Cost Effectiveness of Fish Skin Grafts Versus Standard of Care on Wound Healing of Chronic Diabetic Foot Ulcers

A Retrospective Comparative Cohort Study

Christopher Winters, DPM; Robert S. Kirsner, MD, PhD; David J. Margolis, MD, PhD; John C. Lantis, II, MD

Disclosures

Wounds. 2020;32(10):283-290. 

In This Article

Abstract and Introduction

Abstract

Introduction: Health care policy decision makers seek the highest quality products at the lowest cost for their patients. Cost-benefit analysis is a helpful tool and can be used together with other sources of information to ensure the most efficient use of medical resources.

Objective: The objective of this retrospective comparative cohort study is to evaluate the cost effectiveness of fish skin therapy compared with standard of care (SOC) on chronic diabetic foot ulcers (DFUs).

Methods: Retrospective patient data collected in a single wound care setting from 2014 to 2017 were included. In total, 59 DFUs treated with fish skin were used to calculate transition probabilities for a Markov model in which a hypothetical patient cohort treated with fish skin was compared with an identical hypothetical patient cohort treated with SOC. Cost was from the perspective of the payer, and the time horizon was set at 1 year.

Results: The model indicated that fish skin treatment could result in lower costs ($11 210 vs. $15 075 per wound), more wounds healing (83.2% vs. 63.4%), fewer amputations (4.6% vs. 6.9%), and a higher quality of life (0.676 vs. 0.605 quality-adjusted life year [QALY]) than the SOC. A probabilistic sensitivity analysis, based on a Monte Carlo simulation, indicated that the fish skin treatment (on DFUs) would be 93.6% likely to be cost effective for a willingness to pay at $100 000 per QALY and 71.4% likely to be cheaper than SOC.

Conclusions: Including fish skin grafts in the SOC for DFU treatment has the potential to reduce costs while improving patient outcomes.

Introduction

Diabetes mellitus (DM) has become a worldwide epidemic, affecting more than 400 million people as of 2014; with a prevalence of 8.5% in the world's adult population, which was up from 4.7% in 1980; these numbers are expected to continue to increase.[1,2] Patients with diabetes and neuropathy are at risk of developing diabetic foot ulcers (DFUs), which are chronic ulcers resulting from a localized injury to the foot. Found most often in patients with foot deformity, neuropathy, and/or insufficient blood flow, patients with DM have an estimated lifetime risk of developing a DFU to be about 15% to 25%.[3–5] Patients with DFUs face an increased risk of infection, amputation, and death, with a 5-year mortality rate of 45%.[6] Roughly 40% of patients with a DFU go on to have a DFU-related amputation, and within 5 years of amputation, 70% of individuals with a DFU-related amputation will die.[5,7,8]

The standard of care (SOC) treatment for DFUs consists of debridement, controlling and preventing infections, addressing ischemia, dressing the wound to maintain a moist wound environment, and offloading practices.[9] Ideally, offloading should utilize total contact casting (TCC), although only 2% to 5% of patients in the United States receive a TCC.[10,11] Offloading more commonly entails removable walking boots and other special footwear, crutches, and/or a wheelchair.[10,11] This combined treatment was described in a consensus statement from the American Diabetes Association,[9] and although the more commonly used methods of offloading may be suboptimal, it is often the standard in clinical trials and the type of care most patients receive in the community. While this therapy is relatively inexpensive, it is estimated that only 50% of all DFUs heal within 1 year in the United States, and the longer the wound persists, the greater the chance of critical complications, which are difficult and costly to treat.[12,13] Hence, DFUs place a substantial burden on both private and public payers and often reduce quality of life (QoL) in this patient population. Promoting and accelerating DFU healing can result in the avoidance of amputations, resulting in better patient QoL as well as reducing overall hospitalization rates, contributing to overall cost savings, and potentially supporting higher initial spending.

Alternatives When SOC Fails

There are many advanced tissue strategies available to treat DFUs that should be considered if 50% wound size reduction is not achieved within 4 weeks of SOC.[14,15] However, the costs of these advanced treatments are usually higher, and they often have unproven or unclear clinical benefits.[16–18] Among these treatments are various allografts and xenografts, ranging from minimally manipulated to heavily processed, as well as bioengineered acellular or cellular grafts.

Characteristics of Fish Skin Grafts

Fish skin grafts are made from the skin of North Atlantic cod. The product, Omega3 Wound (Kerecis), is cleared by the US Food and Drug Administration as an unclassified collagen wound dressing (under the product code KGN).[19] As opposed to mammalian-derived products, no disease transmission risk exists from North Atlantic cod to humans; as a result, the fish skin can be lyophilized, decellularized, and sterilized in a comparatively gentle manner, leaving the fish skin dermal structure and native bioactive lipids intact.[20–23] Once grafted, the fish skin is gradually infiltrated by cells and incorporated into the tissue prior to the next application. Human and fish skin are structurally similar due to evolutionary homology (Figure 1).[24] An important difference is that cold water fish skin is naturally richer in omega-3 polyunsaturated fatty acids, which are precursors to specialized pro-resolving lipid mediators that have a role in host defense, resolution of inflammation, remodeling of tissue, and pain response.[24–26] Two double-blind randomized controlled trials on acute wounds showed that fish skin grafts promote significantly faster healing compared with a porcine intestinal submucosa product and an amniotic/chorion membrane product.[21,27]

Figure 1.

Scanning electron micrographs of cross sections of fish skin graft and human skin. The dermis is a fibrous connective layer of a lighter color. Like human skin, the decellularized, freeze dried fish skin has several layers, which form a complex 3-dimensional structure with compartments and tunnels. This network of passages then provides niches that human cells can infiltrate and proliferate in during the healing process. (A) The image of the fish skin shows a relatively loosely packed epidermis with large, empty pockets, where the scales have been removed. The dermal layers are more densely packed toward the bottom, down to where the fascia was removed during the processing of the graft. (B) The image of human skin shows a cornified top epidermal layer on top of a living epidermal layer, which reaches into the tissue below (ie, the dermis).

The graft is stable at room temperature for 3 years. It is applied to the wound bed following debridement and can be used with negative pressure wound therapy. The fish skin graft is held in place with a nonadherent contact layer or Steri-Strips (3M). Alternatively, it can be fastened with stitches or staples. The graft is bolstered or stacked in case of deep or cavernous wounds. The material itself is skin-like in appearance, robust and pliable, and difficult to tear. It can be easily cut or meshed and only requires brief hydration with saline before application.

Cost Associated With DFUs

The total cost of DFU treatment in the United States is estimated to be at least $38 billion, with hospitalization costs being the largest factor.[28,29] One study showed costs for patients with DFUs to be more than triple that of patients with DM but without ulcers.[30] In addition to direct costs, there is a substantial indirect cost incurred due to loss of productivity, disability, and premature mortality.[31]

Role of Cost Simulations in Deciding Health Care Spending

Cost-benefit, cost-effectiveness, and cost-utility analyses can assist health care providers in making better evidence-based decisions by identifying, analyzing, and comparing the impact of different treatment options on public health and health care expenditure.[32] In simple terms, a cost-effectiveness analysis compares 2 available treatment approaches, usually a standard method and a novel one, and asks the following: (A) is one more effective than the other?; and, if so, (B) is there a difference in cost? If a therapy is both cheaper and more effective, it should be recommended or at least strongly considered. If a therapy is more effective but also more expensive, one can take into account the payer's willingness to pay (WTP) per gained unit of health; if the extra cost per unit gained is lower than the WTP, the added expenditure can be considered acceptable.[33–35]

Definitions of Cost and Utility

While comparative economic analyses are becoming increasingly more important in decision-making, cohesive and unified guidelines on how to conduct such analyses are still lacking. Generally, cost-utility studies are considered to be the gold standard for measuring treatment cost effectiveness.[36–39] A cost-utility analysis is a type of cost-effectiveness study that evaluates both cost and quality-adjusted life-years (QALYs). One QALY equals 1 year in perfect health and zero QALY represents death.[40] Commonly referenced WTP values for 1 QALY in the United States are $50 000 and $100 000, while values in Europe are often lower.[41–47] The cost perspective can either be that of the third-party payer (ie, insurance companies, governmental agencies, employers), or society. The societal perspective includes all incurred costs to society, including lost labor, and can be difficult to implement; the payer's perspective is more commonly reported.[31,35]

Use of Predictors of Wound Closure and Cost Benefit Models

Several easy-to-apply predictors of healing have been described in wound care.[48–50] These are often dependent on both the age and surface area of the wound. Using such established predictors of wound closure in comparative analyses has the potential to standardize cohorts across studies and reduce the effect of bias due to confounding variables. This method is used as a way of comparing the actual performance of an active tissue-based product with historically validated expectations for SOC in a population with DFUs treated at one wound care setting in the United States. By applying a weekly cost to the 2 therapies, potential cost savings with the new therapy can be projected.

Objective

The objective of this retrospective comparative cohort study was to compare the rates of healing, number of amputations, and cost/utility in the treatment of DFUs using either SOC alone or intact fish skin treatments.

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