Simvastatin Effects on Venous Ulcer Healing

  Venous ulcers (VU) are an often neglected condition of the lower limb, as patients may not recognize the weeping skin of venous dermatitis as a wound meriting treatment. Clinical use of evidence-based interventions is gradually increasing.

  Sustained graduated compression1 sufficient to reduce the edema associated with venous insufficiency is as necessary for the VU2 as continuous off-loading is for a diabetic foot ulcer.3 Though moist wound healing with hydrocolloid dressings has been confirmed to improve VU healing compared to primary gauze dressing rates in some systematic reviews,4,5 controversy is fueled by confusion between “moist”6and “modern”7 wound healing. Encouraging self-care interventions, such as leg elevation, walking, or exercise by individuals with venous insufficiency increased VU-free days during one 18 month study,8 and decreased recurrence in another study,9 underscoring importance of patient involvement in VU care. Here we review systemic10 and topical11 interventions to heal nonhealing VU and risk factors for nonhealing that can add to variability, thereby masking potential efficacy when studying or treating these troublesome wounds.

Laura Bolton, PhD
Adjunct Associate Professor
Department of Surgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ

  Reference: Evangelista M, Casintahan MF, Villafuerte LL. Simvastatin as a novel therapeutic agent for venous ulcers: a randomized, double-blind, placebo-controlled trial. Br J Dermatol. [Epub ahead of print February 7, 2014].

  Rationale: Simvastatin has shown potential wound healing properties, but has not been explored in VU.

  Objective: This randomized controlled trial (RCT) explored safety and efficacy of simvastatin used as adjunctive therapy with good standard of care including compression for venous ulcers.

  Methods: A dermatology outpatient clinic in Manila, Philippines, conducted a prospective, double-blind, placebo-controlled RCT of subjects willing to use elastic compression and who had 1 or more VU of at least 3 months duration. Venous insufficiency was confirmed by duplex scanning for subjects 18-85 years of age with normal or high blood cholesterol. Subjects who had 1 VU measuring < 10 cm in baseline diameter were stratified into subsets of < 5 cm or > 5 cm in diameter, and were randomly assigned to receive oral simvastatin 40 mg per day (n = 32) or a similar placebo (n = 34) at bedtime for up to 10 weeks. All subjects avoided drinking alcohol while participating in the study and received standard outpatient VU care including saline VU cleansing and saline gauze compresses twice daily, in addition to compression and leg elevation. The primary outcome was percent of VU healed at 10 weeks compared using Pearson’s chi squared test. Secondary outcomes included healing time analyzed separately for VU < 5 cm or > 5 cm diameter at baseline, using Kaplan-Meier survival analysis and log rank test for healing time analyses. Total surface area healed and dermatology life quality indices (DLQI) were compared at enrollment and at the end of the study. Intent-to-treat analyses used P < 0.05 for statistical significance.

  Results: The 2 groups were comparable at baseline on age, gender, presence of diabetes, venous disease and ulcer duration, baseline ulcer diameter and surface area, proportion of ulcers > 5 cm diameter, baseline liver enzymes, lipid profiles, and DLQIs. During up to 10 weeks of therapy, 26 (81%) of simvastatin-treated subjects and 13 (38%) of placebo-treated subjects healed (P < 0.05) in a mean of 7.53 weeks with simvastatin or 8.55 weeks with placebo. All 20 VU measuring < 5 cm in diameter and treated with simvastatin healed in a mean of 6.9 weeks, compared to 13 (46%) placebo-treated subjects that healed in a mean of 8.4 weeks (P < 0.001). For VU > 5 cm in diameter, none of the 10 placebo-treated subjects’ VU closed in 10 weeks, compared to 50% of the 12 simvastatin-treated subjects’ VU, which healed in a mean of 9.2 weeks. DLQI scores improved more for subjects receiving simvastatin (P = 0.0004). Simvastatin-treated study subjects who healed were younger (51 years of age) than those taking simvastatin who did not heal (72 years of age). Subjects in both groups were less likely to heal VU with longer duration or greater baseline area.

  Authors’ Conclusions: Taken by patients receiving good standard of care including compression, 40 mg daily of simvastatin improved VU healing rate and time, and subject quality of life, compared to those taking a placebo receiving the same standard of care.

  Reference: Lantis JC 2nd, Marston WA, Farber A, et al. The influence of patient and wound variables on healing of venous leg ulcers in a randomized controlled trial of growth-arrested allogeneic keratinocytes and fibroblasts. J Vasc Surg. 2013;58(2):433-439.

  Rationale: Venous ulcers are one of the most frequent chronic wounds, yet few topical therapies have proven effective.

  Objective: This analysis explored patient and wound variables presumed to influence healing outcomes in the context of a RCT exploring efficacy of growth-arrested neonatal dermal fibroblasts and keratinocytes delivered topically to VU via pump spray in a fibrin sealant-based matrix, with a foam secondary dressing and 4-layer compression bandaging.

  Methods: During a 2-week run-in period, subjects with duplex-confirmed venous insufficiency and a VU of 6-104 weeks duration and area 2-12 cm2 were treated with a primary cadexomer iodine dressing and 4-layer compression to exclude rapidly healing (> 0.349 cm2 area reduction) or infected VU, or those with uncontrolled edema. Twenty-eight North American ambulatory, private, hospital-based, or university-based wound clinics randomly assigned 206 people to receive a once-a-week treatment of either a spray pump application of fibrin sealant-based matrix (control, n = 50), or 0.5 x 106 (n = 46) or 5 x 106 cells (n = 43); or once-every-2-week application of 0. 5 x 106 cells/ml (n = 44) or 5 x 106 cells/ml (n=45). The cells delivered in the spray formulation were growth-arrested neonatal dermal fibroblasts and keratinocytes.

  All subjects received a foam cover dressing plus a 4-layer compression bandage. Treatment continued for up to 12 weeks. Percent healed at 12 weeks did not differ significantly among groups.12 Observed patterns of effects of patient and wound-related variables were evaluated using univariate and multivariate analyses of effects on complete wound healing at 12 weeks. A Cochran-Mantel-Haenzel test adjusted for pooled sites tested for treatment effects on proportions healed at 12 weeks. Multiple logistic regression applied Cox proportional hazards statistics to test strength of 12-week healing predictors at P < 0.05.

  Results: All subjects were free of infection at enrollment, with all groups comparable on patient or wound variables at baseline. Smaller wound area and shorter duration at baseline predicted healing in 12 weeks. No significant relationship was found between VU healing and debridement or total colony forming units of microorganisms per gram (CFU/g) of 4 mm biopsy tissue. Overall concentrations of bacteria associated with inhibited healing (ie, β-haemolytic streptococci, Morganella morganii, Pseudomonas spp, Enterococcus spp, Klebsella spp, Enterobacter spp, Escherichia coli) were similar between cell- and vehicle-treated groups; however, 92% of vehicle-treated wounds harboring a high ratio of inhibitory bacteria to noninhibitory bacteria remained open at the end of treatment, compared to 51% of cell-treated wounds similarly populated with inhibitory bacteria (P = 0.01). Wounds harboring increasing numbers > 104 CFU/g of these inhibitory species also had a longer duration (P < 0.001). Age, gender, race, diabetes, HbA1c, peripheral neuropathy, and serum prealbumin did not significantly affect healing in either treatment group.

  Authors’ Conclusions: Wound duration is a quantifiable surrogate for 1 or more undefined variables that can have a profound negative effect on VU healing. Cell therapy overcame the barriers to healing posed by harboring > 104 CFU/g of inhibitory bacterial species. Interventional trials may be more informative if they monitor effects of candidate barriers on healing efficacy to improve understanding of the basis for wound chronicity.

  Both studies confirm that larger or longer duration VUs are less likely to heal, independent of therapy applied. Findings of Lantis et al11 add important perspective to the promising results reported using simvastatin.10Venous ulcers associated with unresolved chronic edema or those harboring inhibitory microorganisms may require special attention to initiate healing before entering a clinical trial to avoid masking efficacy of interventions studied. Another helpful guide to healing VU in subjects with clotting disorders may be DNA, as we enter the age of patient-centered therapy. Careful evaluation of patients and nonhealing VU may alert clinicians to act early on nonhealing VU cues to address recognized risk factors for delayed VU healing (Table 1). This evidence-based patient-centered approach may improve healing outcomes during routine clinical care and/or help prepare subjects for RCTs to minimize error variability when testing safety and efficacy of VU interventions.