin for venous ulcer healing to further explore these initial findings.
Sulodexide The antithrombotic and anti-fibrinolytic properties of sulodexide by factor Xa and thrombin inhibition make it a possible candidate in the treatment of chronic venous ulcers. Two RCTs have been completed investigating its effect. An Italian pilot study evaluated the efficacy of sulodexide in 94 patients with venous leg ulcers secondary to post-
Figure 3. Methodological quality summary: review authors’ judgements about each methodological quality item for each included study in the Cochrane review on pentoxifylline for treating venous leg ulcers. Reproduced with permission.22
thrombotic syndrome (mainly to deep venous thrombosis) and non-thrombotic venous ulceration. In this study, the patients were randomised to standardised therapy with or without sulodexide for 60 days. The primary endpoint was proportion of ulcers healed after two months of treatment and the secondary endpoint was mean healing times in the two study groups. The study found that after two months of treatment, a significantly higher proportion of patients had complete ulcer healing (58%) than standard treatment
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Figure 4. Methodological quality summary: review authors’ judgements about each methodological quality item for each included study in the Cochrane review on flavonoids for treating venous leg ulcers. Reproduced with permission.44
(36%) (p ¼ 0.03). Additionally, in the sulodexide group the time to ulcer healing was 72 days whereas in the control group it was 110 days (p ¼ 0.08).37 These findings were further confirmed by the Sulodexide Arterial Venous Italian Study (SUAVIS).
Two hundred and thirty patients enrolled in the ‘venous arm’ of the study were randomised to receive either sulodexide or placebo for three months. The primary endpoint was complete ulcer healing and ulcer area. A two-month healing rate of 35% was seen in patients on
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Table 1. Side effects and cost of drugs. Drug
Main side effects 22
Side effect incidence
Daily cost
72% Not stated
Pentoxifylline Aspirin
Gastrointestinal disturbance Not stated36
Sulodexide
Skin rash, diarrhoea, epigastric pain, itching and headache39 Skin rash, headache, pruritus, palpitations, congestive heart failure, orthostatic hypotension, episodes of fainting, superficial thrombophlebitis, bronchopneumoniaa40 Diarrhoea and vomiting (1 case), headache (2 cases), hypotension (1 case), and nausea (1 case)41 Skin changes, gastrointestinal disturbances (including diarrhoea) and hypertension44 No side effects reported54
Not stated
20p (E0.23/$0.30) 1p (E0.01/$0.02) Enteric coated aspirin 5p (E0.05/$0.10) Not in BNF
8%
£1.20 (E1.51/$1.92)
Total incidence: 11.36% (5/44)
Only nebuliser preparation in BNF
Not stated
Not in BNF
Not stated
Not in BNF
Constipation, Nausea and dizziness (3)
Not stated
£0.14 (E0.19/$0.21)
Mesoglycan
Prostaglandins and prostacyclin analogue Flavonoids
Thromboxane A2 antagonist (ifetroban) Zinc a
Adverse events were recorded irrespective of their presumed relationship to the study treatment.
sulodexide compared to 21% in the placebo arm (p < 0.018). A further improvement was noted after three months with healing rates of 52.5% versus 32.7% (p < 0.004) in the sulodexide and placebo arms, respectively. Furthermore, the time course of the reduction in ulcer area during treatment was faster with sulodexide. A caveat highlighted by the researchers is that the control arm treatment was non-standardised and allowed stretch elastic bandages, adhesive bandages, self-adherent bandages, zinc oxide bandages and fourlayer bandages.38 Pooled results from both these trials, however, have shown that sulodexide in comparison to placebo may not have beneficial effects as an adjunct to ulcer healing in addition to conventional therapy (RR 0.16 95% CI 0.06 to 0.26). The main adverse effects reported from the use of sulodexide were cutaneous rash, diarrhoea, epigastric pain and headache (Table 1).39
Mesoglycan Mesoglycan is a sulphate polysaccharide extracted from porcine intestinal mucosa and is composed of variable quantities of heparan sulphate, dermatan sulphate, electrophoretically slow-moving heparin and chondroitin sulphate. Various properties of mesoglycan such as its ability to reduce capillary permeability and inhibit neutrophil adhesion and activation suggest that
theoretically it may be a useful adjunct in the treatment of venous ulcers.40 In a study investigating the effect of mesoglycan as an adjunct for chronic venous ulcers, 183 patients with median ulcer area >3 cm2 were randomised to mesoglycan or placebo as an adjunct to compression therapy and topical wound care. Patients were observed until complete ulcer healing or for 168 days. The primary endpoint was time to healing of the target ulcer. The estimated time to heal 75% patients in the mesoglycan group was 90 days compared to 136 days in the placebo group. The cumulative rate of healing was 97% and 82% in the mesoglycan group and placebo group, respectively, by the end of observation (p < 0.05).40 This study had a large sample size and a low risk of bias for several domains of the Cochrane Risk of Bias Assessment Tool. Total adverse event incidence in the mesoglycan group was 8% compared to 7% in the placebo group (Table 1). There were two cases which required permanent treatment discontinuation due to intercurrent clinical events but otherwise mesoglycan treatment was tolerated by all of the other patients.40
Prostaglandins and prostacyclin analogue Based on the theory that hypoxia has a central role in the development of chronic venous ulcers, Milio et al.41
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investigated whether prostaglandin E1 (PGE-1) had beneficial effects on the treatment of venous ulcers via its anti-ischaemic properties. Eighty-seven patients with mean ulcer area >10 cm2 were randomised to the treatment or placebo group in association with compression and local therapy. The primary endpoint was the percentage of ulcers that had recovered at the end of the 120-day observation period. In the PGE-1 treated group, 100% of ulcers had healed in 100 days whereas in the placebo group 84% of ulcers had healed (p < 0.05). It demonstrated that PGE-1 reduces healing time in venous ulcers with an acceptable side effect profile and good tolerability. The adverse events incidence was 11.36% (5/44 patients) in the PGE-1 group and 4.65% (2/43 patients) in the placebo group (Table 1). One patient in the PGE-1 group had a serious event and had to discontinue treatment due to diarrhoea and vomiting.41 Iloprost, a prostacyclin analogue, has been shown to reduce the expression of leukocyte adhesion molecules, tumour necrosis factor alpha receptors and interleukin6 production in human monocytes, all of which have been implicated in the pathogenesis of venous ulcers. The use of iloprost as an adjunct to venous ulcer treatment was investigated in 98 patients with venous ulcers in a single-blinded randomised controlled trial. Fortyeight patients received iloprost in saline solution for three weeks and the placebo group received a venous infusion of saline solution in addition to local therapy and elastic compression. In the treatment group, all of the ulcers had healed after 90 days (p < 0.0001) whereas in the placebo group only 50% of ulcers had healed after 105 days (p < 0.0001) and only 84.09% of ulcers had healed by the end of the study (at 150 days). No adverse outcomes or side effects were reported in the study.42
Flavonoids Flavonoids are naturally occurring phlebotropic and vascular protective agents that protect the microcirculation from inflammatory processes and apoptosis. They have been shown to decrease the leukocyte– endothelial cell interaction by reducing the expression of some endothelial adhesion molecules.43 A recent Cochrane review44 investigated two flavonoid preparations, Micronised purified flavonoid fraction (MPFF 500 mg) and hydroxyethylrutosides (HR), for the treatment of venous leg ulcers. The review included nine studies involving 1075 participants. Five of these studies investigated MPFF45–49 and four investigated HR.44,50–52 A meta-analysis within this Cochrane review, assessing the effect of oral treatment with 1 g MPFF in addition to standard treatment on venous leg ulcer healing,
included five randomised controlled studies with 723 patients. With respect to the number of ulcers completely healed, pooling of the five trials showed a statistically significant effect in favour of MPFF (RR 1.36; 95% CI 1.07 to 1.74). However, the most rigorously conducted study,49 which showed no additional benefit with MPFF (RR 0.94%; 95% CI 0.73 to 1.22), had a low risk of bias and was an unpublished commercial trial, raising the possibility of publication bias in studies involving flavonoids.44 A statistically significant effect in favour of HR with regards to number of ulcers completely healed was demonstrated (RR 1.70; 95% CI 1.24 to 2.34) when results from three trials involving 279 participants were pooled, all at unclear risk of bias.44 Although the trials included in this review demonstrated that flavonoids have a beneficial effect in the treatment of venous ulcers, the authors have highlighted the caveat that all of the studies were poorly reported and had unclear risk of bias for randomisation, allocation concealment and blinding as well as attrition and publication bias, requiring the results to be interpreted with caution.44 In addition, one meta-analysis demonstrated the limited indication of MPFF in the treatment of venous ulcers as benefit was only found in the subgroup of ulcers between 5 and 10 cm2 as well as in patients with ulcers of 6 to 12 months duration making clinical benefit questionable.53 A well-designed independent trial is required.
Thromboxane A2 antagonist (ifetroban) The use of an orally active thromboxane A2 inhibitor and anti-inflammatory agent, ifetroban, as an adjunct to sustained graduated compression and hydrocolloid was investigated for the treatment of chronic venous ulcers. Fifty-five patients with an average index ulcer size of 13 cm2 and 81 patients with an average ulcer size of 12 cm2 were randomised to the ifetroban group and placebo group, respectively, for 12 weeks. Complete ulcer healing was achieved after 12 weeks in 55% of patients receiving ifetroban and in 54% of those taking placebo, an insignificant difference (p ¼ 0.93). No patients had significant reactions to the medications (Table 1).54
Zinc Zinc is an essential trace metal that is necessary for some enzymes and hormones to function. The exact mechanism of how zinc can promote wound healing is unknown but it is thought to have anti-inflammatory effects and those with zinc deficiency have demonstrated slower wound healing.55 A Cochrane review
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shows that pooling the results of four trials comparing oral zinc sulphate with placebo in people with venous ulcers showed no statistically significant difference between the two groups (RR 1.22, 95% CI 0.88 to 1.68).55
Discussion Amongst the many systemic pharmacological agents investigated as adjuncts to venous ulcer healing, currently pentoxifylline (400 mg, three times a day) is the only drug showing promise as an effective adjunct although its use for the management of chronic venous ulcers is currently unlicensed.15 In addition, pentoxiphylline has been used in the past for many vascular and cutaneous disorders;56 however, its current use is limited which raises the question as to why this is the case. Aspirin has shown early promise in a small randomised study and large confirmatory studies are awaited. Other compounds are in early stage research. This review summarised all the currently available evidence for the systemic compounds used as adjuncts to venous ulcer healing. However, it was limited by not including topical agents such as sucralfate and topical mesoglycan, as they have no direct effect on venous ulcer healing. The current monthly cost of treating venous ulcers is approximately £120,14 whereas the monthly cost of pentoxifylline treatment is approximately £6.57 A recent cost-effectiveness analysis of oral pentoxifylline compared with placebo as an adjunct to compression therapy in the treatment of chronic venous ulcers suggested a mean cost saving of £98.09 (95% CI 49.21 to 245.00) per QALY gained if pentoxifylline was used. However, this does not take into consideration the costs of adverse reactions. The primary implication of this review for clinicians is that, although there are a number of drugs mentioned in the literature as possible adjuncts for venous ulcer healing, systemic therapy with pentoxifylline is the only treatment to significantly advance the rate of ulcer healing with a favourable cost-effective profile. This warrants its use as the principal adjunctive agent in patients with chronic venous ulcers. Further RCTs into the beneficial effects of aspirin as an adjunct for venous ulcer healing is required.
What’s already known about this topic? Many drugs have been investigated for the treatment of venous ulcers, but the only drug with proven benefit for the treatment of chronic venous ulcers is Pentoxiphylline.
What does this study add? This review will provide an overview of current evidence from RCTs investigating pharmacological adjuncts for the treatment of venous ulcers. There are limited reviews in the literature that collectively analyse the available evidence. With such a high social and economic cost, any simple, safe pharmacological agent which could reduce time to healing by even a month would be useful. Conflict of interest None declared.
Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
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13. Iglesias CP, Nelson EA, Cullum N, et al. Economic analysis of VenUS I, a randomized trial of two bandages for treating venous leg ulcers. Br J Surg 2004; 91: 1300–1306. 14. Rippon M, Davies P, White R, et al. The economic impact of hard-to-heal leg ulcers. Wounds UK 2007; 3: 58. 15. Scottish Intercollegiate Guidelines Network (SIGN). Guideline 120: management of chronic venous leg ulcers 2010, www.sign.ac.uk/pdf/sign120.pdf. (2013, accessed 25 July 2013). 16. Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 2009; 339: b2535. 17. Review Manager (RevMan). [Computer program]. Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014. 18. Layton AM, Ibbotson SH, Davies JA, et al. Randomised trial of oral aspirin for chronic venous leg ulcers. Lancet 1994; 344: 164–165. 19. Ibbotson SH, Layton AM, Davies JA, et al. The effect of aspirin on haemostatic activity in the treatment of chronic venous leg ulceration. Br J Dermatol 1995; 132: 422–456. 20. Higgins J and Green S. Cochrane handbook for systematic reviews of interventions, 5.1. 0 (updated March 2011). The Cochrane collaboration 2011, www cochrane-handbook org (2015, accessed 29 April 2015). 21. Jull A, Waters J and Arroll B. Pentoxifylline for treatment of venous leg ulcers: a systematic review. Lancet 2002; 359: 1550–1554. 22. Jull AB, Arroll B, Parag V, et al. Pentoxifylline for treating venous leg ulcers. Cochrane Database Syst Rev 2012; 12: CD001733. 23. Weitgasser H. The use of pentoxifylline (Trental 400) in the treatment of leg ulcers: results of a double-blind trial. Pharmatherapeutica 1983; 2(suppl 1): 143–151. 24. Schu¨rman W and Eberhardt R. The efficacy of pentoxifylline added to topical and compression therapy in patients with varicose and postthrombotic leg ulcers [Wirksamkeit von Pentoxifyllin als Zusatz zu Kompressions– und Lokaltherapie bei Patienten mit Ulcus cruris varicosum/ postthromboticum]. Therapiewoche 1986; 36: 2343–2345. 25. Arenas R and Atoche C. Postthrombotic leg ulcers: safety and efficacy of treatment with pentoxifylline (doubleblind study in 30 patients). Dermatologia Rev Mexicana Segunda Epoca 1988; 32: 34–38. 26. Colgan MP, Dormandy JA, Jones PW, et al. Oxpentifylline treatment of venous ulcers of the leg. BMJ 1990; 300: 972–975. 27. Barbarino C. Pentoxifylline in the treatment of venous leg ulcers. Curr Med Res Opin 1992; 12: 547–551. 28. Pizarro I, Aburto EUI, Parra JA, et al. Venous leg ulcers: in search of the best treatment [ulceras venosas de las piernas : en busca del mejor tratamiento]. Rev Chil Cir 1996; 48: 453–460. 29. Herdy CDC, Thomaz JB, Souza SR, et al. Efficacy of pentoxifylline in the healing of venous leg ulcers: a clinical comparative study [acao da pentoxifilina na cicatrizacao das ulceras de estase: um estudo clinico–comparativo]. Arq Bras Med 1997; 71: 157–161.
30. Dale JJ, Ruckley CV, Harper DR, et al. Randomised, double blind placebo controlled trial of pentoxifylline in the treatment of venous leg ulcers. BMJ 1999; 319: 875–878. 31. Falanga V, Fujitani RM, Diaz C, 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: 208–213. 32. Belcaro G, Cesarone MR, Nicolaides AN, et al. Treatment of venous ulcers with pentoxifylline: a sixmonth randomized, double-blind, placebo controlled trial. Angiology 2002; 53(Suppl 1): S45–S47. 33. Nikolovska S, Pavlova L, Petrova N, et al. Pentoxifylline – efficient in the treatment of venous ulcers in the absence of compression? Acta Dermatovenerol Croat 2002; 10: 9–13. 34. Apollonio A and Angeletti R. Conservative treatment of venous leg ulcers (pentoxifylline vs defibrotide) [Terapia conservativa delle ulcere flebostatiche (confronto tra pentossifillina e defibrotide impiegati per via generale)]. G Ital Angiol 1992; 12: 151–156. 35. Cyrus T, Sung S, Zhao L, et al. Effect of low-dose aspirin on vascular inflammation, plaque stability, and atherogenesis in low-density lipoprotein receptor-deficient mice. Circulation 2002; 106: 1282–1287. 36. del Rio Sola ML, Antonio J, Fajardo G, et al. Influence of aspirin therapy in the ulcer associated with chronic venous insufficiency. Ann Vasc Surg 2012; 26: 620–629. 37. Scondotto G, Aloisi D, Ferrari P, et al. Treatment of venous leg ulcers with sulodexide. Angiology 1999; 50: 883–889. 38. Coccheri S, Scondotto G, Agnelli G, et al. Randomised, double blind, multicentre, placebo controlled study of sulodexide in the treatment of venous leg ulcers. Thromb Haemost 2002; 87: 947–952. 39. Andreozzi GM. Sulodexide in the treatment of chronic venous disease. Am J Cardiovasc Drugs 2012; 12: 73–81. 40. Arosio E, Ferrari G, Santoro L, et al. A placebo-controlled, double-blind study of mesoglycan in the treatment of chronic venous ulcers. Eur J Vasc Endovasc Surg 2001; 22: 365–372. 41. Milio G, Mina C, Cospite V, et al. Efficacy of the treatment with prostaglandin E-1 in venous ulcers of the lower limbs. J Vasc Surg 2005; 42: 304–308. 42. Ferrara F, Meli F, Raimondi F, et al. The treatment of venous leg ulcers – A new therapeutic use of Iloprost. Ann Surg 2007; 246: 860–865. 43. Lyseng-Williamson KA and Perry CM. Micronised purified flavonoid fraction: a review of its use in chronic venous insufficiency, venous ulcers and haemorrhoids. Drugs 2003; 63: 71–100. 44. Scallon C, Bell-Syer SE and Aziz Z. Flavonoids for treating venous leg ulcers. Cochrane Database Syst Rev 2013; 5: CD006477. 45. Guilhou JJ, Dereure O, Marzin L, et al. Efficacy of Daflon 500 mg in venous leg ulcer healing: a doubleblind, randomized, controlled versus placebo trial in 107 patients. Angiology 1997; 48: 77–85.
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46. Glin´ski W, Chodynicka B, Roszkiewicz J, et al. Beneficial augmentative effect of micronised purified flavonoid fraction (MPFF) on the healing of leg ulcers: a multicenter controlled study. Phlebology 1999; 14: 151–157. 47. Roztocil K, Stvrtinova V and Strejcek J. Efficacy of a sixmonth treatment with Daflon 500 mg in patients with venous leg ulcers associated with chronic venous insufficiency. Int Angiol 2003; 22: 24–31. 48. Saveljev VS, Pokrovsky AV, Kirienko AI, et al. Analysis report of an open, randomised, multicentre comparative study of efficiency and safety of detralex in complementary treatment of complications of chronic venous insufficiency of lower extremities (trophic ulcers). France: Lab Servier, 2002. 49. Zuccarelli F and Rieger H. Effect of daflonÕ 500 mg (2 tablets daily) on venous leg ulcers healing in 160 patients treated over a six-month period. A multicentre, doubleblind, randomised, controlled versus placebo, parallel group study (clinical report). France: Lab Servier, 2004, [unpublished data]. 50. Stegmann WAE, Deichmann B, Hubner K, et al. Therapeutic benefit of hydroxyethylrutosides (HR) in venous ulcer treatment. A controlled multicentre study. Phlebology 1986; 617–20.
51. Schultz-Ehrenburg U and Muller B. Two multicentre clinical trials of two different dosages of O(B-Hydroxyethyl)-Rutosides in the treatment of leg ulcers. Phlebology 1993; 8(Suppl 1): 29–30. 52. Zuccarelli F, Taccoen A, Coget JM, et al. Treatment of venous ulcers with troxerutin: a randomised double- blind, controlled study. Int Angiol 1996; 15(Suppl 1–2): 53. 53. Coleridge-Smith P, Lok C and Ramelet AA. Venous leg ulcer: a meta-analysis of adjunctive therapy with micronized purified flavonoid fraction. Eur J Vasc Endovasc Surg 2005; 30: 198–208. 54. Lyon RT, Veith FJ, Bolton L, et al. Clinical benchmark for healing of chronic venous ulcers. Venous Ulcer Study Collaborators. Am J Surg 1998; 176: 172–175. 55. Wilkinson EA. Oral zinc for arterial and venous leg ulcers. Cochrane Database of Systematic Reviews 2014, Issue 9. Art. No.: CD001273. DOI: 10.1002/ 14651858.CD001273.pub3. 56. Kulcu Cakmak S, Cakmak A, Gonul M, et al. Pentoxifylline use in dermatology. Inflamm Allergy Drug Targets 2012; 11: 422–432. ([Bentham Science Publishers]). 57. British National Formulary (online). BMJ group and pharmaceutical press, www.medicinescomplete.com (2013, accessed 10 January 2013).
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Phlebology OnlineFirst, published on June 1, 2015 as doi:10.1177/0268355515587194
Original Article
Pharmacological adjuncts for chronic venous ulcer healing: a systematic review
Phlebology 0(0) 1–10 ! The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0268355515587194 phl.sagepub.com
Lavanya Varatharajan, Ankur Thapar, Tristan Lane, Alex B Munster and Alun Huw Davies
Abstract Background: The aim of this study was to systematically review the current evidence and determine whether there is a clinical benefit for using pharmacological agents as adjunctive treatment for chronic venous ulcers. Method: A systematic review of the MEDLINE and EMBASE (from 1 January 1947 through 15 August 2013) and Cochrane databases (from inception through 15 August 2013) was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Inclusion criteria were all randomised controlled trials investigating pharmacological adjuncts for the treatment of venous ulcers with a minimum sample size of 20 patients for each treatment arm. Results: Ten relevant articles were identified; one pilot randomised controlled trial and four Cochrane reviews were included. Pentoxifylline, aspirin, sulodexide, mesoglycan, flavonoids, thromboxane A2 antagonist (ifetroban), zinc, prostaglandin and prostacyclin analogues were the drugs reviewed. Pentoxifylline was found to be more effective than placebo in terms of complete ulcer healing or in causing a significant improvement (greater than 60% reduction in ulcer size) (RR 1.70, 95% CI 1.30 to 2.24). Aspirin and flavonoids show potential to be effective adjuncts but methodological shortcomings and issues with bias limit the validity of results from trials involving each of these drugs, respectively. There was no significant difference between placebo and Ifetroban and likewise pooled results from trials investigating sulodexide and zinc showed no benefit in comparison to placebo. Conclusion: Many systemic pharmacological agents have been investigated as adjuncts to venous ulcer healing; however, pentoxifylline (400 mg, three times a day) is currently the only drug that has promising evidence to support its use. Other compounds are in early stage research.
Keywords Chronic venous ulcers, pharmacological adjuncts, pentoxifylline, aspirin
Introduction Chronic venous ulceration is defined as ‘a break in the skin below the knee that has not healed within two weeks’.1 It affects 1% of the adult population with an estimated economic burden in the UK of £300 million per year.2,3 These costs are amplified for ulcers refractory to treatment with approximately 1 to 2% of the NHS budget being spent on ulcers.4 The currently accepted theory is that venous hypertension results in venous valve deterioration, remodelling of the vessel wall and microcirculatory dysfunction via a common mechanism involving leukocyte–endothelium interaction.5,6 The persistently elevated venous pressure is thought to also cause tissue oedema by capillary transudation of fluid, promoting the deposition of protein molecules within the subcutaneous tissue, which impedes tissue oxygenation causing hypoxia of the overlying skin, culminating in ulceration.7
Although current management with four-layer compression bandaging results in approximately four months to heal 55% and one year to heal 78% of venous ulcers,8,9 its use is limited by a number of factors. Firstly, not all patients are candidates for compression due to concurrent arterial disease. Secondly, compliance remains an issue both because of difficulty in arranging nursing care and the discomfort when compression is applied or in hot weather.10 Finally, venous ulcer healing is slow and requires repetitive dressing changes.11,12 Based on 2001 prices, the cost
Academic Section of Vascular Surgery, Imperial College London, UK Corresponding author: Lavanya Varatharajan, Vascular Surgery Research Office, Charing Cross Hospital, 4 North, London W6 8RF, UK. Email: [email protected]
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of treating one ulcer was estimated to be £1,298–£1,526 per year in a trial conducted within a specialist leg ulcer clinic,13 compared to a median of £6,804 in 2012.11 Approximately 20,000 venous leg ulcers will not heal despite being treated with high compression therapy in the UK and the annual cost of treating these ulcers is estimated to be around £30 million (E46 million).14 Recent recommendations by the Scottish Intercollegiate Guidelines Network (SIGN) suggest that venous ulcers should be treated with cleansing and debridement if required, simple non-adherent dressings and routine use of high compression multicomponent bandaging. Consideration is given to systemic therapy with pentoxifylline 400 mg three times daily for up to six months.15 With such a high social and economic cost, any simple, safe pharmacological agent which could reduce time to healing by even a month would be useful. The aim of this study was to systematically review the current evidence and determine whether there is a clinical benefit for using pharmacological agents as an adjunctive treatment for chronic venous ulcers.
Methods The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines16 were used to conduct this systematic review. The MEDLINE and EMBASE databases were searched from 1 January 1947 to 15 August 2013 by two independent reviewers (LV, AM) to identify relevant randomised controlled trials (RCTs). The keyword search string used for both databases was ‘ulcer AND venous OR vein AND drug OR pharma* OR adjunct OR therapy OR aspirin OR pentoxifylline OR sucralfate OR oxerutins OR sulodexide OR mesoglycan OR iloprost OR prostaglandin OR flavonoids OR antibiotics OR rutosides OR stanozolol OR thromboxane alpha 2 antagonist OR zinc OR calcium dobesilate’. Additionally, the Cochrane Database of Systematic Reviews was searched from inception to 15 August 2013 with the combined term ‘venous ulcer’. All systematic reviews pertaining to the pharmacological management of venous ulcers were manually examined to identify further RCTs not retrieved by the initial electronic searches. Inclusion criteria were all RCTs investigating oral pharmacological adjuncts for the treatment of venous ulcers with a minimum sample size of 20 patients for each treatment arm. Exclusion criteria were duplicate publications, editorials, narrative reviews, case reports, abstracts, non-English language articles and studies where full text was not available (including from the author). No limits or filters were applied on publication status or date. The Cochrane Review Manager Version 5.2 was used for data analysis.17
Results Description of studies Ten relevant articles were identified: one pilot randomised controlled trial and three Cochrane reviews (Figure 1). Studies were excluded at the full-text stage for the following reasons: non-venous leg ulcers, narrative reviews, duplicate publications, trials that were not RCTs, RCTs unrelated to research question, RCTs investigating topical agents, antibiotics and antiseptics as adjuncts, RCTs with insufficient number of study participants and RCTs investigating the effect of drugs on ulcer recurrence. The pilot study investigating aspirin as adjunctive treatment for venous ulcers was excluded due to the small sample size in each group from which no reliable conclusions can be made regarding the effect of aspirin on venous ulceration healing.18,19
Methodological quality Two review authors independently assessed the risk of bias of the included studies using the guide by the Cochrane Handbook for Systematic Reviews of Interventions.20 Six specific domains are addressed: sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting and other bias. A risk of bias table was created for each eligible study. Any uncertainties regarding bias were discussed amongst all review authors to reach a consensus (Figures 2 to 4).
Pentoxifylline Pentoxifylline, a haemorrheological agent, is thought to alter the microcirculation by promoting leukocyte migration, reducing platelet aggregation and fibrinogen levels and decreasing plasma viscosity.21 The most recent Cochrane review assessing the efficacy of pentoxifylline for treating venous leg ulcers identified 12 randomised trials involving a total of 864 participants.22 Eleven trials compared pentoxifylline with placebo23–32 or no treatment33 and one trial compared pentoxifylline with the anticoagulant defibrotide.34 Despite the quality of the trials being variable (Figure 3) and the heterogeneity in sample populations,10 pentoxifylline was found to be more effective than placebo in terms of complete ulcer healing or in causing a significant improvement (greater than 60% reduction in ulcer size) (RR 1.70, 95% CI 1.30 to 2.24). Additionally, pentoxifylline plus compression was more effective than placebo plus compression (RR 1.56, 95% CI 1.14 to 2.13) and pentoxifylline in the absence of compression appeared to be more effective than no treatment at all (RR 2.25, 95% CI 1.49 to 3.39). The main
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Figure 1. PRISMA diagram of search on MEDLINE and EMBASE using search term string: ‘ulcer AND venous OR vein AND drug OR pharma* OR adjunct OR therapy OR aspirin OR pentoxifylline OR sucralfate OR oxerutins OR sulodexide OR mesoglycan OR iloprost OR prostaglandin OR flavonoids OR antibiotics OR rutosides OR stanozolol OR thromboxane alpha 2 antagonist OR zinc OR calcium dobesilate’.
side effects reported were gastrointestinal disturbances such as nausea, indigestion and diarrhoea (Table 1).22
Aspirin The use of acetylsalicylic acid as an adjunct for the treatment of venous ulcers has been evaluated in one pilot study and one randomised controlled trial to date. The rationale behind these studies is attributed to the irreversible cyclooxygenase-mediated reduction in thromboxane A2 implicated in platelet aggregation.35 Ibbotson et al. investigated the effect of aspirin on haemostatic activity in 20 patients with venous ulcers
and proposed that aspirin could modify abnormalities in haemostatic factors found in patients with venous ulcers. Additionally, an increased rate of ulcer healing occurred in the aspirin-treated group at two and four months.19 Similar findings were reported in a recent randomised controlled trial, which included 51 patients treated with 300 mg aspirin daily versus standardised compression therapy. They found that there was a 46% reduction in healing time in patients receiving aspirin (p ¼ 0.032) and concluded that the use of daily aspirin shortens healing time. There were shortcomings, in the lack of placebo and information regarding blinding included in this study (Figure 2).36 Interestingly, in
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Figure 2. Risk of bias graph: review authors’ judgements about each methodological quality item for each included study.
multivariate analysis, aspirin was not an independent predictor for healing, with only ulcer size at baseline showing an effect. This is an important stratification variable for future randomised trials. Subsequent to these findings, the National Institute for Health Research (NIHR) has recently called for a randomised controlled pilot study for the use of adjunctive aspirin for venous ulcer healing to further explore these initial findings.
Sulodexide The antithrombotic and anti-fibrinolytic properties of sulodexide by factor Xa and thrombin inhibition make it a possible candidate in the treatment of chronic venous ulcers. Two RCTs have been completed investigating its effect. An Italian pilot study evaluated the efficacy of sulodexide in 94 patients with venous leg ulcers secondary to post-
Figure 3. Methodological quality summary: review authors’ judgements about each methodological quality item for each included study in the Cochrane review on pentoxifylline for treating venous leg ulcers. Reproduced with permission.22
thrombotic syndrome (mainly to deep venous thrombosis) and non-thrombotic venous ulceration. In this study, the patients were randomised to standardised therapy with or without sulodexide for 60 days. The primary endpoint was proportion of ulcers healed after two months of treatment and the secondary endpoint was mean healing times in the two study groups. The study found that after two months of treatment, a significantly higher proportion of patients had complete ulcer healing (58%) than standard treatment
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Figure 4. Methodological quality summary: review authors’ judgements about each methodological quality item for each included study in the Cochrane review on flavonoids for treating venous leg ulcers. Reproduced with permission.44
(36%) (p ¼ 0.03). Additionally, in the sulodexide group the time to ulcer healing was 72 days whereas in the control group it was 110 days (p ¼ 0.08).37 These findings were further confirmed by the Sulodexide Arterial Venous Italian Study (SUAVIS).
Two hundred and thirty patients enrolled in the ‘venous arm’ of the study were randomised to receive either sulodexide or placebo for three months. The primary endpoint was complete ulcer healing and ulcer area. A two-month healing rate of 35% was seen in patients on
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Table 1. Side effects and cost of drugs. Drug
Main side effects 22
Side effect incidence
Daily cost
72% Not stated
Pentoxifylline Aspirin
Gastrointestinal disturbance Not stated36
Sulodexide
Skin rash, diarrhoea, epigastric pain, itching and headache39 Skin rash, headache, pruritus, palpitations, congestive heart failure, orthostatic hypotension, episodes of fainting, superficial thrombophlebitis, bronchopneumoniaa40 Diarrhoea and vomiting (1 case), headache (2 cases), hypotension (1 case), and nausea (1 case)41 Skin changes, gastrointestinal disturbances (including diarrhoea) and hypertension44 No side effects reported54
Not stated
20p (E0.23/$0.30) 1p (E0.01/$0.02) Enteric coated aspirin 5p (E0.05/$0.10) Not in BNF
8%
£1.20 (E1.51/$1.92)
Total incidence: 11.36% (5/44)
Only nebuliser preparation in BNF
Not stated
Not in BNF
Not stated
Not in BNF
Constipation, Nausea and dizziness (3)
Not stated
£0.14 (E0.19/$0.21)
Mesoglycan
Prostaglandins and prostacyclin analogue Flavonoids
Thromboxane A2 antagonist (ifetroban) Zinc a
Adverse events were recorded irrespective of their presumed relationship to the study treatment.
sulodexide compared to 21% in the placebo arm (p < 0.018). A further improvement was noted after three months with healing rates of 52.5% versus 32.7% (p < 0.004) in the sulodexide and placebo arms, respectively. Furthermore, the time course of the reduction in ulcer area during treatment was faster with sulodexide. A caveat highlighted by the researchers is that the control arm treatment was non-standardised and allowed stretch elastic bandages, adhesive bandages, self-adherent bandages, zinc oxide bandages and fourlayer bandages.38 Pooled results from both these trials, however, have shown that sulodexide in comparison to placebo may not have beneficial effects as an adjunct to ulcer healing in addition to conventional therapy (RR 0.16 95% CI 0.06 to 0.26). The main adverse effects reported from the use of sulodexide were cutaneous rash, diarrhoea, epigastric pain and headache (Table 1).39
Mesoglycan Mesoglycan is a sulphate polysaccharide extracted from porcine intestinal mucosa and is composed of variable quantities of heparan sulphate, dermatan sulphate, electrophoretically slow-moving heparin and chondroitin sulphate. Various properties of mesoglycan such as its ability to reduce capillary permeability and inhibit neutrophil adhesion and activation suggest that
theoretically it may be a useful adjunct in the treatment of venous ulcers.40 In a study investigating the effect of mesoglycan as an adjunct for chronic venous ulcers, 183 patients with median ulcer area >3 cm2 were randomised to mesoglycan or placebo as an adjunct to compression therapy and topical wound care. Patients were observed until complete ulcer healing or for 168 days. The primary endpoint was time to healing of the target ulcer. The estimated time to heal 75% patients in the mesoglycan group was 90 days compared to 136 days in the placebo group. The cumulative rate of healing was 97% and 82% in the mesoglycan group and placebo group, respectively, by the end of observation (p < 0.05).40 This study had a large sample size and a low risk of bias for several domains of the Cochrane Risk of Bias Assessment Tool. Total adverse event incidence in the mesoglycan group was 8% compared to 7% in the placebo group (Table 1). There were two cases which required permanent treatment discontinuation due to intercurrent clinical events but otherwise mesoglycan treatment was tolerated by all of the other patients.40
Prostaglandins and prostacyclin analogue Based on the theory that hypoxia has a central role in the development of chronic venous ulcers, Milio et al.41
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investigated whether prostaglandin E1 (PGE-1) had beneficial effects on the treatment of venous ulcers via its anti-ischaemic properties. Eighty-seven patients with mean ulcer area >10 cm2 were randomised to the treatment or placebo group in association with compression and local therapy. The primary endpoint was the percentage of ulcers that had recovered at the end of the 120-day observation period. In the PGE-1 treated group, 100% of ulcers had healed in 100 days whereas in the placebo group 84% of ulcers had healed (p < 0.05). It demonstrated that PGE-1 reduces healing time in venous ulcers with an acceptable side effect profile and good tolerability. The adverse events incidence was 11.36% (5/44 patients) in the PGE-1 group and 4.65% (2/43 patients) in the placebo group (Table 1). One patient in the PGE-1 group had a serious event and had to discontinue treatment due to diarrhoea and vomiting.41 Iloprost, a prostacyclin analogue, has been shown to reduce the expression of leukocyte adhesion molecules, tumour necrosis factor alpha receptors and interleukin6 production in human monocytes, all of which have been implicated in the pathogenesis of venous ulcers. The use of iloprost as an adjunct to venous ulcer treatment was investigated in 98 patients with venous ulcers in a single-blinded randomised controlled trial. Fortyeight patients received iloprost in saline solution for three weeks and the placebo group received a venous infusion of saline solution in addition to local therapy and elastic compression. In the treatment group, all of the ulcers had healed after 90 days (p < 0.0001) whereas in the placebo group only 50% of ulcers had healed after 105 days (p < 0.0001) and only 84.09% of ulcers had healed by the end of the study (at 150 days). No adverse outcomes or side effects were reported in the study.42
Flavonoids Flavonoids are naturally occurring phlebotropic and vascular protective agents that protect the microcirculation from inflammatory processes and apoptosis. They have been shown to decrease the leukocyte– endothelial cell interaction by reducing the expression of some endothelial adhesion molecules.43 A recent Cochrane review44 investigated two flavonoid preparations, Micronised purified flavonoid fraction (MPFF 500 mg) and hydroxyethylrutosides (HR), for the treatment of venous leg ulcers. The review included nine studies involving 1075 participants. Five of these studies investigated MPFF45–49 and four investigated HR.44,50–52 A meta-analysis within this Cochrane review, assessing the effect of oral treatment with 1 g MPFF in addition to standard treatment on venous leg ulcer healing,
included five randomised controlled studies with 723 patients. With respect to the number of ulcers completely healed, pooling of the five trials showed a statistically significant effect in favour of MPFF (RR 1.36; 95% CI 1.07 to 1.74). However, the most rigorously conducted study,49 which showed no additional benefit with MPFF (RR 0.94%; 95% CI 0.73 to 1.22), had a low risk of bias and was an unpublished commercial trial, raising the possibility of publication bias in studies involving flavonoids.44 A statistically significant effect in favour of HR with regards to number of ulcers completely healed was demonstrated (RR 1.70; 95% CI 1.24 to 2.34) when results from three trials involving 279 participants were pooled, all at unclear risk of bias.44 Although the trials included in this review demonstrated that flavonoids have a beneficial effect in the treatment of venous ulcers, the authors have highlighted the caveat that all of the studies were poorly reported and had unclear risk of bias for randomisation, allocation concealment and blinding as well as attrition and publication bias, requiring the results to be interpreted with caution.44 In addition, one meta-analysis demonstrated the limited indication of MPFF in the treatment of venous ulcers as benefit was only found in the subgroup of ulcers between 5 and 10 cm2 as well as in patients with ulcers of 6 to 12 months duration making clinical benefit questionable.53 A well-designed independent trial is required.
Thromboxane A2 antagonist (ifetroban) The use of an orally active thromboxane A2 inhibitor and anti-inflammatory agent, ifetroban, as an adjunct to sustained graduated compression and hydrocolloid was investigated for the treatment of chronic venous ulcers. Fifty-five patients with an average index ulcer size of 13 cm2 and 81 patients with an average ulcer size of 12 cm2 were randomised to the ifetroban group and placebo group, respectively, for 12 weeks. Complete ulcer healing was achieved after 12 weeks in 55% of patients receiving ifetroban and in 54% of those taking placebo, an insignificant difference (p ¼ 0.93). No patients had significant reactions to the medications (Table 1).54
Zinc Zinc is an essential trace metal that is necessary for some enzymes and hormones to function. The exact mechanism of how zinc can promote wound healing is unknown but it is thought to have anti-inflammatory effects and those with zinc deficiency have demonstrated slower wound healing.55 A Cochrane review
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shows that pooling the results of four trials comparing oral zinc sulphate with placebo in people with venous ulcers showed no statistically significant difference between the two groups (RR 1.22, 95% CI 0.88 to 1.68).55
Discussion Amongst the many systemic pharmacological agents investigated as adjuncts to venous ulcer healing, currently pentoxifylline (400 mg, three times a day) is the only drug showing promise as an effective adjunct although its use for the management of chronic venous ulcers is currently unlicensed.15 In addition, pentoxiphylline has been used in the past for many vascular and cutaneous disorders;56 however, its current use is limited which raises the question as to why this is the case. Aspirin has shown early promise in a small randomised study and large confirmatory studies are awaited. Other compounds are in early stage research. This review summarised all the currently available evidence for the systemic compounds used as adjuncts to venous ulcer healing. However, it was limited by not including topical agents such as sucralfate and topical mesoglycan, as they have no direct effect on venous ulcer healing. The current monthly cost of treating venous ulcers is approximately £120,14 whereas the monthly cost of pentoxifylline treatment is approximately £6.57 A recent cost-effectiveness analysis of oral pentoxifylline compared with placebo as an adjunct to compression therapy in the treatment of chronic venous ulcers suggested a mean cost saving of £98.09 (95% CI 49.21 to 245.00) per QALY gained if pentoxifylline was used. However, this does not take into consideration the costs of adverse reactions. The primary implication of this review for clinicians is that, although there are a number of drugs mentioned in the literature as possible adjuncts for venous ulcer healing, systemic therapy with pentoxifylline is the only treatment to significantly advance the rate of ulcer healing with a favourable cost-effective profile. This warrants its use as the principal adjunctive agent in patients with chronic venous ulcers. Further RCTs into the beneficial effects of aspirin as an adjunct for venous ulcer healing is required.
What’s already known about this topic? Many drugs have been investigated for the treatment of venous ulcers, but the only drug with proven benefit for the treatment of chronic venous ulcers is Pentoxiphylline.
What does this study add? This review will provide an overview of current evidence from RCTs investigating pharmacological adjuncts for the treatment of venous ulcers. There are limited reviews in the literature that collectively analyse the available evidence. With such a high social and economic cost, any simple, safe pharmacological agent which could reduce time to healing by even a month would be useful. Conflict of interest None declared.
Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
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