These articles have been accepted for publication in the British Journal of Dermatology and are currently being edited and typeset. Readers should note that articles published below have been fully refereed, but have not been through the copy-editing and proof correction process. WileyBlackwell and the British Association of Dermatologists cannot be held responsible for errors or consequences arising from the use of information contained in these articles; nor do the views and opinions expressed necessarily reflect those of Wiley-Blackwell or the British Association of Dermatologists This article is protected by copyright. All rights reserved. Accepted Date : 03-Feb-2014 Article type
: Therapeutics
Simvastatin as a novel therapeutic agent for venous ulcers: a randomized, double-blind, placebo-controlled trial Running head: Simvastatin_for_venous_ulcers Authors and institutions: M.T.P. Evangelista1, M.F.A. Casintahan2, L.L. Villafuerte2 1 Resident, Department of Dermatology, Jose R. Reyes Memorial Medical Center 2 Consultant staff, Department of Dermatology, Jose R. Reyes Memorial Medical Center Corresponding author: Mara Therese P. Evangelista, M.D. Jose R. Reyes Memorial Medical Center Department of Dermatology Rizal Avenue, Sta. Cruz, Manila, 1003 [email protected] +6329323975383 Sources of funding: none Conflicts of interest: none What’s already known in this topic: - The standard treatment for venous ulcers is compression therapy, but drugs may be used as adjunctive therapy to accelerate the healing process. - Statins are cholesterol-lowering drugs that may also have pleiotropic effects which accelerate wound-healing. However, supporting evidences for this is mainly from animal studies. - There are no previous studies investigating the use of statins for venous ulcers. What does this study add? - This is the first study investigating the use of statins (simvastatin 40mg/daily) in venous ulcer healing. - This randomized, double-blind, placebo-controlled trial showed that simvastatin, in addition to standard wound care and compression, is associated with a significant improvement in healing rate and healing time, as well and improved patient quality of life when compared to placebo in the management of venous ulcers. No adverse effects were documented in this study.
This article is protected by copyright. All rights reserved. ABSTRACT Background. 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 for venous ulcers. This study assessed the efficacy and safety of simvastatin in venous ulcer healing when combined with standard treatment for ulcers. Methodology. This was a randomized, double-blind, placebo-controlled trial. Outcome measures were proportion of healed ulcers, healing time, total surface area healed, and dermatology life quality indices (DLQI). Results. 66 patients were randomized, 32 in the simvastatin and 34 in the control group. Among ulcers ≤ 5 cm, 100% healed in the simvastatin group, while 46% healed in the control group (RR 0.11, 95% CI: 0.02 – 0.77). The average healing time for ulcers ≤ 5 cm was 6.89 ± 0.78 weeks and 8.40 ± 1.13 weeks for simvastatin and control groups, respectively (p value = 0.0001). Among ulcers > 5 cm, 50% 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 among the placebo group (RR 0.5, 95% CI: 0.28 – 0.88). The simvastatin group had lower DLQIs (p value = 0.0004) post-treatment. There were no documented adverse effects. Conclusion. Simvastatin 40mg/daily, in addition to standard wound care and compression, is associated with a significant improvement in healing rate and healing time, as well and improved patient quality of life when compared with placebo in the management of venous ulcers.
INTRODUCTION Chronic venous insufficiency (CVI) causes various lower limb pathologies such as stasis ulcers, edema and skin changes like lipodermatosclerosis.1 CVI is the cause of nearly 80% of lower-leg ulcers.2 Venous ulcers are estimated to affect 1% to 1.5% of the adult population. The overall prognosis of venous ulcers is generally poor, with recurrence rates exceeding 3 50%, and more than half of patients requiring a year of therapy.4 Venous ulceration reduces the quality of life and imposes financial constraints.5 Although compression is still the undisputable standard of ulcer management,6 drug therapy may be considered where there is intolerance, contraindications, lack of compliance or as an adjunct to accelerate the healing process.7 Statins are cholesterol-lowering drugs that may have pleiotropic effects which accelerate wound-healing.8-10 Since most available data are based on animal studies,11 there are no studies investigating the use of statins for venous ulcers. Drugs for venous ulceration address the hypoxia and chronic inflammation characteristic of these chronic wounds through venoactive or non-venoactive effects.12 Based on animal models, statins counteract hypoxia through both venoactive13-15 and non-venoactive16-19 properties, and address chronic inflammation through its potent immunomodulatory actions20-22 (Fig. 1). Statins may be superior to other existing systemic wound-healing agents because in addition to the abovementioned venoactive and non-venoactive 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 which represses Keratin 6.23 By inhibiting HMG-CoA reductase, statins inhibit FPP synthesis, thereby preventing repression of keratin 6, and promoting epithelialization. Statins have improved 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
This article is protected by copyright. All rights reserved. Moreover, emerging evidence suggests that statins may treat and prevent different infections,25-27 and may decrease the rate of severe sepsis,28,29 which is essential because bacterial burden adds to the pathogenesis of non-healing wounds.9 Although rare, statins may induce side effects, among which myopathy and liver problems represent the most serious. Other important side effects include cataracts and acute kidney failure. However, these problems were still estimated to be quite uncommon, with cataracts affecting less than 3% and other side effects less than 1%.30 Studies have shown that safety and tolerability profiles of statins were comparable to placebo even in high risk patients (women, older individuals and those with normal cholesterol levels).31,32 The general objective of the study was to assess the efficacy and safety of simvastatin in venous ulcer healing. Specifically, it evaluated and compared the proportion of patients with healed venous ulcers, time to complete healing of ulcers, quality of life based on Dermatology Life Quality Index (DLQI), effects on the lipid profile (total, high and low density lipoprotein cholesterol), liver enzymes (SGPT and SGPT), as well as adverse effects among the simvastatin and placebo groups.
METHODOLOGY 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 Institutional Review Board of the hospital approved the trial protocol prior to commencement. This clinical trial was conducted in compliance with Good Clinical Practice and in accordance with the ethical principles of the Declaration of Helsinki. Male or female patients aged 18 to 85 years old, with single or multiple ulcers that were confirmed by duplex scan to be venous in origin, and who were willing to have elastic compression therapy were recruited. The ulcers had to be open for at least 3 months. In patients with multiple ulcers, the largest ulcer was chosen as reference. Both normo- and hypercholesterolemic patients were included. Females of child bearing potential were advised to avoid being pregnant during the course of the research. Exclusion criteria included application or intake of antibiotics or any phlebotropic or venoactive drugs for at least 2 weeks before enrollment, 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 will increase the risk of adverse events with the intervention. Patients who were taking coumarin derivatives, digoxin, fibrates or high-dose niacin, cyclosporine, nefazodone, methotrexate, verapamil, diltiazem, ACE inhibitors, systemic azole antifungals or systemic macrolide antibiotics, those who were pregnant or lactating, those with known or strong suspicion of significant drug abuse, alcoholism, 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 size (≤ 5 cm and > 5 cm). This size stratification was used because venous ulcers > 5cm have been shown to have slower closure rates than smaller wounds. Materials The simvastatin (40mg/tab) and placebo tablets of the same size, color and shape were placed in identical 50 mL transparent bottles. The bottles were coded (A or B) by the pharmacist.
This article is protected by copyright. All rights reserved. Randomization, treatment allocation, and blinding The statistician generated a list of random numbers using the 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 only disclosed to the investigators at the end of the study. Study intervention 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 ten weeks, or less in case of complete ulcer healing before the end of the ten-week treatment period. All participants were told to avoid drinking alcoholic beverages during the study. Clinical assessment All patients were evaluated by the same dermatologist who was blinded to the codes every two weeks until closure or a maximum of ten 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, high density lipoprotein (HDL) and low density lipoprotein (LDL) cholesterol, serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), DLQI scores and pregnancy tests from female patients with childbearing potential were obtained prior to therapy. Digital photographs, DLQI scores and ulcer surface area (using manual planimetry) were obtained every two weeks. Liver and lipid profiles were repeated after one month of treatment. Stopping guidelines The study was stopped in patients who experienced adverse reactions to the test drug, worsening of the skin lesions, elevation of liver enzymes thrice the upper limit, if the patient became pregnant, or if the patient voluntarily withdrew from the study. These patients were considered as withdrawals from the study. Those who did not comply to 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 two weeks and whose outcome was unknown by the end of the study period. Sample size The sample size was computed using a two-sample comparison of means based on a previous study of thirty patients given 40mg/daily of simvastatin.33 In accordance with the results of this study, standard deviation was estimated at 8.6. Using a two-sided alpha of 0.05 and a power of 0.8, calculations indicated that 29 patients in each study arm were needed. 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, standard deviations and proportions. The means and standard deviations (SD) for the outcome variables were calculated and compared. The two-sided t-test was used to determine if the demographic data gathered were homogenous for both treatment groups, as well as to compare healing times, percentage of surface area healed, DLQI scores, liver and lipid profiles of both groups. The Pearson Chi-Square test was used to compare proportions of patients with complete ulcer healing between groups. Test results with p-values below 0.05 were regarded as statistically significant.
This article is protected by copyright. All rights reserved. Relative risk (RR), relative risk reduction (RRR), absolute risk reduction (ARR) and number needed to treat (NNT) were computed and 95% confidence intervals (CI) were determined. RESULTS Study Population Of the 85 individuals who were 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, 5 were considered as dropouts due to nonattendance at scheduled visits. There was no statistical difference in the number of dropouts between the two groups (p value = 0.592). There were no withdrawals in the study. Since an intention-to-treat analysis was done, all 66 patients were included in the full analysis. The baseline characteristics of the study population are summarized in Table 1. No statistically significant differences were noted between the 2 groups based on age, sex, presence of diabetes, duration of venous disease and ulcer, baseline ulcer diameter and surface area, proportion of ulcers > 5cm, and baseline liver enzymes, lipid profiles and DLQIs. Clinical effects In the simvastatin group, 72% had complete ulcer closure as compared to 32% in the control group (RR 0.32, 95% CI: 0.16 – 0.65) (Table 2). Among the subjects with ulcers ≤ 5 cm, all healed in the simvastatin group, while only 46% had closed ulcers in the control group (RR 0.11, 95% CI: 0.02 – 0.77). Healing time for ulcers ≤ 5 cm was 6.89 ± 0.78 weeks and 8.40 ± 1.13 weeks for simvastatin and control groups, respectively (p value 0.001). Among those with ulcers > 5 cm, 50% 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 among the control group (RR 0.5, 95% CI: 0.28 – 0.88) (Table 3). In addition, the mean healed area of the ulcers was significantly higher (p value = 0.03) in the simvastatin (28.9cm2) than the control group (19.6cm2). Relative risk reduction computation revealed that simvastatin, in addition to standard wound care and compression, will improve venous ulcers 68% more (RRR = 0.68, 95% CI 0.35 – 0.84) than the latter alone. The absolute risk reduction (ARR) was 0.46, favoring simvastatin (ARR = 0.46, 95% CI 0.22 – 0.63). The NNT revealed that two patients were required to be treated with simvastatin to demonstrate complete ulcer closure. The patients whose ulcers did not close in the placebo and simvastatin groups had longer duration of venous ulcers and larger surface areas than those ulcers which closed. Although the patients with closed ulcers in the simvastatin group were significantly younger than those patients with open ulcers, ages of patients were comparable in both open and closed ulcers of the placebo group (Table 4). Gender proportions, presence of diabetes and duration of CVI were not significantly different in the open and closed ulcers of both groups. Dermatology life quality index Both groups demonstrated a decrease in DLQI scores from the baseline (Fig. 3). However, the simvastatin group showed significantly lower (p value = 0.0004) post-treatment DLQI scores and higher percentage reduction (p value = 0.0001) than those in the placebo group. Lipid profile and liver enzymes Patients belonging to the simvastatin group had statistically lower post-treatment total and LDL cholesterol (p value < 0.01), while post-treatment HDL cholesterol was significantly higher (p value = 0.04). There were no significant differences in post-treatment SGPT and SGOT.
This article is protected by copyright. All rights reserved. Adverse effects There were no documented adverse effects in this study. DISCUSSION Simvastatin was superior to placebo in the management of venous ulcers based on higher proportions of healed ulcers, faster healing times and better quality of life indices. This may be explained by both venoactive13-15 and non-venoactive16-29 properties (including an effect on epithelialization) being present in statins, while compression alone will just provide venoactive control of the disease.6 Both groups revealed improvements in DLQIs but more significant decreases were seen in the patients in the simvastatin group. This parallels the superior clinical improvement seen in the treatment group as compared to placebo. This may also be explained by the inhibitory effect of statins on Th-1 cytokine production and release. Pro-inflammatory Th-1 cytokines such as TNF-alpha and interleukin-1 are linked to depression and chronic fatigue in patients,34 and their inhibition may lead to further decrease in DLQI scores. In both simvastatin and placebo groups, better healing outcomes were seen in patients with shorter duration of venous ulceration and smaller surface areas. These results are in accordance with studies investigating the associations of different risk factors and complete ulcer healing, which determined that longer ulcer duration and larger baseline surface areas were poor prognosticators for healing, and that age, gender and presence of diabetes did not seem to affect outcome.35-37 There were no adverse effects in this study. The majority of the patients in the simvastatin group in this study 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 20mg/daily.38 An eight-week clinical trial of simvastatin 40mg/daily in healthy individuals demonstrated an increase of HDL by as much as 20% and a reduction in LDL by as much as 16%.39 These studies, in addition to our findings, show that statin use is not limited to patients with dyslipidemia. 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.40-41 Recent guidelines indicate that ideal LDL for those with no known risk factors for heart disease is below 130 mg/dL (3.4 mmol/L), while for those with risk factors, the target LDL may be below 70 - 100 mg/dL (1.8 - 2.6 mmol/L).42 One limitation of this study is that we only investigated the use of simvastatin as active management for venous ulcers, and not for maintenance therapy or prevention once the ulcers have closed. Additionally, we did not investigate the recurrence rates once simvastatin has been discontinued. We recommend that the use of statins in the abovementioned settings should be investigated in the future because there is evidence suggesting that inflammation is an etiological factor in the development of venous valve dysfunction.43 The anti-inflammatory effects of statins may then improve the venous pathology in CVI, preventing future ulcerations, suggesting the use of simvastatin as both active and maintenance therapy, even for cases of CVI without ulceration. Lastly, simvastatin was only used as an adjunct to compression, and not as monotherapy. Although a case report showed excellent response using simvastatin without compression in a patient with venous ulceration,44 the Institutional Review Board deemed it prudent to use it as an adjunct since this is the first RCT investigating its use in venous ulcers.
This article is protected by copyright. All rights reserved. CONCLUSION Simvastatin 40mg/daily, in addition to standard wound care and compression, is associated with a shorter healing period and improved patient quality of life when compared with placebo in the management of venous ulcers. REFERENCES 1. 2. 3. 4. 5. 6. 7.
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This article is protected by copyright. All rights reserved. 30. Brookes ZL, McGown CC, Reilly CS. Statins for all: the new premed? Br. J. Anaesth.2009; 103(1), 99–107. 31. Wright RA, Flapan AD, McMurray J et al. The Scandinavian Simvastatin study. The Lancet. 1994; 344(8939) 1765-1768. 32. MRC/BHF Heart Protection Study Collaborative Group. Effects of Simvastatin 40mg Daily on Muscle and Liver Adverse Effects in a 5-Year Randomized Placebo-Controlled Trial in 20,536 High-Risk People. BMC ClinPharmacol.2009; 9:6. 33. Guitan G and Paliza A. A randomized, double-blind, placebo controlled trial on the efficacy of simvastatin the treatment of chronic plaque type psoriasis, J Phil Dermatol Soc.2012; 13-21. 34. Gottleib AB, Chao C, Dann F. Psoriasis co-morbidities. J Dermatol Treat. 2008; 19 (1):5-21. 35. Leskovec NK, Perme MP, Jezersˇek M, et al. Initial healing rates as predictive factors of venous ulcer healing: The use of a laser-based three-dimensional ulcer measurement. Wound Rep Reg. 2008. 16: 507–512. 36. Hjerppe A, Saarinen JP, Venermo MA,et al. Prolonged healing of venous leg ulcers: the role of venous reflux, ulcer characteristics and mobility.J Wound Care. 2010 Nov 19 (11): 474 – 478. 37. Collins L and Seraj S. Diagnosis and treatment of venous ulcers. Am Fam Physician. 2010. Apr 15;81(8):98996. 38. Ridker PM, Danielson E, Fonseca FAH,et al. Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-reactive Protein. N Engl J Med.2008; 359: 2195-2207. 39. Cox, JH and Coupland C. Unintended effects of statins in men and women in England and Wales: population based cohort study using the QResearch database. BMJ. 2010; 340:c2197. 40. Alsheikh-Ali AA, Trikalinos TA, Kent DM, et al.Statins, low-density lipoprotein cholesterol, and risk of cancer. J Am Coll Cardiol. 2008 Sep 30;52(14):1141-7. 41. Steinberg D. Statin treatment does not cause cancer. J Am Coll Cardiol. 2008. Sep 30;52(14):1148-9 42. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults.Executive Summary of The Third Report of the National Cholesterol Education Program Expert Panel onDetection, Evaluation, and Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III).JAMA. 2001 May 16;285(19):2486-97. 43. Bergan JJ, Pascarella L, Schmid-Schonbein GW. Pathogenesis of primary chronic venous disease: Insights from animal models of venous hypertension. J VascSurg 2008; 47: 183-92. 44. Evangelista M and Abad F. Simvastatin as a novel therapeutic option for venous ulcers; a report of successful closure after 9 weeks of therapy. Jose Reyes Memorial Medical Center Dermatology Department. (2011). Unpublished.
Table 1. Baseline characteristics of patients. Characteristic Age, mean , years ± SD Sex, male/female, number Diabetes, number (%) Duration of venous disease, mean, years ± SD Duration of venous ulcer, mean, years ± SD Ulcer diameter, mean, cm ± SD Ulcer diameter > 5cm, number (%) Ulcer surface area, mean, cm2± SD Total cholesterol, mean, mmol/L ± SD HDL cholesterol, mean, mmol/L ± SD LDL cholesterol, mean, mmol/L ± SD SGPT, mean, U/L ± SD SGOT, mean, U/L ± SD DLQI, mean ± SD
Placebo n = 34 55.97± 14.96 13/34 5 (14.71%) 8.95± 4.27 3.80± 2.51 4.63 ± 2.05 10 (29.41%) 35.2±21.91 4.79± 0.86 1.01±0.56 2.88± 1.49 22.51±11.40 27.29±6.21 12.65±3.11
Simvastatin n = 32 56.41± 15.35 10/32 3 (9.38%) 9.00± 3.57 3.93± 2.88 4.98 ± 2.15 12 (37.5%) 37.2± 22.15 5.01±1.11 1.18± 0.49 3.03±1.13 21.04±11.63 28.42±5.80 13.34±3.41
P value 0.9074 0.552 0.507 0.9519 0.8401 0.4977 0.486 0.7171 0.3636 0.4262 0.6383 0.5590 0.4459 0.3318
Abbreviations: SD, standard deviation; HDL, high density lipoprotein; LDL, low density lipoprotein; SGOT, serum glutamic oxaloacetic transaminase; SGPT; serum glutamic pyruvic transaminase; DLQI, dermatology life quality index
Table 2. Total proportion of patients with complete healing and time to healing in both groups. Total proportion healed (n, %) Time to healing (mean, weeks) ± SD Abbreviations: SD, standard deviation
Placebo 13 (32) 8.55 ± 1.13
Simvastatin 26 (72) 7.53 ± 1.34
This article is protected by copyright. All rights reserved. Table 3. Proportion of patients with complete healing and time to healing in both groups stratified by size. Ulcers ≤ 5 cm Time to healing Proportion healed (n, %) (mean, weeks) ± SD 13 (46) 8.40 ± 1.13 Placebo 20 (100) 6.89 ± 0.78 Simvastatin Abbreviations: n, number; SD, standard deviation
Ulcers > 5 cm Time to healing Proportion healed (n, %) (mean, weeks) ± SD 0 (0) n/a 6 (50) 9.17 ±1.07
Table 4. Comparison of specific variables of closed and open ulcers in both groups.. Variable
Group Closed Placebo 55.18±14.48 Age, mean, years ± SD Simvastatin 51.8±14.18 Placebo 0(0%) Diabetes, number (%) Simvastatin 2(8.0%) Placebo 4 (36.36%) Gender, M/F, number Simvastatin 8 (32%) Placebo 7.00±5.35 Duration of venous disease, mean, years ± SD Simvastatin 8.64±2.89 Placebo 2.40±2.43 Duration of venous ulcer, mean, years ± SD Simvastatin 3.34±2.32 Placebo 12.16± 3.33 Ulcer surface area, mean, cm2± SD Simvastatin 30.88±20.96 Abbreviations: SD, standard deviation; M, male; F, female
Open 56.35±15.49 72.86±2.97 5(21.74%) 1(14.29%) 9 (39.13%) 2 (28.57%) 9.87±3.40 10.29±5.47 4.46±2.31 6.04±0.84 46.28 ±17.93 59.86±3.45
Figure 1. Statins for venous ulcers: a conceptual framework
P value 0.8354 0.0006 0.094 0.614 0.877 0.863 0.0659 0.2877 0.0247 0.0258 5 cm = 10
Simvastatin n = 32 ≤ 5 cm = 20 > 5 cm = 12
Total drop-out n = 2 Withdrawn n = 0
Total drop-out n = 3 Withdrawn n = 0
Analyzed n = 34 Intention to treat analysis
Analyzed n = 32 Intention to treat analysis
Figure 2.Trial profile showing patient populations.
14 12
DLQI
10 8
Placebo
6
Simvastatin
4 2 0
Baseline and post treatment scores
Figure 3. Decrease in DLQI scores throughout treatment in both groups.
: Therapeutics
Simvastatin as a novel therapeutic agent for venous ulcers: a randomized, double-blind, placebo-controlled trial Running head: Simvastatin_for_venous_ulcers Authors and institutions: M.T.P. Evangelista1, M.F.A. Casintahan2, L.L. Villafuerte2 1 Resident, Department of Dermatology, Jose R. Reyes Memorial Medical Center 2 Consultant staff, Department of Dermatology, Jose R. Reyes Memorial Medical Center Corresponding author: Mara Therese P. Evangelista, M.D. Jose R. Reyes Memorial Medical Center Department of Dermatology Rizal Avenue, Sta. Cruz, Manila, 1003 [email protected] +6329323975383 Sources of funding: none Conflicts of interest: none What’s already known in this topic: - The standard treatment for venous ulcers is compression therapy, but drugs may be used as adjunctive therapy to accelerate the healing process. - Statins are cholesterol-lowering drugs that may also have pleiotropic effects which accelerate wound-healing. However, supporting evidences for this is mainly from animal studies. - There are no previous studies investigating the use of statins for venous ulcers. What does this study add? - This is the first study investigating the use of statins (simvastatin 40mg/daily) in venous ulcer healing. - This randomized, double-blind, placebo-controlled trial showed that simvastatin, in addition to standard wound care and compression, is associated with a significant improvement in healing rate and healing time, as well and improved patient quality of life when compared to placebo in the management of venous ulcers. No adverse effects were documented in this study.
This article is protected by copyright. All rights reserved. ABSTRACT Background. 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 for venous ulcers. This study assessed the efficacy and safety of simvastatin in venous ulcer healing when combined with standard treatment for ulcers. Methodology. This was a randomized, double-blind, placebo-controlled trial. Outcome measures were proportion of healed ulcers, healing time, total surface area healed, and dermatology life quality indices (DLQI). Results. 66 patients were randomized, 32 in the simvastatin and 34 in the control group. Among ulcers ≤ 5 cm, 100% healed in the simvastatin group, while 46% healed in the control group (RR 0.11, 95% CI: 0.02 – 0.77). The average healing time for ulcers ≤ 5 cm was 6.89 ± 0.78 weeks and 8.40 ± 1.13 weeks for simvastatin and control groups, respectively (p value = 0.0001). Among ulcers > 5 cm, 50% 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 among the placebo group (RR 0.5, 95% CI: 0.28 – 0.88). The simvastatin group had lower DLQIs (p value = 0.0004) post-treatment. There were no documented adverse effects. Conclusion. Simvastatin 40mg/daily, in addition to standard wound care and compression, is associated with a significant improvement in healing rate and healing time, as well and improved patient quality of life when compared with placebo in the management of venous ulcers.
INTRODUCTION Chronic venous insufficiency (CVI) causes various lower limb pathologies such as stasis ulcers, edema and skin changes like lipodermatosclerosis.1 CVI is the cause of nearly 80% of lower-leg ulcers.2 Venous ulcers are estimated to affect 1% to 1.5% of the adult population. The overall prognosis of venous ulcers is generally poor, with recurrence rates exceeding 3 50%, and more than half of patients requiring a year of therapy.4 Venous ulceration reduces the quality of life and imposes financial constraints.5 Although compression is still the undisputable standard of ulcer management,6 drug therapy may be considered where there is intolerance, contraindications, lack of compliance or as an adjunct to accelerate the healing process.7 Statins are cholesterol-lowering drugs that may have pleiotropic effects which accelerate wound-healing.8-10 Since most available data are based on animal studies,11 there are no studies investigating the use of statins for venous ulcers. Drugs for venous ulceration address the hypoxia and chronic inflammation characteristic of these chronic wounds through venoactive or non-venoactive effects.12 Based on animal models, statins counteract hypoxia through both venoactive13-15 and non-venoactive16-19 properties, and address chronic inflammation through its potent immunomodulatory actions20-22 (Fig. 1). Statins may be superior to other existing systemic wound-healing agents because in addition to the abovementioned venoactive and non-venoactive 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 which represses Keratin 6.23 By inhibiting HMG-CoA reductase, statins inhibit FPP synthesis, thereby preventing repression of keratin 6, and promoting epithelialization. Statins have improved 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
This article is protected by copyright. All rights reserved. Moreover, emerging evidence suggests that statins may treat and prevent different infections,25-27 and may decrease the rate of severe sepsis,28,29 which is essential because bacterial burden adds to the pathogenesis of non-healing wounds.9 Although rare, statins may induce side effects, among which myopathy and liver problems represent the most serious. Other important side effects include cataracts and acute kidney failure. However, these problems were still estimated to be quite uncommon, with cataracts affecting less than 3% and other side effects less than 1%.30 Studies have shown that safety and tolerability profiles of statins were comparable to placebo even in high risk patients (women, older individuals and those with normal cholesterol levels).31,32 The general objective of the study was to assess the efficacy and safety of simvastatin in venous ulcer healing. Specifically, it evaluated and compared the proportion of patients with healed venous ulcers, time to complete healing of ulcers, quality of life based on Dermatology Life Quality Index (DLQI), effects on the lipid profile (total, high and low density lipoprotein cholesterol), liver enzymes (SGPT and SGPT), as well as adverse effects among the simvastatin and placebo groups.
METHODOLOGY 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 Institutional Review Board of the hospital approved the trial protocol prior to commencement. This clinical trial was conducted in compliance with Good Clinical Practice and in accordance with the ethical principles of the Declaration of Helsinki. Male or female patients aged 18 to 85 years old, with single or multiple ulcers that were confirmed by duplex scan to be venous in origin, and who were willing to have elastic compression therapy were recruited. The ulcers had to be open for at least 3 months. In patients with multiple ulcers, the largest ulcer was chosen as reference. Both normo- and hypercholesterolemic patients were included. Females of child bearing potential were advised to avoid being pregnant during the course of the research. Exclusion criteria included application or intake of antibiotics or any phlebotropic or venoactive drugs for at least 2 weeks before enrollment, 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 will increase the risk of adverse events with the intervention. Patients who were taking coumarin derivatives, digoxin, fibrates or high-dose niacin, cyclosporine, nefazodone, methotrexate, verapamil, diltiazem, ACE inhibitors, systemic azole antifungals or systemic macrolide antibiotics, those who were pregnant or lactating, those with known or strong suspicion of significant drug abuse, alcoholism, 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 size (≤ 5 cm and > 5 cm). This size stratification was used because venous ulcers > 5cm have been shown to have slower closure rates than smaller wounds. Materials The simvastatin (40mg/tab) and placebo tablets of the same size, color and shape were placed in identical 50 mL transparent bottles. The bottles were coded (A or B) by the pharmacist.
This article is protected by copyright. All rights reserved. Randomization, treatment allocation, and blinding The statistician generated a list of random numbers using the 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 only disclosed to the investigators at the end of the study. Study intervention 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 ten weeks, or less in case of complete ulcer healing before the end of the ten-week treatment period. All participants were told to avoid drinking alcoholic beverages during the study. Clinical assessment All patients were evaluated by the same dermatologist who was blinded to the codes every two weeks until closure or a maximum of ten 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, high density lipoprotein (HDL) and low density lipoprotein (LDL) cholesterol, serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), DLQI scores and pregnancy tests from female patients with childbearing potential were obtained prior to therapy. Digital photographs, DLQI scores and ulcer surface area (using manual planimetry) were obtained every two weeks. Liver and lipid profiles were repeated after one month of treatment. Stopping guidelines The study was stopped in patients who experienced adverse reactions to the test drug, worsening of the skin lesions, elevation of liver enzymes thrice the upper limit, if the patient became pregnant, or if the patient voluntarily withdrew from the study. These patients were considered as withdrawals from the study. Those who did not comply to 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 two weeks and whose outcome was unknown by the end of the study period. Sample size The sample size was computed using a two-sample comparison of means based on a previous study of thirty patients given 40mg/daily of simvastatin.33 In accordance with the results of this study, standard deviation was estimated at 8.6. Using a two-sided alpha of 0.05 and a power of 0.8, calculations indicated that 29 patients in each study arm were needed. 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, standard deviations and proportions. The means and standard deviations (SD) for the outcome variables were calculated and compared. The two-sided t-test was used to determine if the demographic data gathered were homogenous for both treatment groups, as well as to compare healing times, percentage of surface area healed, DLQI scores, liver and lipid profiles of both groups. The Pearson Chi-Square test was used to compare proportions of patients with complete ulcer healing between groups. Test results with p-values below 0.05 were regarded as statistically significant.
This article is protected by copyright. All rights reserved. Relative risk (RR), relative risk reduction (RRR), absolute risk reduction (ARR) and number needed to treat (NNT) were computed and 95% confidence intervals (CI) were determined. RESULTS Study Population Of the 85 individuals who were 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, 5 were considered as dropouts due to nonattendance at scheduled visits. There was no statistical difference in the number of dropouts between the two groups (p value = 0.592). There were no withdrawals in the study. Since an intention-to-treat analysis was done, all 66 patients were included in the full analysis. The baseline characteristics of the study population are summarized in Table 1. No statistically significant differences were noted between the 2 groups based on age, sex, presence of diabetes, duration of venous disease and ulcer, baseline ulcer diameter and surface area, proportion of ulcers > 5cm, and baseline liver enzymes, lipid profiles and DLQIs. Clinical effects In the simvastatin group, 72% had complete ulcer closure as compared to 32% in the control group (RR 0.32, 95% CI: 0.16 – 0.65) (Table 2). Among the subjects with ulcers ≤ 5 cm, all healed in the simvastatin group, while only 46% had closed ulcers in the control group (RR 0.11, 95% CI: 0.02 – 0.77). Healing time for ulcers ≤ 5 cm was 6.89 ± 0.78 weeks and 8.40 ± 1.13 weeks for simvastatin and control groups, respectively (p value 0.001). Among those with ulcers > 5 cm, 50% 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 among the control group (RR 0.5, 95% CI: 0.28 – 0.88) (Table 3). In addition, the mean healed area of the ulcers was significantly higher (p value = 0.03) in the simvastatin (28.9cm2) than the control group (19.6cm2). Relative risk reduction computation revealed that simvastatin, in addition to standard wound care and compression, will improve venous ulcers 68% more (RRR = 0.68, 95% CI 0.35 – 0.84) than the latter alone. The absolute risk reduction (ARR) was 0.46, favoring simvastatin (ARR = 0.46, 95% CI 0.22 – 0.63). The NNT revealed that two patients were required to be treated with simvastatin to demonstrate complete ulcer closure. The patients whose ulcers did not close in the placebo and simvastatin groups had longer duration of venous ulcers and larger surface areas than those ulcers which closed. Although the patients with closed ulcers in the simvastatin group were significantly younger than those patients with open ulcers, ages of patients were comparable in both open and closed ulcers of the placebo group (Table 4). Gender proportions, presence of diabetes and duration of CVI were not significantly different in the open and closed ulcers of both groups. Dermatology life quality index Both groups demonstrated a decrease in DLQI scores from the baseline (Fig. 3). However, the simvastatin group showed significantly lower (p value = 0.0004) post-treatment DLQI scores and higher percentage reduction (p value = 0.0001) than those in the placebo group. Lipid profile and liver enzymes Patients belonging to the simvastatin group had statistically lower post-treatment total and LDL cholesterol (p value < 0.01), while post-treatment HDL cholesterol was significantly higher (p value = 0.04). There were no significant differences in post-treatment SGPT and SGOT.
This article is protected by copyright. All rights reserved. Adverse effects There were no documented adverse effects in this study. DISCUSSION Simvastatin was superior to placebo in the management of venous ulcers based on higher proportions of healed ulcers, faster healing times and better quality of life indices. This may be explained by both venoactive13-15 and non-venoactive16-29 properties (including an effect on epithelialization) being present in statins, while compression alone will just provide venoactive control of the disease.6 Both groups revealed improvements in DLQIs but more significant decreases were seen in the patients in the simvastatin group. This parallels the superior clinical improvement seen in the treatment group as compared to placebo. This may also be explained by the inhibitory effect of statins on Th-1 cytokine production and release. Pro-inflammatory Th-1 cytokines such as TNF-alpha and interleukin-1 are linked to depression and chronic fatigue in patients,34 and their inhibition may lead to further decrease in DLQI scores. In both simvastatin and placebo groups, better healing outcomes were seen in patients with shorter duration of venous ulceration and smaller surface areas. These results are in accordance with studies investigating the associations of different risk factors and complete ulcer healing, which determined that longer ulcer duration and larger baseline surface areas were poor prognosticators for healing, and that age, gender and presence of diabetes did not seem to affect outcome.35-37 There were no adverse effects in this study. The majority of the patients in the simvastatin group in this study 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 20mg/daily.38 An eight-week clinical trial of simvastatin 40mg/daily in healthy individuals demonstrated an increase of HDL by as much as 20% and a reduction in LDL by as much as 16%.39 These studies, in addition to our findings, show that statin use is not limited to patients with dyslipidemia. 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.40-41 Recent guidelines indicate that ideal LDL for those with no known risk factors for heart disease is below 130 mg/dL (3.4 mmol/L), while for those with risk factors, the target LDL may be below 70 - 100 mg/dL (1.8 - 2.6 mmol/L).42 One limitation of this study is that we only investigated the use of simvastatin as active management for venous ulcers, and not for maintenance therapy or prevention once the ulcers have closed. Additionally, we did not investigate the recurrence rates once simvastatin has been discontinued. We recommend that the use of statins in the abovementioned settings should be investigated in the future because there is evidence suggesting that inflammation is an etiological factor in the development of venous valve dysfunction.43 The anti-inflammatory effects of statins may then improve the venous pathology in CVI, preventing future ulcerations, suggesting the use of simvastatin as both active and maintenance therapy, even for cases of CVI without ulceration. Lastly, simvastatin was only used as an adjunct to compression, and not as monotherapy. Although a case report showed excellent response using simvastatin without compression in a patient with venous ulceration,44 the Institutional Review Board deemed it prudent to use it as an adjunct since this is the first RCT investigating its use in venous ulcers.
This article is protected by copyright. All rights reserved. CONCLUSION Simvastatin 40mg/daily, in addition to standard wound care and compression, is associated with a shorter healing period and improved patient quality of life when compared with placebo in the management of venous ulcers. REFERENCES 1. 2. 3. 4. 5. 6. 7.
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Table 1. Baseline characteristics of patients. Characteristic Age, mean , years ± SD Sex, male/female, number Diabetes, number (%) Duration of venous disease, mean, years ± SD Duration of venous ulcer, mean, years ± SD Ulcer diameter, mean, cm ± SD Ulcer diameter > 5cm, number (%) Ulcer surface area, mean, cm2± SD Total cholesterol, mean, mmol/L ± SD HDL cholesterol, mean, mmol/L ± SD LDL cholesterol, mean, mmol/L ± SD SGPT, mean, U/L ± SD SGOT, mean, U/L ± SD DLQI, mean ± SD
Placebo n = 34 55.97± 14.96 13/34 5 (14.71%) 8.95± 4.27 3.80± 2.51 4.63 ± 2.05 10 (29.41%) 35.2±21.91 4.79± 0.86 1.01±0.56 2.88± 1.49 22.51±11.40 27.29±6.21 12.65±3.11
Simvastatin n = 32 56.41± 15.35 10/32 3 (9.38%) 9.00± 3.57 3.93± 2.88 4.98 ± 2.15 12 (37.5%) 37.2± 22.15 5.01±1.11 1.18± 0.49 3.03±1.13 21.04±11.63 28.42±5.80 13.34±3.41
P value 0.9074 0.552 0.507 0.9519 0.8401 0.4977 0.486 0.7171 0.3636 0.4262 0.6383 0.5590 0.4459 0.3318
Abbreviations: SD, standard deviation; HDL, high density lipoprotein; LDL, low density lipoprotein; SGOT, serum glutamic oxaloacetic transaminase; SGPT; serum glutamic pyruvic transaminase; DLQI, dermatology life quality index
Table 2. Total proportion of patients with complete healing and time to healing in both groups. Total proportion healed (n, %) Time to healing (mean, weeks) ± SD Abbreviations: SD, standard deviation
Placebo 13 (32) 8.55 ± 1.13
Simvastatin 26 (72) 7.53 ± 1.34
This article is protected by copyright. All rights reserved. Table 3. Proportion of patients with complete healing and time to healing in both groups stratified by size. Ulcers ≤ 5 cm Time to healing Proportion healed (n, %) (mean, weeks) ± SD 13 (46) 8.40 ± 1.13 Placebo 20 (100) 6.89 ± 0.78 Simvastatin Abbreviations: n, number; SD, standard deviation
Ulcers > 5 cm Time to healing Proportion healed (n, %) (mean, weeks) ± SD 0 (0) n/a 6 (50) 9.17 ±1.07
Table 4. Comparison of specific variables of closed and open ulcers in both groups.. Variable
Group Closed Placebo 55.18±14.48 Age, mean, years ± SD Simvastatin 51.8±14.18 Placebo 0(0%) Diabetes, number (%) Simvastatin 2(8.0%) Placebo 4 (36.36%) Gender, M/F, number Simvastatin 8 (32%) Placebo 7.00±5.35 Duration of venous disease, mean, years ± SD Simvastatin 8.64±2.89 Placebo 2.40±2.43 Duration of venous ulcer, mean, years ± SD Simvastatin 3.34±2.32 Placebo 12.16± 3.33 Ulcer surface area, mean, cm2± SD Simvastatin 30.88±20.96 Abbreviations: SD, standard deviation; M, male; F, female
Open 56.35±15.49 72.86±2.97 5(21.74%) 1(14.29%) 9 (39.13%) 2 (28.57%) 9.87±3.40 10.29±5.47 4.46±2.31 6.04±0.84 46.28 ±17.93 59.86±3.45
Figure 1. Statins for venous ulcers: a conceptual framework
P value 0.8354 0.0006 0.094 0.614 0.877 0.863 0.0659 0.2877 0.0247 0.0258 5 cm = 10
Simvastatin n = 32 ≤ 5 cm = 20 > 5 cm = 12
Total drop-out n = 2 Withdrawn n = 0
Total drop-out n = 3 Withdrawn n = 0
Analyzed n = 34 Intention to treat analysis
Analyzed n = 32 Intention to treat analysis
Figure 2.Trial profile showing patient populations.
14 12
DLQI
10 8
Placebo
6
Simvastatin
4 2 0
Baseline and post treatment scores
Figure 3. Decrease in DLQI scores throughout treatment in both groups.
