Funding sources None.
Simvastatin as a novel therapeutic agent for venous ulcers: a randomized, double-blind, placebo-controlled trial
Article first published online: 19 MAY 2014
© 2014 British Association of Dermatologists
British Journal of Dermatology
Volume 170, Issue 5, pages 1151–1157, May 2014
How to Cite
Evangelista, M.T.P., Casintahan, M.F.A. and Villafuerte, L.L. (2014), Simvastatin as a novel therapeutic agent for venous ulcers: a randomized, double-blind, placebo-controlled trial. British Journal of Dermatology, 170: 1151–1157. doi: 10.1111/bjd.12883
Conflicts of interest None declared.
- Issue published online: 19 MAY 2014
- Article first published online: 19 MAY 2014
- Accepted manuscript online: 7 FEB 2014 12:10PM EST
- Manuscript Accepted: 3 FEB 2014
Although the standard treatment for venous ulcers is compression, drugs may be used as adjunctive therapy. Simvastatin has shown potential wound-healing properties; however, no studies have investigated its use in venous ulcers.
To assess the efficacy and safety of simvastatin in venous ulcer healing when combined with standard treatment for ulcers.
This was a randomized, double-blind, placebo-controlled trial. Outcome measures were the proportion of healed ulcers, healing time, total surface area healed and Dermatology Life Quality Index (DLQI) scores.
Sixty-six patients were randomized into two groups: a simvastatin (n = 32) and a control (n = 34) group. Among ulcers ≤ 5 cm, 100% were healed in the simvastatin group, and 50% were healed in the control group [relative risk (RR) 0·10, 95% confidence interval (CI) 0·0141–0·707]. The average healing times for ulcers ≤ 5 cm were 6·89 ± 0·78 weeks and 8·40 ± 1·13 weeks for the simvastatin and control groups, respectively (P < 0·001). Among ulcers > 5 cm, 67% closed in the simvastatin group, with a mean healing time of 9·17 ± 1·07 weeks. No ulcers of this size closed in the control group (RR 0·33, 95% CI 0·132–0·840). The simvastatin group had lower DLQI scores (P < 0·001) post-treatment. No adverse effects were documented.
Simvastatin 40 mg daily, in addition to standard wound care and compression, is associated with a significant improvement in healing rate and time, as well as an improved patient quality of life when compared with placebo in the management of venous ulcers.
Chronic venous insufficiency (CVI) causes various lower limb pathologies, such as stasis ulcers; oedema; and skin changes, such as lipodermatosclerosis. CVI is the cause of nearly 80% of lower leg ulcers. Venous ulcers are estimated to affect 1–1·5% of the adult population.
The overall prognosis of venous ulcers is generally poor, with recurrence rates exceeding 50%, and more than half of patients requiring a year of therapy. Venous ulceration reduces quality of life and imposes financial constraints. Although compression is still the undisputed standard of ulcer management, drug therapy may be considered where there is intolerance, contraindications, lack of compliance or as an adjunct to accelerate the healing process.
Statins are cholesterol-lowering drugs that may have pleiotropic effects that accelerate wound healing.[8-10] As most available data are based on animal studies, there have been no studies investigating the use of statins in the treatment of venous ulcers.
Drugs for venous ulceration address the hypoxia and chronic inflammation that are characteristic of these chronic wounds through venoactive or nonvenoactive effects. Based on animal models, statins counteract hypoxia through both venoactive[13-15] and nonvenoactive[16-19] properties, and address chronic inflammation through their potent immunomodulatory actions (Fig. 1).[20-22]
Statins may be superior to other existing systemic wound-healing agents because, in addition to the above-mentioned venoactive and nonvenoactive effects, statins may also induce epithelialization. This may be due to statin-induced regulation of farnesyl pyrophosphate (FPP) synthesis. FPP acts as an agonist for the glucocorticoid receptor, a known wound-healing inhibitor that represses keratin 6. By inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A reductase, statins inhibit FPP synthesis, thereby preventing repression of keratin 6 and promoting epithelialization. Statins have improved the healing time and quality of healed skin (increased elasticity and decreased fibrosis) in different animal models of acute wound and impaired diabetic healing.[18, 24] Moreover, emerging evidence suggests that statins may treat and prevent different infections,[18, 25, 26] and may decrease the rate of severe sepsis,[27, 28] which is essential as bacterial burden adds to the pathogenesis of nonhealing wounds.
Although rare, statins may induce side-effects, among which myopathy and liver problems are the most serious. Other important side-effects include cataracts and acute kidney failure. However, these problems are estimated to be uncommon, with cataracts affecting < 3% and other side-effects affecting < 1% of patients. Studies have shown that safety and tolerability profiles of statins were comparable with placebo – even in high-risk patients (women, older individuals and those with normal cholesterol levels).[30, 31]
The general objective of the study was to assess the efficacy and safety of simvastatin in venous ulcer healing. Specifically, we evaluated and compared the proportion of patients with healed venous ulcers, time to complete healing of ulcers, quality of life based on the Dermatology Life Quality Index (DLQI), effects on the lipid profile [total, high- (HDL) and low-density lipoprotein (LDL) cholesterol] and liver enzymes [serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT)], as well as adverse effects among patients in the simvastatin and placebo groups.
Materials and methods
Patients and study design
This study was a randomized, double-blind, placebo-controlled trial conducted at the Jose R. Reyes Memorial Medical Center Dermatology Outpatient Department from February 2012 to May 2013. The hospital's review board approved the trial protocol before the study was started. This clinical trial was conducted in compliance with good clinical practice and in accordance with the ethical principles of the Declaration of Helsinki.
Men or women aged 18–85 years, with single or multiple ulcers confirmed by duplex scan to be venous in origin, and who were willing to have elastic compression therapy, were recruited. The ulcers had to have been open for at least 3 months. In patients with multiple ulcers, the largest ulcer was chosen as the reference. Both normo- and hypercholesterolaemic patients were included. Women of childbearing age were advised to avoid becoming pregnant during the course of the study.
Exclusion criteria included the application or intake of antibiotics or any phlebotropic or venoactive drugs for at least 2 weeks before enrolment; large, circumferential ulcers (> 10 cm); grossly infected lesions needing oral or intravenous antibiotics and ancillary therapy; elevated liver enzymes or hepatic disease; renal pathology; myopathies; cataracts; compromised immune states; or any other major medical problems that the investigator deemed to increase the risk of adverse events with the intervention. Patients who were taking coumarin derivatives, digoxin, fibrates or high-dose niacin, ciclosporin, nefazodone, methotrexate, verapamil, diltiazem, angiotensin-converting enzyme inhibitors, systemic azole antifungals or systemic macrolide antibiotics; those who were pregnant or lactating; those with known or suspected drug abuse problems; alcoholics; or those who were unlikely to be amenable to follow-up were also excluded.
Written informed consent was obtained from all eligible patients prior to their inclusion in the study. Eligible patients were stratified according to ulcer size (≤ 5 cm and > 5 cm). This size stratification was used because venous ulcers > 5 cm have been shown to have slower closure rates than smaller wounds.
The simvastatin (40 mg) and placebo tablets – of the same size, colour and shape – were placed in identical 50-mL transparent bottles. The bottles were coded (A or B) by the pharmacist.
Randomization, treatment allocation and blinding
The statistician generated a list of random numbers using a table of random numbers. An assigned resident, who was blind to the codes, performed random allocation using the list, and dispensed the packaged bottles accordingly. The codes were disclosed to the investigators only at the end of the study.
All patients underwent standardized, local management of ulcers (wound cleansing with saline solution, saline compresses twice daily, compression therapy and leg elevation). Patients were instructed to take the simvastatin or placebo tablet once daily at bedtime for a maximum of 10 weeks (or less in the case of complete ulcer healing before the end of the 10-week treatment period). All participants were told to avoid drinking alcoholic beverages during the study.
All patients were evaluated by the same dermatologist, who was blinded to the codes, every 2 weeks until closure or a maximum of 10 weeks of therapy. The primary outcome measure of the study was the proportion of patients with complete healing in each group. Secondary outcome parameters included time to complete healing, percentage of surface area healed, effects on lipid and liver profiles, DLQI scores and the incidence of adverse effects.
Baseline ulcer diameter and surface area, total, HDL and LDL cholesterol, SGOT, SGPT, DLQI scores and pregnancy tests from women of childbearing potential were obtained prior to therapy. Digital photographs, DLQI scores and size of the ulcer surface area (using manual planimetry) were obtained every 2 weeks. Liver and lipid profiles were repeated after 1 month of treatment.
The study was stopped in patients who experienced adverse reactions to the test drug, worsening of the skin lesions or elevation of liver enzymes three times the upper limit, or if the patient became pregnant or voluntarily withdrew from the study. These patients were considered to be withdrawals from the study. Those who did not comply with the once-daily intake of the tablets, or those who used other medications, were also withdrawn from the study. Dropouts were defined as those who did not follow up within 2 weeks and whose outcome was unknown by the end of the study period.
The sample size was computed using a two-sample comparison of means based on a previous study of 30 patients given 40 mg daily of simvastatin. In accordance with the results of this study, the SD was estimated as 8·6. Using a two-sided α of 0·05 and a power of 0·8, our calculations indicated that 29 patients were needed in each study arm. We aimed to recruit 64 patients to allow for a 10% dropout rate.
Data processing and analysis
Descriptive analysis was performed using central tendency measures: means, SDs and proportions. The means and SDs of the outcome variables were calculated and compared. The two-sided Student's t-test was used to determine whether the demographic data gathered were homogeneous for both treatment groups, as well as to compare healing times, percentage surface area healed, DLQI scores, and the liver and lipid profiles of both groups. The Pearson χ2-test was used to compare the proportion of patients with complete ulcer healing between groups. Both available case and intention-to-treat analyses were done. Test results with P-values < 0·05 were considered to be statistically significant. Relative risk (RR), RR reduction (RRR), absolute risk reduction (ARR) and number needed to treat (NNT) were computed, and 95% confidence intervals (CIs) were determined.
Of the 85 participants screened, 66 met the entry criteria and were randomized to treatment (simvastatin, n = 32) and control (placebo, n = 34) groups (Fig. 2). Of these patients, five were considered to be dropouts owing to nonattendance at scheduled visits. There was no statistical difference in the number of dropouts between the two groups (P = 0·592). There were no withdrawals from the study. The baseline characteristics of the study population are summarized in Table 1. No statistically significant differences were noted between the two groups based on age, sex, presence of diabetes, duration of venous disease and ulcer, baseline ulcer diameter and surface area, proportion of ulcers > 5 cm, and baseline liver enzymes, lipid profiles and DLQI scores.
|Characteristic||Placebo (n = 34)||Simvastatin (n = 32)||P-value|
|Age (years) mean ± SD||55·97 ± 14·96||56·41 ± 15·35||NS|
|Sex, male/female, n||13/34||10/32||NS|
|Diabetes, n (%)||5 (15)||3 (9)||NS|
|Duration of venous disease (years) mean ± SD||8·95 ± 4·27||9·00 ± 3·57||NS|
|Duration of venous ulcer (years) mean ± SD||3·80 ± 2·51||3·93 ± 2·88||NS|
|Ulcer diameter (cm) mean ± SD||4·63 ± 2·05||4·98 ± 2·15||NS|
|Ulcer diameter > 5 cm, n (%)||10 (29)||12 (38)||NS|
|Ulcer surface area (cm2) mean ± SD||35·20 ± 21·91||37·20 ± 22·15||NS|
|Total cholesterol (mmol L−1), mean ± SD||4·79 ± 0·86||5·01 ± 1·11||NS|
|HDL cholesterol (mmol L−1), mean ± SD||1·01 ± 0·56||1·18 ± 0·49||NS|
|LDL cholesterol (mmol L−1), mean ± SD||2·88 ± 1·49||3·03 ± 1·13||NS|
|SGPT (U L−1) mean ± SD||22·51 ± 11·40||21·04 ± 11·63||NS|
|SGOT (U L−1) mean ± SD||27·29 ± 6·21||28·42 ± 5·80||NS|
|DLQI, mean ± SD||12·65 ± 3·11||13·34 ± 3·41||NS|
In the simvastatin group, 90% of patients had complete ulcer closure compared with 34% of patients in the control group (RR 0·158, 95% CI 0·053–0·474) (Table 2). Among patients with ulcers ≤ 5 cm, all the ulcers in patients in the simvastatin group healed, while in the control group only 50% of patients had closed ulcers (RR 0·10, 95% CI 0·0141–0·707). Healing times for ulcers ≤ 5 cm were 6·89 ± 0·78 weeks and 8·40 ± 1·13 weeks for the simvastatin and control groups, respectively (P = 0·001). Among patients with ulcers > 5 cm, 67% in the simvastatin group had closure, with a mean healing time of 9·17 ± 1·07 weeks. None of the ulcers of this size closed in patients in the control group (RR 0·33, 95% CI 0·132–0·840) (Table 3). In addition, the mean healed area of the ulcers was significantly higher (P = 0·030) in the simvastatin group (28·9 cm2) than in the control group (19·6 cm2).
|Total proportion healed, n (%)||11 (34)||26 (90)|
|Time to healing (weeks), mean ± SD||8·55 ± 1·13||7·53 ± 1·34|
|Ulcers ≤ 5 cm||Ulcers > 5 cm|
|Proportion healed, n (%)||Time to healing (weeks), mean ± SD||Proportion healed, n (%)||Time to healing (weeks), mean ± SD|
|Placebo||11 (50)||8·40 ± 1·13||0 (0)||NA|
|Simvastatin||20 (100)||6·89 ± 0·78||6 (67)||9·17 ± 1·07|
RRR computation revealed that simvastatin, in addition to standard wound care and compression, will improve venous ulcers 84% more (RRR 0·842, 95% CI 0·526–0·948) than compression alone. ARR was 0·55, favouring simvastatin (ARR = 0.553, 95% CI 0.317–0.708). NNT analysis revealed that two patients were required to be treated with simvastatin to demonstrate complete ulcer closure. (NNT = 2, 95% CI 1–3). Sensitivity case analysis (intention-to-treat analysis using worst case scenario) of all healed ulcers showed an RR of 0.304 (95% CI 0.141 – 0.655), which signifies that the main analysis (available case analysis) was robust
The patients whose ulcers did not close in the placebo and simvastatin groups had a longer duration of venous ulcers and larger surface areas than those whose ulcers closed. Although the patients with closed ulcers in the simvastatin group were significantly younger than those with open ulcers, the age of the patients was comparable in both open and closed ulcers of those in the placebo group (Table 4). The proportion of men and women, the presence of diabetes and the duration of CVI were not significantly different in patients with open and closed ulcers in both groups.
|Age (years), mean ± SD||Placebo||55·18 ± 14·48||56·35 ± 15·49||NS|
|Simvastatin||51·80 ± 14·18||72·86 ± 2·97||0·001|
|Diabetes, n (%)||Placebo||0 (0)||5 (22)||NS|
|Simvastatin||2 (8)||1 (14)||NS|
|Sex, male, n (%)||Placebo||4 (36)||9 (39)||NS|
|Simvastatin||8 (32)||2 (29)||NS|
|Duration of venous disease (years), mean ± SD||Placebo||7·00 ± 5·35||9·87 ± 3·40||NS|
|Simvastatin||8·64 ± 2·89||10·29 ± 5·47||NS|
|Duration of venous ulcer (years), mean ± SD||Placebo||2·40 ± 2·43||4·46 ± 2·31||0·025|
|Simvastatin||3·34 ± 2·32||6·04 ± 0·84||0·026|
|Ulcer surface area (cm2), mean ± SD||Placebo||12·16 ± 3·33||46·28 ± 17·93||< 0·001|
|Simvastatin||30·88 ± 20·96||59·86 ± 3·45||0·012|
Dermatology Life Quality Index
Patients in both groups demonstrated a decrease in DLQI scores from the baseline (Fig. 3). However, patients in the simvastatin group showed significantly lower (P < 0·001) post-treatment DLQI scores and a higher percentage reduction (P < 0·001) than those in the placebo group.
Lipid profile and liver enzymes
Patients in the simvastatin group had significantly lower post-treatment total and LDL cholesterol (P < 0·010), while post-treatment HDL cholesterol was significantly higher (P = 0·040). There were no significant differences in baseline and post-treatment SGPT or SGOT.
No adverse effects were documented.
Simvastatin was superior to placebo in the management of venous ulcers based on a higher proportion of healed ulcers, faster healing times and better quality-of-life indices. This may be explained by both venoactive[13-15] and nonvenoactive[16-28] properties (including an effect on epithelialization) being present in statins; compression alone will provide only venoactive control of the disease.
Patients in both groups revealed improvements in DLQI scores, but more significant decreases were seen in patients in the simvastatin group. This parallels the superior clinical improvement seen in the treatment group compared with the placebo group. This may also be explained by the inhibitory effect of statins on T helper (Th)1 cytokine production and release. Proinflammatory Th1 cytokines, such as tumour necrosis factor-α and interleukin-1, are linked to depression and chronic fatigue; inhibiting their production may lead to further decreases in DLQI scores.
In both the simvastatin and placebo groups, better healing outcomes were seen in patients who had ulcers of shorter duration and smaller surface area. These results are in accordance with studies that investigated the associations of different risk factors and complete ulcer healing, which determined that longer ulcer duration and larger baseline surface areas were poor prognosticators of healing, and that age, sex and the presence of diabetes did not seem to affect outcome.[34-36]
There were no adverse effects seen in patients in this study. The majority of patients in the simvastatin group had normal cholesterol levels. The efficacy and safety of using statins for patients with normal cholesterol has been documented in the Justification for the Use of Statins in Prevention: An Intervention (JUPITER) trial, which showed that myopathy, hepatic injury and cancer did not occur more frequently in healthy volunteers taking rosuvastatin 20 mg daily. An 8-week clinical trial of simvastatin 40 mg daily in healthy individuals demonstrated an increase of HDL of as much as 20% and a reduction in LDL of as much as 16%. These studies, in addition to our findings, show that the use of statins is not limited to patients with dyslipidaemia. Currently, there is no evidence that statin-induced low LDL cholesterol levels are harmful, and studies also suggest that the lower the LDL cholesterol level is, the higher the cardioprotective effect will be.[39, 40] Recent guidelines indicate that the ideal LDL level for those with no known risk factors for heart disease is < 130 mg dL−1 (3·4 mmol L−1), while for those with risk factors, the target LDL may be < 70–100 mg dL−1 (1·8–2·6 mmol L−1).
One limitation of this study is that we investigated only the use of simvastatin as active management for venous ulcers, and not for maintenance therapy or prevention once the ulcers had closed. Additionally, we did not investigate recurrence rates once simvastatin had been stopped. We recommend that the use of statins in the above-mentioned settings should be investigated in the future as there is evidence to suggest that inflammation is an aetiological factor in the development of venous valve dysfunction. The anti-inflammatory effects of statins may improve the venous pathology in CVI, preventing future ulcerations, which suggests that simvastatin could be used in both active and maintenance therapy – even for cases of CVI without ulceration. Finally, simvastatin was used only as an adjunct to compression, and not as monotherapy. Although a patient with venous ulceration was seen to have had an excellent response to simvastatin without compression (M. Evangelista and F. Abad-Casintahan, unpublished data), our institutional review board deemed it prudent to use it as an adjunct, as this is the first randomized controlled trial to investigate its use in venous ulcers.
In conclusion, simvastatin 40 mg daily, in addition to standard wound care and compression, is associated with a significant improvement in healing rate and time, as well as improved patient quality of life when compared with placebo in the management of venous ulcers.
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