Venous ulcer care: which dressings are cost effective?

Abstract

Healed or open venous ulcers may be present in up to 1% of Western populations and consume a large amount of healthcare resources. These ulcers are characterized by a chronic inflammatory environment with impaired healing and often require months for closure. The average monthly cost of care for an open ulcer has been estimated to be $4095. The fundamental tenets of ulcer care include adequate compression and maintaining a moist wound environment with an appropriate primary dressing. A number of specialized products including semi-occlusive/occlusive, antimicrobial, and advanced wound matrix dressings are now available. However, there is little data from appropriate clinical studies to suggest significantly improved outcomes with any of these dressings. Data regarding their cost-effectiveness is also limited, often conflicting, and subject to bias. At present, there is little solid evidence to guide the choice of primary dressings and a patient-centered approach focusing on characteristics of both the patient and their ulcer, while paying attention to costs, may be most appropriate.

Keywords

Venous leg ulcer compression wound care wound dressings comparative effectiveness

Leg ulceration is the most advanced stage of chronic venous disease. The prevalence of active venous ulcers is estimated to be 0.1 to 0.3% of the adult population in Western countries¹, corresponding to approximately 500,000 patients in the United States. However, open ulcers constitute only 20% to 25% of the total and the population prevalence of open and healed ulcers may be closer to 1%.^2,3 Initial ulceration occurs after age 50 in 60% of patients.⁴ Accordingly, the incidence of venous ulcer is highest in older patients and is estimated to be about 3.5 per 1000 in those over 45 years of age.⁵

The costs of managing venous ulceration include the direct costs related to diagnostic investigation, medical and nursing personnel, hospitalization, medications, dressings, bandages, and other treatments. Indirect costs include those related to lost productivity of patients and their caregivers. At least some data suggests that the costs of ulcer care are divided between direct care costs (48%), medication (33%), hospitalization (16%) and time lost from work (3%).⁶ Most economic analyses are conducted from the payer’s perspective, ignoring the indirect societal costs of time away from productive activity and personal costs to the patient.⁷ However, these indirect costs are not insubstantial–the mean number of lost workdays has been estimated to be 7 and 12 days per year in German males and females respectively.⁸

There is substantial geographic variation in resource utilization associated with the management of venous leg ulcers.⁹ Direct management costs are estimated to account for 1 to 2% of the healthcare budgets of Western countries and range from €600 million to €2.5 billion per year.⁸ Costs per patient may vary from €814 to €1994 in the United Kingdom to €1332 to €2585 in Sweden.⁹ Comparable costs in the United States have approximated $9685 (±$14, 136) per ulcer.¹⁰ Adjusted for inflation, this cost translated to $16, 524 per episode or an average monthly cost of $4095 in 2011.¹¹

Given the resources devoted to the care of venous leg ulcers, it is perhaps not surprising that there are an increasing number of wound care products, usually costing more than established alternatives. Although many are based on the underlying pathophysiology of chronic venous disease and principles of wound healing, several factors are important in determining whether these products are of value and whether they are cost effective.

Pathophysiology of venous ulceration

Although venous hypertension clearly underlies the manifestations of advanced chronic venous insufficiency, the pathophysiologic relationship between venous hypertension and ulceration remains unclear. Among several hypotheses, inflammatory processes are emerging as the most important factor in the pathogenesis of chronic venous insufficiency. (Figure 1) An underlying inflammatory etiology was first suggested by the observation that the leukocytes are sequestered in the dependent lower extremities of patients with venous disease.^12–14 The interaction between leukocytes and the endothelium under conditions of venous hypertension appears to be critical in the pathophysiology of chronic venous disease. As trapped leukocytes are activated, endothelial permeability increases and they migrate extravascularly, releasing toxic oxygen metabolites, proteolytic enzymes and cytokines.

Figure 1.

Pathophysiology of chronic venous insufficiency. Although both primary and secondary venous disease may lead to advance chronic venous insufficiency, it is clear that ambulatory venous hypertension leading to a chronic inflammatory state underlies most of the clinical sequelae.

Altered connective tissue remodeling, which is characterized by an imbalance between tissue degradation and repair with increased turnover of the extracellular matrix, is likely mediated by chronic inflammation.^15,16 This chronic inflammatory environment impairs cellular migration and proliferation. Chronic wound fluid from ulcers contains proinflammatory cytokines (IL-1ß, IL-6, TNF-α), growth factors (TGF-α, TGF-ß, IGF-1), matrix metalloproteinases, and reactive oxygen species–all of which may impair wound healing. Experimentally, chronic wound fluid has been demonstrated to decrease the viability of cultured fibroblasts and to promote cytoskeletal disruption.¹⁷

Ulcer healing depends on overcoming the effects of this chronic inflammatory milieu. Although not often supported by strong evidence, many of the components of wound care are specifically designed to overcome these deleterious conditions–controlling venous hypertension, mitigating chronic inflammation, managing chronic wound exudate, and maintaining an optimal wound healing environment.

Compression therapy

Compression therapy and maintenance of a moist wound environment are the fundamental tenets of modern ulcer care and compression remains the standard treatment to which all other therapies must be compared. Compression has a variety of effects on venous hemodynamics that ultimately serve to control edema and alter the microcirculatory milieu. At the microcirculatory level, endothelial - leukocyte interactions may be altered by a compression-related increase in wall shear stress.¹⁸ Beidler¹⁹ measured an array of inflammatory cytokines in 30 ulcerated limbs before and after institution of compression bandages. Prior to compression, the peri-ulcer tissue demonstrated a pro-inflammatory state with elevated levels of multiple cytokines. All cytokine levels with the exception of TGF-ß, an important regulator of fibroblast activity and tissue fibrosis, decreased with compression.

The clinical benefits of compression in ulcer healing are well documented. Among 22 randomized trials included in a systematic review by the Cochrane collaboration, 6 compared the use of compression therapy to treatment without compression.²⁰ Although the trials were sufficiently different to prevent pooled analysis, all showed higher rates of healing with compression, reaching statistical significance in 4 of 6.

A variety of compression modalities are available including single component elastic or inelastic systems, multiple component bandage systems, tubular compression devices, compression boots, and stockings. Multilayered compression bandages with high levels of compression are associated with healing rates of 60 to 80% at 6 months and are often considered the gold standard in venous leg ulcer treatment.²¹ One large metanalysis has suggested multi-component compression systems are more effective than single component systems and that those including an elastic bandage are more effective than inelastic components.²² However, a more recent analysis found no difference in the proportion of ulcers healed (70% versus 71%) or median time to healing (98 days versus 99 days) between four-layer compression bandages and two-layer hosiery. Twelve-month recurrence rates were, however, significantly higher with four-layer bandages (23% versus 14%).²³ Others have similarly found no difference in 12-week healing rates between 4 layer bandages (58%) and short stretch bandaging systems (53%) applied by a community nurse.²⁴

Wound dressings for chronic venous ulcers

Despite the importance of compression in healing venous ulcers, it is imperfect therapy–only 50 to 65% of ulcers will heal within 6 months.¹¹ Primary dressings are placed directly over the ulcer, beneath compression dressings. They serve to provide a moist healing environment, control exudate and prevent adherence of the compression bandages to the wound. Dressings that promote a warm, moist healing environment have been shown to increase the epithelialization rate by 40% in comparison to non-occlusive dressings.²⁵ A moist healing environment promotes autolytic debridement, angiogenesis and granulation tissue while encouraging keratinocyte migration.²⁶ Secondary dressings, such as an absorbent pad, may occasionally be applied over the primary dressing. The ideal dressing would theoretically provide a moist wound environment while at the same time preventing maceration, maintaining an optimal pH, protecting against toxins that impair wound healing, and minimizing the number of required dressing changes at the lowest possible cost.¹

Practice guidelines have recommended that simple non-adherent wound dressings combined with compression bandages be used in treating chronic venous ulcers.²⁷ However, more complex, specialized dressings have more recently become available. A variety of classifications have been proposed for ulcer dressings. These have included classification as passive, active, or reactive²¹ From a practical standpoint, available dressings include simple non-adherent, non-occlusive dressings; semi- and non-occlusive dressings; those specifically designed to control wound exudate; antimicrobial dressings; and advanced wound care matrices that either provide or indirectly stimulate growth substances within the wound. The spectrum of currently available dressing is shown in Table 1.

Table 1.

Wound dressings.

Dressing Type	Source	Purported Benefits	Commercial Products
Films	Polyurethane film with adhesive	Moisture retaining	Tegaderm HP® OpSite Flexigrid®
Hyddrogels Hydrocolloids	Hydrophilic polymers Gelatin, Pectin, Carboxymethylcellulose	Moisture retaining Autolytic debridement Promote granulation	Carrasyn Hydrogel® Curagel® Tegasorb® Duoderm CGF®
Alginates	Brown Seaweed	Control exudate Autolytic debridement Control bleeding	Algosteril ® Tegaderm Alginate ® Sorbsan ®
Foam	Polyurethane Foam Hydrocellular Foam	Control exudate Atraumatic removal	Cutinova ® Allevyn® Non-Adhesive Biatain ® Non-Adhesive Mepilex ®
Antimicrobial Dressings	Silver Cadexomer Iodine Polyhexamethyl Biguanidine	Broad spectrum antimicrobial	Acticoat® Iodosorb® AMD Antimicrobial Plus Foam®
Advanced Wound Care Matrices	Living skin constructs Bovine submucosa Diatoms	Wound coverage Growth factor production Protease inactivation Angiogenesis	Apligraf ® Oasis ® Talymed

Non-occlusive and semi-occlusive dressings are distinguished by their ability to prevent transmission of water vapor and heat. These dressings vary in their ability to reduce water vapor transmission and other desirable characteristics.²⁸ Hydrogels and hydrocolloids function to maintain a moist wound environment and may facilitate autolytic debridement.²⁶ Alginates, derived from brown seaweed, and hydrofibers, composed of carboxymethylcellulose, absorb fluids and are most appropriate for highly exudative wounds. These dressings tend to form a gel, reducing maceration. Foam dressings, composed hydrocellular or polyurethane foam, sometimes with a silicone backing, are indicated once an ulcer is granulating. Film dressings, composed of transparent, adherent polyurethane, protect and insulate the wound while promoting autolytic debridement of the eschar. Since this dressing type does not absorb wound drainage, maceration of the surrounding skin can occur. Finally, antimicrobial dressings contain silver, iodine, or polihexanide.

Several systematic reviews have evaluated the efficacy of modern wound dressings.^1,21,29 Most have found the overall quality of data to be poor. O’Donnell evaluated 20 randomized trials that included compression in both the control and experimental arms of the study. Heterogeneity prevented metanalysis of the 8 trials of semi-occlusive dressings, including foams, alginates, hydrogels, and hydrocolloids. However, only 2 of these 8 trials (zinc oxide impregnated bandage versus zinc oxide impregnated stockingette or a calcium alginate fiber dressing; Tegasorb versus DuoDerm) showed a significant increase in the proportion of wounds healed. In another metanalysis, Palfreyman²¹ also found significant heterogeneity in the data and identified no significant differences in wound healing between hydrocolloids and low adherent dressings (relative risk 1.0, 95% confidence interval 0.83–1.25), foam dressings (0.98, 0.79–1.22), or alginate dressings (0.72, 0.48–1.69). Similarly, no benefits were noted for foam dressings in comparison to low adherent dressings (1.35, 0.93–1.94) or alginate dressings (1.75, 0.79–3.88) or for hydrogel (1.53, 0.96–2.42) or alginate (1.08, 0.86–1.36) in comparison to low adherent dressings. Another metanalysis of 5 randomized clinical trials found no difference in the proportion of ulcers completely healed among patients treated with foam or hydrocolloid dressings (1.00, 0.81–1.22).³⁰ A final systematic review of five, mostly low quality randomized clinical trials found no significant benefit for alginates in comparison to either hydrocolloid or plain non-adherent dressings.¹

Evidence supporting the use of antimicrobial dressings is also sparse. A randomized trial including 213 patients with venous ulcers demonstrated no difference in 12-week healing rates between silver donating (59.6%) and non-adherent dressings (56.7%) when applied beneath multilayer compression bandages (relative risk of healing 1.06, 95% confidence interval 0.80–1.40).³¹

Advanced wound care matrices include both cellular and acellular products that may have a variety of effects including wound coverage, growth factor production, protease inactivation, and accelerated angiogenesis.¹¹ Apligraf is a commercially available, bi-layered living skin construct that closely approximates human skin. It derived from neonatal foreskin fibroblasts and keratinocytes and includes an epidermis overlying a dermis of fibroblasts in a bovine collagen matrix. Oasis is an acellular collagen matrix derived from porcine intestinal submucosa. Talymed is a thin poly-N-acetyl glucosamine (pG1cNAc) polymer matrix derived from diatoms.

Mostow³² compared collagen derived from porcine small intestinal submucosa (Oasis) to the semi-occlusive dressing, Allevyn. Wounds healed in 55% of the Oasis group in comparison to 34% in the Allevyn group. Falanga³³ compared Apligraf (allogenic cultured human skin equivalent) to a Tegapore film dressing in 309 participants followed for 6 months. A complex protocol allowed five applications of Apligraf over the first three weeks of the trial if less than 50% of the wound surface was covered. Ulcer healing was observed in 63% of patients treated with Apligraf in comparison 49% of controls. A meta-analysis of advanced wound care matrices estimated the number needed to treat (NNT–number of patients treated to achieve one additional healed ulcer) as 2 (95% confidence interval 2–8), 5 (3–39) and 6 (3–24) for Talymed, Oasis, and Apligraf respectively.¹¹

The comparative effectiveness of ulcer care

Comparative effectiveness has been defined as a “rigorous evaluation of different treatment options that are available for treating a given medical condition for a particular set of patients”.³⁴ The analysis may focus only on the relative medical benefits and risks of each option, or it may weight both the costs and benefits of those options. Comparative effectiveness research offers a strategy to determine what works best for which patients under what circumstances, considering clinical outcomes and costs in the comparison of alternative treatment strategies. The incremental cost effectiveness ratio (ICER), or cost per quality-adjusted life-year gained, is the standard measure in most cost-effectiveness analyses. Although this has been used in some ulcer care studies, many others have used the direct cost per ulcer healed as the primary outcome.

There are several important considerations in considering the cost-effectiveness of venous ulcer care. Dressing manufacturers have supported many cost analyses and the possibility of bias must be considered. A variety of approaches have been utilized, but most have been from the payer’s perspective, focusing only on the direct costs of medical care while ignoring the overall costs to the patient and to society. Others have focused only on the costs of dressings while neglecting other direct cost components. Although the cost of wound care products is an important consideration, total costs include those for nursing and physician time, hospitalization costs, the cost of complications, and home health costs. Total costs are directly related to the number of dressing changes required and the time to achieve complete healing. Among 20 wound care products included in a systematic review, 8 required weekly dressing changes while 5 required twice weekly dressing changes.²⁹ Over the course of a year, ulcer patients require a mean of 28 to 33 nursing visits consuming 16 to 18 hours of nursing time.²⁴

The 12 week costs of treating a venous ulcer are highly variable, ranging between $1,873 and $15,053 in one modeled analysis including 36 randomized, controlled studies of three ulcer treatment protocols.³⁵ Differences in cost were primarily attributed to the frequency of dressing changes and associated nursing costs, rather than to the cost of the dressings themselves, which constituted only a fraction of total costs. For example, nursing costs for saline dressings ($560) were substantially more than those for hydrocolloid (<$230) and Apligraf ($138).³⁶ In this model, incorporating personnel costs in addition to those for dressings and compression, hydrocolloid dressings were associated with the lowest cost followed by impregnated saline gauze and human skin constructs. Similarly, in a longitudinal cohort study, total per patient costs of treating a venous ulcer averaged $9685 (±$14, 136) with home health care, home dressing changes, and hospitalization accounting for 48%, 25%, and 21% of costs respectively.¹⁰ Labor costs in other studies have varied between 54 and 69% of the total costs in Sweden and the United Kingdom.⁹ In contrast, the cost of dressing supplies was only 13 to 25% of total costs. It is therefore clear that the absolute cost of specific dressing supplies is only a component, and sometimes a relatively minor one, of the total costs of caring for venous ulceration. Despite potentially higher costs, therapeutic interventions that decrease the time to complete healing afford a potential for significant cost savings.

Despite the clinical effectiveness of compression therapy, the comparative effectiveness of different compression modalities remains unclear. Among 3 studies evaluating the cost of compression, 3 reported lower costs with compression therapy, while the third reported no significant differences in cost compared to usual care.²² Morrell⁷ compared treatment with four-layer compression bandaging in a dedicated ulcer clinic with usual care provided by community nurses.⁷ Although median healing times (20 versus 43 weeks) were lower among patients treated in specialized ulcer clinics, yearly costs were higher (£804.3 versus £681.04). However, ulcer clinic treatment resulted in 5.9 more ulcer free weeks per year for an incremental cost effectiveness ration of £2.46 per ulcer free week. A randomized clinical trial comparing 4-layer bandages with short stretch bandaging systems applied by a community nurse, found 4-layer bandages to be associated with a small, 0.009 increase in quality adjusted life years for an incremental cost effectiveness ratio of $46, 667 per quality adjusted life year.²⁴ Similar analysis of a randomized trial comparing 4-layer compression bandages with two-layer hosiery showed average mean costs to be approximately £300 pounds higher in the hosiery group, largely due to more frequent nurse consultations.²³

Evidence regarding the cost-effectiveness of primary ulcer dressings is limited, often conflicting, and sometimes fraught with bias. A systematic review identified only three trials with cost data comparing alginates to hydrocolloids.¹ Only one trial included nursing costs in addition to dressing costs; alginate dressings being slightly more costly than hydrocolloids on a per ulcer healed basis ($1723.59 versus $1699.71). For foam dressings, two trials reported equivalent wear times for foam and hydrocolloid dressings, although cost comparisons are not available.³⁰ A randomized trial has demonstrated silver donating dressing to be no more effective than non-adherent dressings (relative risk of healing 1.06, 95% confidence interval 0.80–1.40), but to be associated with more clinic visits (8.00 versus 5.61), the largest contributor to cost.³¹ Silver donating dressings were judged to be cost-ineffective with an incremental cost-effectiveness ratio of £489, 250 per quality adjusted life-year (QALY) gained.

Evidence regarding the cost effectiveness of advanced wound care matrices is also sparse and conflicting. The cost of Apligraf per patient healed has been report to range from $15,053 to $16,936 in comparison to approximately $1800 for duoderm.³⁷ However, in other studies this translated into an incremental cost of $18 to $22 per ulcer day averted with Apligraf. The authors concluded that despite the high cost, these products may be cost-effective if limited to unresponsive ulcers. Among ulcers present for a year or longer, a theoretical semi- Markov model suggested that both annual costs ($20, 041 versus $24, 493) and healed months per year (4.60 versus 1.75) favored the use of Apligraf over paste bandages.³⁸ However, another cost analysis suggested that the incremental cost to achieve an additional successfully treated patient was $1600 ($1600 - $6400), $3150 ($1890 - $24, 570) and $29, 952 ($14,976 - $119,808) for Talymed, Oasis, and Apligraf respectively.

Summary

Clear evidence suggests that compression therapy is the cornerstone of venous leg ulcer care and that maintaining a moist wound environment is important in ulcer healing. Multilayer bandaging including an elastic layer appears to be associated with the highest rates of ulcer healing, although patients may require alternatives if intolerant of some forms of compression. Unfortunately there is little, rigorous data from properly conducted randomized trials suggesting that one primary wound dressing is superior to another. In choosing among the alternatives, the optimal dressing may depend on difficult to quantify factors related to the patient and their wound as well as cost.

However, important limitations of the clinical trials included in this review must also be considered. Unfortunately, most wound care trials have important methodological flaws and are often industry sponsored, a potential source of bias. These trials generally have strict inclusion and exclusion criteria that limit their generalizability and may have important health economic implications. For example, the cost considerations in treating small ulcers of short duration, often excluded from clinical trials, may be substantially different than those of treating large, long-standing ulcers that are associated with a long duration of treatment, greater utilization of resources, and higher costs. Furthermore, it is critical that appropriate endpoints, specifically the proportion of ulcers completely healed, be used in place of surrogates such as partial wound healing (e.g. percent area reduction). The United States Food and Drug administration has suggested the percentage of patients achieving complete wound closure, assessed at 2 consecutive visits 2 weeks apart, as the most meaningful trial endpoint.¹¹ Many clinical trials also suffer from a limited follow-up period, sometimes as short as 6 to 12 weeks. Short follow-up intervals may obscure the costs of treating an ulcer to the point of complete epithelialization. It is clear that labor costs and the frequency of dressing changes may be more important than the absolute cost of dressing supplies.

The available evidence suggests that the clinical and cost benefits of modern ulcer dressings are limited at best. However, it is important that this evidence be interpreted in light of flawed trial methodology and the overall poor quality of the data. Although the evidence may be useful in guiding the management of large populations, it is important to remember that patients with specific wound characteristics may have been excluded from randomized trials. Although difficult to show that routine use of specific dressings is cost-effective for a healthcare system, it is possible that patients with specific wound characteristics might benefit from these dressings and some judgment by the clinician will always be required.

Footnotes

Conflict of interest

The author has no conflict of interest and nothing to disclose.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors

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