Clinical superiority of an innovative two-component compression system versus four-component compression system in treatment of active venous leg ulcers: A randomized trial

Abstract

Objective

To evaluate the efficacy, safety and acceptability of an innovative two-component versus a well-established four-component compression systems in the management of venous leg ulcer.

Method

Multicentre randomized controlled trial in patients with active venous leg ulcer. Patients were followed-up monthly for a maximum of 16 weeks. The primary endpoint was the complete healing rate at 16 weeks.

Results

Ninety-two patients were randomized to either the two-component BIFLEX® Kit group (n = 49) or the four-component PROFORE® group (n = 43). In the full analysis set (n = 88), a complete healing rate of 48.9% and 24.4% was reported in BIFLEX® Kit versus PROFORE® groups, respectively (i.e. a superiority of 24.5%, p = 0.02). Acceptability of BIFLEX® Kit was higher from both the patients’ and physicians’ perspectives.

Conclusion

The BIFLEX® Kit represents a valid alternative therapy in the management of venous leg ulcer according to its clinical efficacy, safety and acceptability with potential positive impacts on healthcare costs.

Keywords

Venous leg ulcer compression therapy multi-layer compression system complete healing

Introduction

An active venous leg ulcer (VLU) is defined as a leg wound which has not healed for more than six weeks, and for which there is no arterial involvement (Comprehensive Classification System for Chronic Venous Disorders (CEAP) class 6).^1,2 Although not life threatening, VLUs result in significantly impaired quality of life,³ particularly due to the resulting pain, secondary infections, lack of mobility and restriction of routine activities.

In developed countries, chronic leg ulcers affect up to 1% of the population; 0.6–3% of those aged over 60 years, increasing to 3% of those aged over 80 years.^4,5 Given their high prevalence, management of VLUs represents an economic burden to healthcare systems. The mean healing time of VLUs is long; therefore, the costs per patient are huge and can be multiplied by a factor of 4 to 5 when managing an unhealed or recurrent VLU.^6–8 In Western European countries, the total treatment cost of VLUs is estimated as 1% of the total annual healthcare budget. A recent prospective multicentre study performed in Germany calculated the mean total cost of a VLU per patient per year to be €9569 (92% direct costs and 8% indirect costs).⁹ In the United States, VLUs are estimated to result in the loss of two million working days per year and the annual cost of treatment approach $2.5 billion.

The recommended treatment of VLUs is based on compression therapy. For VLU patients with an ankle brachial index (ABI), between 0.8 and 1.3, a high-pressure level compression therapy is the standard of care.¹⁰ According to international clinical guidelines on VLUs and the latest French guidelines from the Haute Autorité de Santé (HAS), multilayer systems are the first-line treatment of VLU.¹¹ Healing rates with compression therapy range from 30 to 60% at 24 weeks and 70 to 85% after one year. Although average healing times range from 12 to 30 weeks,¹² some venous ulcers do not heal. Risk of recurrence is estimated between 30 and 70% within 5 years¹³ impacting significantly the patient’s quality of life and costs.¹⁴

The PROFORE® system (Smith & Nephew Medical Limited, UK) is a well-established single-use four-component bandage system. Its efficacy in the management of VLU has been demonstrated by several studies.^15–19 It is composed of one padding bandage, one crepe bandage, one light compression bandage and one cohesive compression bandage.

Thuasne Group (Saint-Etienne, France) has developed the BIFLEX® Kit; a two-component compression system composed of two different short-stretch graduated elastic bandages. The BIFLEX® Kit is washable and reusable.

The objective of the study was to compare the efficacy and safety of the BIFLEX® and PROFORE® systems in the management of VLU.

Patients and methods

Study design

This non-inferiority, phase IIIb, randomized controlled study was conducted in 30 French medical centres. Investigators were phlebologists, primary care physicians, vascular medicine specialists and dermatologists with extensive experience in compression systems and wounds in hospitals and/or private practice. At inclusion, patients were randomized to either BIFLEX® Kit or PROFORE® treatment. Randomization was computer-generated, balanced per centre and treatment was allocated using a telephone service.

Patients

The study was carried out in accordance with the declaration of Helsinki. Patients received information according to French legislation, and their informed consent for participation in the study was recorded. The agreement of the Comités de Protection des Personnes (CPP) ethics committee and the Agence Nationale de Sécurité du Médicament were obtained in 2014 (registration number: 2014-A00287-40, ClinicalTrials.gov: NCT02782689). Approval from the Commission Nationale de l'Informatique et des Libertés was obtained for reference methodology (MR001).

In- and out-patients aged 18–95 years with active VLU were recruited. Inclusion criteria were: VLU for 1–36 months; VLU size between 2 and 70 cm²; VLU with venous origin, superficial or post-thrombotic, confirmed by venous Doppler ultrasound in the previous 6 months; ankle circumference between 18 and 25 cm (to enable the compression system to be applied). In the case of multiple ulcers, the largest, at least 3 cm distant from the others, was considered.

Exclusion criteria were: ulcer surgery planned within 16 weeks following inclusion; ulcer with clinical infection not controlled with oral antibiotic treatment; cancerous ulcer or completely covered by a dry fibrous tissue or by a black necrotic plaque over more than 10% of the surface; deep vein thrombosis within the previous 3 months; active chronic conditions such as arteriopathy of the lower limbs or microangiopathy (ABI < 0.8 or >1.3); uncontrolled type 2 diabetes, type 1 diabetes or any uncontrolled severe and progressive disease; inability to wear a multilayer compression system.

Study protocol

At inclusion, the examiner recorded demographic data, leg ulcer history, a detailed ulcer description (duration, recurrence, size, leg laterality, pain) associated symptoms and vital signs. They also applied the compression system according to the randomization schedule and manufacturer’s instructions. Monthly, at weeks 4, 8 and 12 (±3 days), the physician collected data on ulcer healing, number of compression systems used, tolerance, acceptability, standard follow-up data and pictures of ulcers. Dressing changes were conducted by the investigator at the monthly visit and by private nurses between visits. These data were collected daily in patient diaries, with the help of a nurse at home if needed and recorded by the investigator in the Case Report Form (CRF). The ulcer was cleaned according to the convention of each centre, and choice of primary dressing was at the investigator’s discretion. Details of topical and systemic concomitant treatments were recorded. The end-of-study visit was performed at week 16 (±3 days) or earlier in cases of complete healing.

Endpoints

The primary endpoint was the percentage of ulcers completely healed (i.e. 100% epithelialization and no exudate), confirmed by investigator, at week 16.

Secondary efficacy endpoints were: the percentage of healed patients at weeks 4, 8 and 12; the mean complete healing time; the change in ulcer pain evaluated monthly by the patient with a Visual Analogue Scale; the acceptability of the compression system evaluated by both the patient and investigator using a four-level verbal scale completed at the last study consultation; the change in quality of life evaluated by the patient at inclusion and week 16 (or before if healed) using the self-administered SF12 questionnaire.²⁰

Safety endpoints were all adverse events (AEs) (number, severity, gravity, relationship to the product) occurred throughout the study.

Medico-economic criteria, recorded in patient diaries and CRF, were: the number of compression systems used per week; the number of nurse visits; the number and type of dressings used; the number of compresses used.

Statistics

Based on published literature, an ∼80% ulcer healing rate was expected at week 16.¹⁶ With an alpha risk of 0.05 and a statistical power of 80%, it would be necessary to recruit 88 patients into each treatment group.

Statistical analyses were conducted using SAS® software, version 9.4 (SAS Institute, Cary NC, USA). Descriptive statistics of all variables are presented overall. Quantitative variables are described by count, missing data, mean, standard deviation, median and range. Qualitative variables are described by absolute frequency and count percentage.

Primary non-inferiority analysis was performed on the Per Protocol (PP) population and, for robustness, on the Full Analysis Set (FAS) population.

To determine the primary outcome, complete healing at week 16 in each treatment group, the percentage of healed patients at week 16 was described with a one-sided 95% confidence interval (CI). The difference between the rates of healed patients at week 16 was calculated as well as its one-sided 95% CI. Non-inferiority was concluded in the PP population if the lower limit of the one-sided 95% CI of this difference was above –15% (an acceptable margin for Health Authorities).

Secondary endpoints were compared at a global significance level of 0.05 using: Pearson’s Chi-squared or Fisher’s exact test for qualitative variables; Student’s t-test or variance analysis for Gaussian quantitative variables or non-parametric Wilcoxon Mann–Whitney or Kruskal–Wallis test for non-Gaussian quantitative or semi-quantitative variables.

Results

Patient demographics and disposition

In total, 92 patients were included in 27 centres from November 2014 to December 2016 and randomized to either the BIFLEX® Kit (n = 49) or PROFORE® (n = 43) group. Four patients (two in each group) were excluded from statistical analysis; three were not properly followed up and one withdrew consent (Figure 1). Therefore, the FAS population was composed of 88 patients; 47 in the BIFLEX® Kit and 41 in the PROFORE® group. The PP population was composed of 83 patients (45 in the BIFLEX® Kit and 38 in the PROFORE® group), as five patients with major deviations were excluded from the FAS population (one did not meet inclusion criteria, two met exclusion criteria and two with less than one week of treatment).

Figure 1.

Flow chart indicating the generation of the FAS and PP populations.

Patients’ characteristics and baseline clinical parameters are shown in Table 1. All included patients suffered from an active VLU, C6 class (CEAP classification). At inclusion, both treatment groups were similar in most documented items (∼74 years old, ∼68% female), but showed some imbalances on prognostic factors of ulcer healing, also listed in Table 1.

Table 1.

Patients characteristics and clinical parameters at baseline.

	BIFLEX® Kit group (n = 47)	PROFORE® group (n = 41)
Demographics
Male/female (%)	34.0/66.0	29.3/70.7
Age (years)	74.4 ± 12.4	73.5 ± 14.3
BMI (kg/m²)	30.1 ± 6.5	27.7 ± 5.9
BMI (kg/m²) > 30	44.7%	31.7%
Clinical parameters
Mobility without assistance	61.7%	82.9%
Documented (echo Doppler) post-thrombotic venous insufficiency	25.5%	17.1%
History of varicose	59.6%	68.3%
History of DVT	38.3%	26.8%
Duration of ulcer (months)	9.4 ± 8.5	6.5 ± 5.3
Recurring ulcer	63.8 %	51.2 %
Size of ulcer
2–5 cm²	40.4%	19.5%
5–25 cm²	48.9%	53.7%
25–50 cm²	10.6%	26.8%
Leg laterality
Right	36.2%	31.7%
Left	63.8%	68.3%
Ankle circumference (cm)	23.7 ± 1.3	22.7 ± 1.6
Pain (VAS) mm	30.8	34.2

Unless otherwise specified, values are expressed as mean ± SD.

SD: standard deviation; BMI, body mass index; DVT, deep venous thrombosis; VAS, visual analogic scale.

At inclusion, all patients were equally treated with primary dressings, including (in the BIFLEX® and PROFORE® groups, respectively): hydro-cellular (31.9% vs. 35%), hydro-fibres (34 and 32.2%) and alginate (12.8 and 15%).

Efficacy results

Primary endpoint

In the PP population, complete healing rates of 48.9% in the BIFLEX® Kit group versus 26.3% in the PROFORE® group were observed, i.e. a difference of 22.6% with a 95% CI of [0.9; 42.6] in favour of BIFLEX® Kit. Similar results were obtained in FAS population (Figure 2). As the lower limit of the CI was superior to the non-inferiority margin (–15%), non-inferiority of BIFLEX® Kit was therefore accepted. BIFLEX® Kit was also found significantly superior to PROFORE® in both PP (p = 0.043) and FAS population (p = 0.027).

Figure 2.

Complete healing rates in the BIFLEX® Kit and PROFORE® groups in the PP and FAS populations.

Secondary efficacy endpoints

Linear regression analysis was performed to deal with baseline differences in potential prognostic factors between the treatment groups (Table 2). Independently of any factor, patients had three times more probability to heal in the BIFLEX® Kit than PROFORE® group (odds ratio (OR) of 3.01; 97.5% CI of [1.1; 8.6], p = 0.03).

Table 2.

Complete healing rates according to different prognostic factors (FAS population).

	BIFLEX® Kit (N = 47)	PROFORE® (N = 41)	FAS (N = 88)
Ulcer origin
Superficial venous disease, complete healing rates % (n/N)	45.7% (16/35)	26.5% (9/34)	36.2% (25/69)
Post-thrombotic venous insufficiency complete healing rates % (n/N)	58.3% (7/12)	14.3% (1/7)	42.1% (8/19)
Ulcer size
[2–5] cm², complete healing rates % (n/N)	63.2% (12/19)	50.0% (4/8)	59.3% (16/27)
[5–25] cm², complete healing rates % (n/N)	43.5% (10/23)	22.7% (5/22)	33.3% (15/45)
[25–50] cm², complete healing rates % (n/N)	20.0% (1/5)	9.1% (1/11)	12.5% (2/16)
Ulcer date of onset
≤6 months, complete healing rates % (n/N)	60.0% (15/25)	32.0% (8/25)	46.0% (23/50)
>6 months, complete healing rates % (n/N)	36.4% (8/22)	12.5% (2/16)	26.3% (10/38)
Ulcer recurrence
Recurrent ulcer, complete healing rates % (n/N)	36.7% (11/30)	14.3% (3/21)	27.5% (14/51)
First ulcer, complete healing rates % (n/N)	70.6% (12/17)	35.0% (7/20)	51.4% (19/37)

This also show a better healing rate in the BIFLEX® Kit versus PROFORE® group whatever the prognostic factor considered. According to the actuarial method, survival curves show a significant difference in healing rate between the groups in favour of BIFLEX® Kit (p < 0.001) at week 16 and an even greater estimated difference at week 20, when real data from patients visits occurred until the 19th week were considered (Figure 3).

Figure 3.

Healing rates in the BIFLEX® Kit and PROFORE® groups expressed as survival curves over 16 weeks.

Pain was significantly improved by week 16, compared with baseline in both groups (adjusted mean in millimetre (SD) of –13.83 (3.68) for BIFLEX® Kit and –15.68 (4.0) for PROFORE®) with no statistical difference in between groups. Quality of life was significantly improved by week 16, compared with baseline in both groups for mental and social score (adjusted mean of 1.95 (1.51) for BIFLEX® Kit and 0.76 (1.46) for PROFORE®) and physical score (adjusted mean of 0.61 (1.27) for BIFLEX® Kit and 1.27 (1.23) for PROFORE®) with no statistical difference in between groups.

Safety endpoints

Few AEs possibly related to the treatment were reported five in BIFLEX® Kit group and four AEs in PROFORE® group, i.e. <10%. These were mainly skin reaction such as pruritus, eczema, erythema and skin ulcer (Table 3). No serious adverse events (SAEs) were related to the medical devices; five unrelated SAEs were reported in the BIFLEX® Kit and six in the PROFORE® group. Among them, one case of erysipela was reported in each group. No weight change was observed in either group.

Table 3.

Adverse reactions observed in both treatment groups during the study

	BIFLEX® (N = 49)		PROFORE® (N = 43)		Safety population (N = 92)
Number of patients (n) %	n	%	n	%	n	%
With at least one adverse reaction	4	8.2	4	9.3	8	8.7
Skin and subcutaneous tissue disorders	3	6.1	3	7	6	6.5
Pruritus	2	4.1	0	0	2	2.2
Skin ulcer	1	2	1	2.3	2	2.2
Eczema	1	2	0	0	1	1.1
Erythema	0	0	1	2.3	1	1.1
Pustular psoriasis	0	0	1	2.3	1	1.1
Musculoskeletal and connective tissue disorders	1	2	1	2.3	2	2.2
Pain in extremity	1	2	1	2.3	2	2.2

Acceptability of the compression systems

Compression system assessments, made independently by patients and investigators, are described in Figure 4. Patients reported significantly greater satisfaction with the softness (p = 0.024), breathability (p = 0.010), thickness (p = 0.011) and putting shoes on simplicity (p = 0.033) of BIFLEX® Kit than PROFORE®. Physicians indicated significantly higher satisfaction with BIFLEX® Kit compared to PROFORE® for: application simplicity (p = 0.024); application time (p = 0.003); practicality of the system (p = 0.002) and comfort during handling (p = 0.002). No difference in slippage along the leg was reported between groups (p = NS).

Figure 4.

(a) Satisfaction with the BIFLEX® and PROFORE® Kits according to the study team in the FAS population. (b) Satisfaction with the BIFLEX® and PROFORE® Kits according to the patients in the FAS population.

Medico-economic endpoints

The average number of kits used per patient was 17.6 for BIFLEX® versus 33.2 for PROFORE® (corresponding to a reduction of 47%, p < 0.001) over a similar average follow-up period (12.7 weeks) and nurse-visits (39.8 in BIFLEX® vs. 39.4 in PROFORE® group) (Table 4). Lower consumption of BIFLEX® Kits was observed regardless of complete versus partial healing at week 16. A lower consumption of gauzes (154.5 ± 156.1, N = 12 vs. 180.7 ± 136.9, N = 12) and dressings (23.7 ± 23.3, N = 12 vs. 54.1 ± 108.9, N = 13) were observed in BIFLEX® group versus PROFORE®.

Table 4.

Mean number of devices used per patient and mean number of nurse visit per patient during the study.

	BIFLEX® (N = 49)	PROFORE® (N = 43)	Tolerance population (N = 92)
Number of kits used (mean ± SD)	17.6 ± 13.9 (N=43)	33.2 ± 20.2 (N=39)	25.0 ± 18.8 (N=82)
Number of nurse visits (mean ± SD)	39.8 ± 23.3 (N=17)	39.4 ± 21.5 (N=18)	39.6 ± 22.1

Discussion

This study was designed to evaluate efficacy and safety of a new two-component bandage system, compared with a well-established four-component system, in patients suffering from active VLU.

It has been demonstrated that BIFLEX® Kit is superior to PROFORE® in terms of complete healing rate by week 16.

Several factors such as age, obesity, size of the ulcer, wound duration or existence of deep venous aetiology can influence VLU healing.^21–23 Logistic regression analysis confirmed the superiority of BIFLEX® Kit, regardless of any associated factors. An OR of ∼3 for BIFLEX® Kit over PROFORE® emphasized its benefit. The other independent factors influencing complete healing were recurrence status (OR: 3.2) and size (OR: 0.4) of the VLU, as previously reported.^21,22,24

Previous studies reported higher healing rates with PROFORE® from 32 to 74% after 12–24 weeks.^{17,18,25–28} Indeed, Partsch et al.¹⁶ reported healing rate of 62% after 16 weeks with PROFORE® but ulcers were smaller (mean 1.5 cm²) and more recent (mean duration 5 weeks). He also observed a healing rate about 33% in the larger ulcer size group versus 77% in the smaller one with PROFORE® System.

Similar results were obtained in the UK where closure was achieved in 74% of venous ulcers after 12 weeks.¹⁵ Again, it was on small (84% of patients had an ulcer size under 10 cm²) and recent ulcers (median ulcer duration was 6 weeks). More recently, in the ODYSSEY trial, healing rate of 39% in PROFORE® group after 12 weeks of treatment had been observed.²⁷ Again, ulcer size (mean 10 cm²; median 6.08 cm²) was probably lower than in our study. Last, a German team studied a more comparable population in terms of ulcer size (median 17.7–24.3 cm²) and ulcer duration (52% of patients with an ulcer lasting from more than 6 months).¹⁸ In that study, 32% of ulcers healed after 12 weeks. In the present study, 26.8% of the ulcers in the PROFORE® group were larger than 25 cm² and 53.7% were comprised between 5 and 25 cm². In the smallest ulcer size category (2–5 cm²), healing rate in PROFORE® group was 50% at 16 weeks which is found similar to other published data according to the recent meta-analysis for PROFORE® group treatment.²⁹

The bandages characteristics may also explain the healing rate differences between both treatments. The bandages of the BIFLEX® Kit are calibrated and marked, making its application easier, time saving and the required level of pressure reproductible and guaranteed. This point is important as pressure is crucial for healing independently from nurses’ skills. Stensal et al.³⁰ in an observational prospective trial conducted in France found that bandage application technique was inadequate in nearly half the patients. Only about 30% of general nurses and 50% of specialized nurses applied the bandages correctly. These findings underline the need for a simple bandage system or any specific indication on the provided level of pressure. Although numerous studies have evaluated the impact of compression therapy on complete healing,^{15,19,26–28,31} few data focused on the acceptability. Compliance in compression therapy is often reported as poor, ranging from just 15 to 30% in France and other European countries.^32,33 Poor compliance is recognized as responsible for a poor healing rate and higher rate of ulcer recurrence. The primary reasons for non-compliance are poor tolerance or constraints due to daily usage.³² Therefore, development of an effective new high-pressure level compression system composed of two bandages, which are less bulky, easy to use and which can be repositioned and washed up to three times, provides better practicality which is likely to improve compliance and reduce recurrence.^26,34 Several layer bandage like the PROFORE® system makes the footwear more complex and limits the mobility of the patient.

Although compliance was excellent in both groups, most ratings of user-friendliness criteria favoured BIFLEX® Kit including: practicality for physicians and patients (when bandages was applied by private nurses between visits), application simplicity and time and global satisfaction.

A similar number of nurses’ visits in the two groups was recorded; however, the average total kit consumption per patient was 17.6 for BIFLEX® and 33.2 for PROFORE®. This corresponds to a highly significant reduction of 47%, for a similar average period of follow-up (12.7 weeks). This was observed regardless of healing at week 16 (complete or partial) and could result in a substantial health economic benefit.^8,35,36 This may be related to the washable advantage of the new system.

The similar rate of nurse-visits, even with a higher healing rate for BIFLEX® group, is probably motivated by other patient needs of this elderly population (wound dressing, assistance with toilet use, pharmacological treatment). Reasons for nurse visits were not collected in the trial.

Several limitations of this study should be considered. Due to visual difference of the compression systems, blinding was not possible. Nevertheless, patients were followed by specialists with expertise in venous disease management and strong ability to assess objectively complete ulcer healing, as recommended by French Authorities.¹¹

Another limitation was the number of patients included. Due to enrolment difficulty, the study was stopped early. Baseline imbalances were considered in the statistical analyses, and despite fewer patients than expected, significant superiority of the BIFLEX® Kit was confirmed. Last, choice of primary dressings was at investigator’s discretion which may in store bias even if randomization per centre was done to minimize it.

Conclusion

This trial confirms that the new double short-stretch bandage, BIFLEX® Kit, is efficient, safe, easy to use and a well-accepted device. It is a cost-effective alternative to existing compression devices in the treatment of VLUs due to its calibrated, marked, repositionable and washable properties.

Footnotes

Declaration of Conflicting Interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr Gillet reports personal fees from Thuasne during the conduct of the study as principal investigator of the present study; Dr Guex, Pr Allaert and Dr Avouac report grants from Thuasne as scientific board members of the present study. Ms Pasqualini; Dr Ben Amor and Dr Simon are employed by Thuasne. Dr Leutenegger declares fees and payment from Thuasne for writing the manuscript.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/ or publication of this article: The authors received financial support from Thuasne (Saint-Etienne, France) for the research, authorship, and/or publication of this article.

Ethical Approval

The study was carried out in accordance with the declaration of Helsinki. Patients received information according to French legislation, and their informed consent for participation in the study was recorded. The agreement of the Comité de Protection des Personnes (CPP) ethics committee and the French Competent Authority, ANSM (Agence Nationale de sécurité du Médicament), were obtained in 2014 (registration number: 2014-A00287-40, ClinicalTrials.gov: NCT02782689). Approval from the CNIL (Commission Nationale de l'Informatique et des Libertés) was obtained for reference methodology (MR001).

Guarantor

The guarantor was Thuasne (Saint-Etienne, France).

Contributorship

Statistical analyses were performed by AdBIOSTAT (Arcueil, France). Editorial support was provided by Eric Leutenegger, MD, PhD (Paris, France) and Jonathan Robertson from Scinopsis Ltd (Brighton, UK).

Acknowledgements

The authors are very grateful to the patients and the patients’ families for their committed participation in the study; they also thank all the investigators.

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