A Randomized, Controlled Clinical Pilot Study Comparing Three Types of Compression Therapy to Treat Venous Leg Ulcers in Patients with Superficial and/or Segmental Deep Venous Reflux

Abstract

  Compression therapy — including inelastic, elastic, and intermittent pneumatic compression — is the standard of care for venous ulcers (VLUs) and chronic venous insufficiency, but there is no consensus in the literature regarding the most effective type of compression therapy. A prospective, randomized, clinical pilot study was conducted among 70 patients with unilateral VLUs treated in a hospital dermatology department in Poland to compare three types of compression therapy (intermittent pneumatic compression, stockings, and short-stretch bandages) in persons with superficial deep venous reflux alone or combined with the segmental variety.

Study endpoints were change in ulcer dimensions and proportions healed. Patients with superficial or combined superficial and deep vein insufficiency were randomly allocated to receive one of the three therapies (one of each vein type for each treatment option, six groups total). All patients received saline-soaked gauze dressings along with micronized purified flavonoid fraction, diosmin, hesperidin, and Daflon 500 once daily. Compression treatments were changed or pneumatic compression provided daily for 15 days. Wound size reduction and percentage of wounds healed were significantly higher in groups receiving intermittent pneumatic compression or stockings than in groups using short-stretch bandages (for percentage change of ulcer surface area, P = 0.02; for healing rates P = 0.01). These results warrant additional randomized controlled clinical studies with a larger sample size and longer patient follow-up.

 Potential Conflicts of Interest: none disclosed

Introduction

  Venous leg ulcers (VLU) are defined by a loss of skin below the knee in response to venous insufficiency and account for the majority (70% to 90%) of lower extremity ulcers. The pathophysiology of venous ulcers is not entirely clear.^1,2 Carpentier et al’s¹ recent literature review concluded venous incompetence and associated venous hypertension are thought to be the primary mechanisms for ulcer formation. Factors that may lead to venous incompetence include immobility, ineffective pumping of the calf muscle, venous valve dysfunction from trauma, congenital anatomical endothelial dysfunction, venous thrombosis, and phlebitis. Subsequently, chronic venous stasis causes pooling of blood in the venous circulatory system, triggering further capillary damage and activation of the inflammatory process. Leukocyte activation, endothelial damage, platelet aggregation, and intracellular edema contribute to venous ulcer development and impaired wound healing.

  According to Jones and Carek,² venous disease resulting in valve reflux appears to be the underlying pathophysiology for the formation of varicose veins. Rather than blood flowing from distal to proximal and superficial to deep, failed or incompetent valves in the venous system allow blood to flow in the reverse direction. With increased pressure on the local venous system, the larger affected veins may become elongated and tortuous. Although no specific etiology is noted, in most cases the valvular dysfunction is presumed to be caused by a loss of elasticity in the vein wall, with failure of the valve leaflets to fit together.

  VLUs pose a serious clinical dilemma and an economic burden on health services. European studies have reported that VLUs affect 1.5% to 1.8% of adults in industrialized countries and have a considerable impact on health and quality of life in terms of patient pain, social isolation, and quality of life. Some European national healthcare systems (British, French, German, and Polish) provide nursing and medical care, as well as dressings, bandages, drug treatments, and physical therapies for persons with a VLU.^1,3,4

  A cross-sectional epidemiologic study¹ was conducted among the general population in four locations in France (Tarentaise, Grenoble, Nyons, and Toulon). Random samples of 2,000 subjects per location were interviewed by telephone, and a subsample of subjects completed medical interviews and underwent physical examination, during which prevalence of varicose veins, trophic changes, and venous symptoms were recorded and found not to be statistically different in the four locations. However, gender-related differences were significant: 50.5% of women versus 30.1% of men had varicose veins (P <0.001), 2.8% of women versus 5.4% of men had trophic skin changes (P >0.05), and 51.3% of women versus 20.4% of men had venous symptoms (P <0.001). A strong positive correlation was found for varicose veins and age and family history in both men and women and pregnancy in women. Female gender was a significant factor only for nonsaphenous varicose veins. Varicose veins, age, and pitting edema were the most significant risk factors for trophic skin changes. The risk factors for venous symptoms were female gender, the presence of varicose veins, and prolonged sitting or standing. Age also was a bigger risk factor in women.

  According to a cross-sectional study⁵ of 1,566 patients, ages 25 to 64 years, from an urban population, VLUs have been estimated to cost the UK National Health Service £400 million a year. A prospective study⁶ performed in 23 specialized wound centers in Germany calculated the mean total cost of a VLU per patient per year to be €9569 (€8658, 92% direct costs). According to data from a US, multicenter, observational, cross-sectional study⁷ of 2,598 patients, the financial burden of venous ulcers was estimated to be $2 billion per year.

  Compression therapy is the standard of care for venous ulcers and chronic venous insufficiency. Many clinical studies^8-13 have examined the effectiveness of compression therapy in leg ulcer healing. A recent Cochrane review¹² found venous ulcers heal more quickly with compression therapy than without. The literature discusses many methods of applying external graduated compression, such as elasticized bandages, Unna’s boots, multilayer elastic compression bandages, short-stretch bandages, and elastomeric hosiery.

  Study results do not clearly indicate which type of compression therapy is most effective, and the relative efficacy of various types of compression, compression techniques, or pressure values remains unclear.^8,9,12 It is also problematic whether intermittent pneumatic compression therapy increases healing rates and, if it does, whether any particular treatment regimen is optimal.

  The purpose of this study was to compare three types of compression therapy (intermittent pneumatic, stockings, and short-stretch bandages) in the VLUs of two groups of participants: one with superficial deep venous reflux alone and the other with combined superficial plus segmental venous reflux. The primary study endpoint was change in ulcer surface area, volume, and linear dimensions in the observed groups. Secondary endpoints were the number of healed wounds (completely epithelialized) and percentage change of ulcer surface area between three types of compression therapies, separately in two groups of participants (with superficial alone and combined superficial plus segmental deep venous reflux).

Methods and Procedures

  Design and criteria. A prospective, randomized, single-blind clinical pilot study was conducted from June 2010 to July 2012 among patients with VLU treated at the Department of Dermatology of the Medical University of Silesia, Katowice, Poland. Patients were eligible for participation if they had been diagnosed with a VLU and the following tests had been ordered at least twice within the previous 3 months: standard blood morphology, immunological studies, HbA1c, cholesterol panel and liver enzymes, serum creatinine/glomerular filtration rate, urine testing, and electrocardiogram. Exclusion criteria were an ankle brachial pressure index (ABPI) <1.0, history of diabetes mellitus, cancer, peripheral nerve injury, rheumatoid arthritis, ventricular arrhythmia, cardiac pacemaker, ulcer surgery, skin infection, pregnancy, post-steroid therapy, and bilateral ulcers. Patients with a documented history of lymphedema, pulmonary edema, congestive heart failure, and chronic renal failure also were excluded and not recruited or screened for eligibility.

  All participants provided written informed consent to this project, which was approved by the local Bioethics Committee of the Medical University of Silesia in Katowice.

  Patients eligible for participation were randomly allocated to six groups. Computer-generated random numbers were sealed in a predetermined amount of sequentially numbered envelopes. The physician allocating patients to groups had 70 envelopes (33 envelopes for patients with isolated superficial vein insufficiency and 37 envelopes for patients with combined superficial and deep vein insufficiency), each containing a piece of paper marked with either A, C, and E groups (participants with superficial venous reflux alone) or B, D, and E groups (participants with superficial plus segmental deep venous reflux). The physician drew and opened an envelope in the presence of a physiotherapist to see the symbol and direct the patient to one of the comparative groups accordingly.

  Procedures.
  Patient assessment. All patients received a detailed venous examination (nine segments: upper and lower greater saphenous vein, short saphenous vein, proximal and distal femoral vein, proximal and distal popliteal vein, saphenofemoral junction, and saphenopopliteal junction) by duplex scanning (EUB 555, Hitachi Inc, Japan). The thigh veins were examined with the participant standing, and the calf veins were examined with the patient sitting with the leg dependent. Each vein segment was imaged both in cross-section and longitudinally. When the vessels were imaged in cross-section, the direction of the Doppler shift was represented by a color scale over the blood vessels (red = flow in proximal direction, blue = flow in distal, retrograde direction). In longitudinal images, the numerical velocity of red blood cells within each segment was plotted against time. A transient increase in proximal flux was generated by manually squeezing the limb distal to the segment under examination. On releasing the distal compression, substantial amounts of blood pass distally (pathological reflux) if the valve proximal to the site of examination does not close properly. For assessment of the calf veins, the foot was compressed; for assessment of the thigh veins, the calf was compressed. Criteria for pathological reflux were duration of 0.5 seconds and peak reflux velocity 10 cm/second. The Doppler examination was provided on both legs.

  All patients exhibited symptoms of chronic venous insufficiency (CVI) — ie, edema, skin hyperpigmentation, and lipodermatosclerosis of the affected limb. The body mass index (BMI) was calculated for all patients. According to international norms, a BMI >30 kg/m² indicated adipositas. The number of smokers was recorded as well. Patients were evaluated using the clinical, etiological, anatomical, and pathological elements (CEAP) classification¹⁴ of chronic venous insufficiency.

  Intervention. To commence with the study, the participating facility provided patients in all treatment groups a standard regimen of drug therapy for 2 months that included micronized purified flavonoid fraction, 450 mg diosmin, 50 mg hesperidin, and Daflon 500 (two tablets, 500 mg each) once daily. Gauze dressings saturated in 0.9% sodium chloride were applied to the wounds and changed once a day.

  Compression was applied by a clinic physiotherapist, a professional practitioner with 15 years of experience who completed a course on management of leg ulcers and additional training before the study (20 days to practice applying bandaging with Kikuhime manometer, Advanci’s Medical, UK).

  Patients in group A (isolated superficial vein insufficiency) and group B (combined superficial and deep vein insufficiency) received 12-chamber intermittent pneumatic compression therapy. The Flowtron Hydroven 12 System device (Huntleigh Healthcare, UK) was applied to compress the cuff fitted over the foot, lower leg, knee, and thigh. Cuff length was 109 cm (1 foot representing 33 cm in length). The cuff extended from foot (circumference 38 cm) to thigh (circumference 71 cm). All patients were treated with 60 mm Hg of pressure at the ankle, and in the upper chamber, less pressure was exerted, decreasing to 40 mm Hg in the chamber at the level of the groin. Ventricular filling time was 60 seconds, with a discharge time of 30 seconds. Treatments were performed once daily for 15 days; a single treatment lasted 60 minutes. Treatment was provided with the patient lying supine. Before inserting the patient’s limb into the cuff, the clinician wrapped the leg in a bandage to protect the cuff from wound exudate. Additionally, the cuff was disinfected by Liquid Spray Incidin (Ecolab, Poland) after each use. Gauze dressings saturated in 0.9% sodium chloride were applied to the wounds inbetween pneumatic compression.

  Patients in group C (isolated superficial vein insufficiency) and group D (combined superficial and deep vein insufficiency) were treated with an ulcer stocking system (Ulcer X, Sigvaris, Gianzoni & Cie AG, Switzerland), providing pressure of 30 mm Hg to 40 mm Hg at the ankle. The system was put on the leg at the outpatient clinic every morning, worn during the day (approximately 10–12 hours), and removed at night. Treatments were performed daily for 15 days.   Patients in group E (isolated superficial vein insufficiency) and group F (combined superficial and deep vein insufficiency) were treated using two-layer, short-stretch bandaging (Sigvaris, Gianzoni & Cie AG, Switzerland). The pressure values were standardized using the Kikuhime manometer (30 mm Hg to 35 mm Hg for superficial reflux and 35 mm Hg to 40 mm Hg for superficial with deep venous reflux). Bandages were applied in two layers with spiral turns on the foot and spiral eights on the calf. The bandages were worn during the day (10–12 hours) and removed at night. Treatments were performed daily for 15 days. The sub-bandage parameter settings in comparative groups were consistent with recent recommendations.^8,12

  Therapy progress was assessed using analysis of healing rates and digital planimetry (Kurta XGT, Altek Inc, Norgwyn Montgomery Software Inc, North Wales, PA). Wound depth was measured using a digital caliper with a depth gauge (MIB-Messzeuge IP67 Germany) at the wound’s deepest point. The volume was calculated by Kurta’s software. Wounds were assessed at baseline and after 15 days of treatment. Proportion of wounds healed (number of patients) was compared to the total number of patients in all groups.

  Data collection. A nurse from the hospital collected all data and coded it for data entry in an Excel database. The blinded results were transferred to Statistica version 10.0 (StatSoft Inc, Poland) database by a technician from Department of Medical Biophysics. The research coordinators had no contact with patients and could not identify them.

  Statistical analysis. The chi-squared independence test (greatest reliability level) and nonparametric Kruskal Wallis one-way analysis, an element of a module of the analysis of variance, were used to compare variables in all patient groups. Outcome measurements were compared between groups using Fisher’s test and within the groups using nonparametric Wilcoxon signed-rank test. Two-sided P (level of significance) values of <0.05 were considered statistically significant.

Results

  A total of 140 patients were evaluated for inclusion. Patients were excluded from the study based on ABPI <1.0 (21 patients), diabetes (eight), cancer (one), peripheral nerve injury – peroneal nerve (one), rheumatoid arthritis (nine), ventricular arrhythmia (five), cardiac pacemaker (one), history of ulcer surgery (11), skin infection (three), pregnancy (two), post-steroid therapy (five), and bilateral ulcers (10). Three patients refused to participate in the study. In total, 70 patients with unilateral VLUs were enrolled. The average age of all participants was 62.28 years (SD 12.35 years) and most had ulcers in the medial ankle (55.71%). The average duration of ulcers was 29.65 months (SD 27.89 months). The average initial size of wounds was 20.98 cm2 (SD 22.34 cm2). Patient group characteristics were not significantly different between groups (see Table 1). CEAP classifications were also evenly distributed between intervention groups and not significantly different (see Table 2).   After the 15-day study, the difference between baseline and final wound dimensions was statistically significant in all treatment groups. In patients with reflux in superficial veins, the average wound size decreased from 20.12 cm² to 10.21 cm² after pneumatic compression, from 19.45 cm² to 10.45 cm² after compression stocking system, and from 17.23 cm² to 8.46 cm² after bandages. In patients with reflux in superficial and deep veins, the ulcer area decreased from 19.35 cm² to 10.02 cm² (intermittent compression therapy), from 25.09 cm² to 20.04 cm² (stockings) and from 24.67 cm² to 21.89 cm² (bandages) (see Table 3).

  The proportion of completely healed ulcers after 15 days in patients with reflux in the superficial veins was highest in the group managed with the ulcer stocking system (27.27%), followed by the intermittent pneumatic compression system (25%). In patients with reflux in superficial and deep veins, the proportion of healed ulcers was similar (20%) in the intermittent pneumatic compression and ulcer stocking system group (see Table 4). The lowest rates were found in groups E (short-stretch bandages in patients with reflux in superficial and veins, 10%) and F (bandages in patients with reflux in superficial and deep veins, 6%) (P = 0.01) compared to groups A, B, C, and D.

  Similarly, percent change in total wound surface area was significantly higher in groups C (42.11%, stockings in patients with reflux in superficial veins), A (41.22%, intermittent pneumatic compression in patients with reflux in superficial veins), D (39.22%, stockings in patients with reflux in superficial and deep veins), and B (38.68%, intermittent pneumatic compression in patients with reflux in superficial and deep veins) than in groups E and F (18.77% after bandages in superficial and 15.89% in superficial plus deep insufficient veins) P = 0.02 (see Table 4).

Discussion

  The current clinical trial showed the most effective therapy for VLU size reduction and rate of healing (regardless of the anatomic location of venous insufficiency) is the use of intermittent pneumatic compression and compression stockings, and the least effective treatment is two-layer compression therapy with bandages. Thus far, researchers have not analyzed intermittent pneumatic compression therapy in two groups of participants with superficial alone and combined superficial plus segmental deep venous reflux. This study is the first attempt of this kind to relate findings to data in the literature.

  Only one meta-analysis¹⁵ (ie, Cochrane Review) addressed intermittent pneumatic compression in VLUs. This meta-analysis included trials that compared the effects of pneumatic compression with control (sham or no compression) or compared the effects of different intermittent compression treatment regimens in VLU management. The authors identified seven randomized controlled trials that included 367 patients in total. Only one trial was at low risk of bias, having reported adequate randomization, allocation concealment, and blinded outcome assessment. In one trial (N = 80), more ulcers healed with intermittent compression than with dressings (62% versus 28%, P = 0.002). Four trials compared intermittent pneumatic plus compression with compression alone; one (N = 45) noted more ulcer healing with intermittent pneumatic plus compression than with compression alone (risk ratio for healing 11.4, 95% confidence interval 1.6–82). The remaining three trials (N = 122 total) found no evidence of a benefit from intermittent pneumatic plus compression compared with compression alone. One (N = 16) found no difference between intermittent compression therapy (without additional compression) and compression bandages alone, and another that compared different ways of delivering intermittent compression found that rapid (filling time in chambers 45 to 60 seconds) pneumatic procedures healed more ulcers than slow (filling time 15 to 30 seconds) procedures (86% versus 61%). In conclusion, the literature showed intermittent compression therapy may increase healing compared to no compression, but it is not clear whether it increases healing when added to treatment with bandages or if it can be used instead of compression bandages. Further trials are required to determine whether pneumatic compression increases the healing of VLUs when used in modern practice where compression therapy is widely used.

  In a randomized, clinical trial that compared the effect of two different combinations of intermittent compression therapy pump settings (rapid versus slow) in VLU healing, Nikolovska et al¹⁶ randomized 104 patients with VLUs to receive either rapid (60-second filling time) or slow (30-second filling time) procedures for 1 hour daily. The primary and secondary endpoints were the complete healing of the reference ulcer and the change in the area of the ulcer over the 6-month observational period, respectively. Complete healing of the reference ulcer occurred in 45 of the 52 patients treated with rapid pneumatic procedures and in 32 of the 52 patients treated with slow procedures. The results, using survival curve analysis (Kaplan-Meier plot), showed the proportion of ulcers healed at 6 months was 86% in the group treated with the fast intermittent regimen, compared with 61% in the group treated with a slow regimen (P = 0.003, log-rank test). The mean rate of healing per day in the rapid intermittent pneumatic compression group was found to be significantly faster than the slow procedure group (0.09 cm2 versus 0.04 cm², P = 0.0002).

  In a clinical study that compared intermittent compression pump versus compression bandages (multilayer technique), as well as patient compliance and satisfaction with the two techniques in the treatment of VLU, Rowland¹⁷ found no significant difference between treatment types among 11 patients with regard to ulcer healing rates or control of leg edema. Patients found the pump easier and more comfortable to use than bandages, with a trend toward increased compliance.

  Vowden¹⁸ maintains in a systematic review that even with the application of four-layer bandaging (the current authors tested only two-layer, short-stretch bandages), the recommended treatment for VLU, patients with reduced mobility have delayed ulcer healing. In her opinion, the intermittent pneumatic compression has an established role in deep vein thrombosis prophylaxis and has been shown to influence fibrinolysis, tissue oxygenation, edema, and venous return. It also has been suggested, but not yet proven, that pneumatic compression may improve VLU healing. An extensive review of the literature (publication pending) has demonstrated the use of this treatment on patients with reduced mobility has not been previously studied; yet, analysis of difficult-to-heal ulcer patients would indicate this method of treatment may be appropriate and requires further study.

  The current authors found many studies in the literature are based on a small number of patients, unclear randomization, lack of inclusion and exclusion criteria, Doppler duplex flowmetry, and evaluation by CEAP scale. Further clinical trials are needed comparing various types of compression in VLU (separately in combined superficial plus deep vein insufficiency and isolated superficial alone). Only Kalodiki et al,¹⁹ in an experimental study, tested the hypothesis that intermittent pneumatic compression applied in combination with a four-layer bandage in patients (SCD Compression System, Covidien, Mansfield, MA) with VLU increases popliteal vein volume flow and velocity. Researchers studied 20 limbs of 18 patients, median age 76 years. The total volume flow (TVF) and the peak systolic velocity (PSV) were recorded in the popliteal vein using duplex ultrasonography. Measurements were made without bandage, with four-layer bandage, and following the application of the compression system on top of a four-layer bandage for at least 15 minutes. The median PSV was 8.4 cm/second without bandage, 13 cm/second with the four-layer bandage, and 27 cm/second with the addition of the compression system. Both TVF and PSV increased slightly with the addition of the four-layer bandage. However, with the addition of the compression system, these parameters increased three-fold (TVF 20.22 cm/second and PSV 25.02 cm/second), showing capillary blood flow increases and less reflux.

Limitations

  The small number (70) of patients with VLU that participated in six comparative groups (combined superficial plus deep veins insufficiency and superficial alone) was considered a limitation of this pilot study. In the future, results should be verified on a larger group of patients and analyzed using parametric statistics (the Gauss decay and analysis of variance ANOVA). Results should be more long-term (2 months and follow-up observation of recurrence after 6 and 12 months) rather than the 2 weeks of therapy studied to facilitate calculation of Kaplan-Meier survival analysis with log-rank comparisons. Although study outcomes were consistent in each treatment group, the absence of blinding and lack of a placebo limit generalization of the findings. In the future, the authors would like to provide quasi-compression therapy in control groups and present complete results.

  Another limitation is the current standard of care (saline-soaked gauze), which may be considered suboptimal. In addition, only two-layer, short-stretch bandaging with a pressure of 30 mm Hg to 40 mm Hg (not a multilayer system with 40 mm Hg to 50 mm Hg) was applied. This may be why bandages and stockings produced such different healing outcomes. Future studies might benefit from comparing intermittent pneumatic compression and stockings to bandages with higher pressure values.

Conclusion

  According to recent literature, providing compression therapy via stretch stockings and bandages in the healing of venous leg ulcers is more popular than intermittent pneumatic compressions. However, the results of this pilot study show that combined superficial and deep vein insufficiency/isolated superficial alone VLUs treated with intermittent pneumatic compression therapy (12 chambers, 60 mm Hg at ankle, 60 minutes daily) exhibited a significantly faster reduction in wound surface area than ulcers treated with two-layer, short stretch bandages and standard care only. Clinical study will continue beyond this pilot endeavor, but at this moment there is some evidence of benefit (in some cases comparable to compression stockings or multilayer compression systems) of intermittent pneumatic compression in the treatment of VLU. Future studies should follow patients until healing, and randomized controlled clinical studies are needed.

Dr. Pawel Dolibog is an engineer and assistant; and Prof. Franek is an engineer and Head, Department of Medical Biophysics, Medical University of Silesia, Katowice, Poland. Prof. Taradaj is a physical therapist and Head; and Dr. Polak is a physical therapist and assistant, Department of Physiotherapy Basics, Academy of Physical Education, Katowice, Poland. Dr. Patrycja Dolibog is a medical physicist and assistant; Prof. Blaszczak is a statistical analyst and senior lecturer, Department of Medical Biophysics; Prof. Wcislo is a dermatologist and Head, Department of Dermatology; Prof. Hrycek is an internist and Head, Department of Internal, Autoimmune and Metabolic Medicine; Prof. Urbanek is a vascular surgeon and senior lecturer, Department of General and Vascular Surgery; Prof. Ziaja is a vascular surgeon and senior lecturer, Department of General, Vascular and Transplant Surgery; and Dr. Kolanko is a dermatologist and assistant, Department of Dermatology, Medical University of Silesia. Please address correspondence to: Prof. Jakub Taradaj, Department of Physiotherapy Basics, Academy of Physical Education, Mikolowska Street 72A 40-065, Katowice, Poland; email: j.taradaj@awf.katowice.pl.

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