Reduced Hospitalizations and Amputations in Patients with Diabetic Foot Ulcers Treated with Cyclical Pressurized Topical Wound Oxygen Therapy: Real-World Outcomes

Introduction

Diabetic foot ulcers (DFUs) are concerning, particularly as nonhealing and recurrent DFUs can lead to hospitalization, amputation, and death. ^1,2 Estimates of the 5-year mortality rate after lower extremity amputation range from 46% to 57%, depending on the type of amputation. ³ As a result, DFUs continue to be a serious and costly condition. ^4,5 A 2014 study estimated that DFUs cost U.S. public and private payers $9–13 billion per year in addition to costs associated with diabetes. ⁶

Standard of care (SOC) treatment for DFUs is widely accepted to include debridement, effective offloading, treatment of infection, and vascular intervention as required. ^7,8 However, DFU is a complex condition and despite optimal SOC, many wounds remain difficult to heal or frequently recur. ² While a number of adjunctive therapies are available for use, the quality of evidence about their respective efficacy rates is regarded to be low, due primarily to small and poorly designed studies, as well as difficulty extrapolating drawn conclusions to the general, real-world DFU population. ^9,10

Oxygen therapy has been widely studied in the treatment of DFU, as oxygen is critical to the process of healing a wound. ¹¹ Nonetheless, efficacy results from studies of hyperbaric oxygen therapy and topical oxygen therapy (TOT) vary, and conclusions regarding effectiveness are inconsistent. ^{12 –14} A recent double-blind, sham-controlled trial, however, showed significantly improved healing of chronic DFUs with multimodal cyclical pressurized topical wound oxygen therapy (TWO2) at both 12 weeks and 12 months. ¹⁵

There are several different types of TOTs, each with unique properties in terms of dressings and/or mode of delivery of oxygen topically to the wound bed. These can be categorized as (1) normobaric flow of continuous diffusion of oxygen under proprietary dressing devices, (2) low constant pressure devices in a contained chamber, and (3) the device used in this study, incorporating cyclically pressurized (10–50 mb) and humidified oxygen delivery within a contained chamber or boot. ¹¹

Unfortunately, there is a paucity of studies to support the use of TOT within real-world, representative populations. This study, therefore, sought to evaluate the real-world impact of home-based cyclical pressurized topical wound oxygen therapy on DFUs by analyzing subsequent hospitalizations and amputations in a large, real-world, representative patient population.

Methods

Results

Outcomes for unmatched cohorts

Table 2 presents outcomes for all cohorts. Within unmatched cohorts for C1, compared with NO TWO2, the proportion of TWO2 patients requiring hospitalization and amputation was 88% lower (6.6% vs. 54.1%, p < 0.0001) and 71% lower (12.1% vs. 41.4%, p < 0.0001), respectively, within 360 days (Fig. 1).

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Figure 1.

Matched and unmatched study outcomes. Comparison #1 (C1) compares patients who ever received TWO2 (TWO2) to those who never received TWO2 (NO TWO2). Patients in both cohorts may have also received other adjunctive therapy. Comparison #2 (C2) compares patients who only received TWO2 and no other adjunctive therapy (TWO2 ONLY) to those who received NPWT, SS, and/or GF, but not TWO2 (OTHER TX ONLY). Propensity score matching was performed on the following 9 factors; age, sex, ethnicity, wound severity, prior amputation, use of offloading, use of NPWT, use of SS, and use of GF. All patients received appropriate SOC. GF, growth factor; NPWT, negative pressure wound therapy; SOC, standard of care; SS, skin substitutes.

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Table 2.

Patients with hospitalization and amputation across cohorts

	Unmatched Cohorts						Propensity Score–Matched Cohorts
	Comparison #1 (C1)			Comparison #2 (C2)			Comparison #1 (C1)
	TWO2 N = 91	NO TWO2 N = 111	p	TWO2 ONLY N = 58	OTHER TX ONLY N = 34	p	TWO2 N = 70	NO TWO2 N = 70	p
Patients with hospitalization, n (%)	6 (6.6)	60 (54.1)	<0.0001	4 (6.9)	20 (58.8)	<0.0001	5 (7.1)	28 (40.0)	<0.0001
Patients with amputation, n (%)	11 (12.1)	46 (41.4)	<0.0001	8 (13.8)	12 (35.3)	0.016	6 (8.6)	22 (31.4)	0.0007

Comparison #1 (C1) compares patients who ever received TWO2 (TWO2) to those who never received TWO2 (NO TWO2). Patients in both cohorts may have also received other adjunctive therapy. Comparison #2 (C2) compares patients who only received TWO2 and no other adjunctive therapy (TWO2 ONLY) to those who received NPWT, SS, and/or GF, but not TWO2 (OTHER TX ONLY). Propensity score matching was performed on the following 9 factors; age, sex, ethnicity, wound severity, prior amputation, use of offloading, use of NPWT, use of SS, use of GF. All patients received appropriate SOC.

Within unmatched cohorts for C2, in contrast with OTHER TX ONLY, the proportion of TWO2 ONLY patients with a wound-related hospitalization was 88% lower (6.9% vs. 58.8%, p < 0.0001) and the proportion with amputation was 61% lower (13.8% vs. 35.3%, p = 0.016) within 360 days (Fig. 1).

Discussion

This study demonstrates the real-world effectiveness of cyclical pressurized topical wound oxygen therapy in reducing wound-related hospitalizations and amputations for patients with DFU compared with patients who did not receive this intervention. Both amputations and hospitalizations have been shown to contribute substantially to the overall cost burden of an ulcerated patient. ^{4 –6}

Studies have also demonstrated that the annual cost of care for DFU is higher in patients with amputation due to increased health care utilization, such as increased provider visits, rehabilitation care, and other medical expenses. ¹⁹ In 2010, Franklin et al. estimated such costs within the VA to be $60,647 per patient. ²⁰ Our results, therefore, support the use of TWO2 in the management of DFU to dramatically improve serious, painful, as well as costly patient outcomes. Equally important, this therapy is self-administered in the comfort of the patient's own home and does not require frequent visits to a specialized unit for such care.

Due to the real-world nature of the data, this study also included background use of other adjunctive therapies (NPWT, SS, and GF). For C1 (TWO2 vs. NO TWO2), the use of TWO2 was additive to other adjunctive therapies. However, in C2, when patients received TWO2 ONLY or OTHER TX ONLY (including SS, NPWT, and GF), the TWO2 ONLY group still demonstrated a meaningful reduction in the proportion of patients with hospitalization (6.9% vs. 58.8%, p < 0.0001) and amputation (13.8% vs. 35.3%, p = 0.016) at 360 days.

This suggests that TWO2 confers a significant benefit alone compared with other adjunctive therapies. These findings demonstrate the real-world, patient-centric clinical value of TWO2 both as adjunctive therapy and as a potential alternative to other advanced wound care modalities.

To our knowledge, few other studies have evaluated the impact of adjunctive modalities, including TOT, on near-term hospitalizations and amputations. In a retrospective uncontrolled chart review evaluating the impact of another type of TOT device on a variety of wound types, the overall amputation rate for patients treated with TOT was 2.4%. ²¹ Although lower than observed for patients in this study (9–14% across cohorts treated with TWO2), comparisons are difficult to make due to the heterogeneity of wound types in the former study.

Furthermore, while our average DFU duration was ∼6 months, the majority of all wounds in the Copeland study were 3 months or less in duration. ²¹ Nonetheless, other controlled studies and several recent RCTs have demonstrated improved healing rates and time to closure of DFUs when using TOT as compared with controls. ^{15,22 –24}

In a sham-controlled, double-blinded RCT on the same TWO2 therapy explored in this study, Frykberg et al. found that 56% of TWO2 patients achieved 100% healing at 12 months (vs. 27% in the sham arm, p = 0.013) and only a 5% amputation rate at 1 year from enrollment. ¹⁵ Our analysis complements Frykberg et al. by showing a significant reduction in hospitalizations and amputations, also at 12 months, in a large, real-world patient population with background use of adjunctive therapies. Taken together, the value of TWO2 is clearly demonstrated and warrants close consideration of its foundational role in the treatment of DFU.

Our overall 12-month amputation rate for these chronic DFU patients was 28%, consistently and significantly lower in each of the analyzed cohorts that had used TWO2. The 1-year rates of amputation seen in the cohorts without TWO2 (NO TWO2: 41% unmatched, 31% matched; OTHER TX ONLY: 35%) are fairly comparable with that seen (42.3%) in another recent retrospective study by Blumberg and Warren that also included VA hospitals. ²⁵

Similar to our matched NO TWO2 cohort, a 2020 meta-analysis of 21 studies and 6,505 patients by Lin et al. demonstrated on average that nearly 31% of patients with DFU receive amputations. ²⁶ Another recent study from the VA indicated that there was an increase in the rate of amputations in veterans during the years 2008 to 2018. ²⁷ Interestingly, these data are derived from years overlapping our own patient data and show that the increase in rates came primarily from increases in toe- and transmetatarsal-level amputations.

While our data did not categorize specific levels of amputations performed, modern limb-salvage practice has a relatively low threshold for such minor amputations in the presence of deteriorating diabetic foot wounds. ²⁸ This is reflected in recent nation-wide increases in the rate of diabetes-related minor amputations in the United States, manifested as a 50% increase in the total amputation rate in the years 2009–2015. ²⁹

The 1-year rate of amputation in our analysis may be the result of several additional factors. First, patients in this study may have had existing, nonhealing wounds before first documentation in their medical records. Second, patients with DFU in this study had high rates of PAD (77–86% across cohorts) as well as prior amputation (27–45% across cohorts). Several studies have shown that PAD and prior amputation are important risk factors for subsequent amputation in DFU. ^27,30 The patients in our study with high rates of PAD and prior amputation were therefore at higher risk for further amputation.

Renal insufficiency and end-stage renal disease are common complications in diabetes and are often considered to be predictors of failure to heal. As indicated in Table 1, 90 (99%) patients in the TWO2 group had any stage of kidney disease, with almost half having Stage III kidney disease. In contrast, 92 (83%) patients in the No TWO2 group had any stage of kidney disease, with 21 (18.9%) patients within this cohort requiring dialysis. Nonetheless, when including kidney disease stage as a covariate along with treatment in the analysis for both Hospitalization and Amputation outcomes, the kidney disease stage term was nonsignificant at p < 0.05 [Hospitalization p = 0.8218, Amputation = 0.1004].

We also recognize and acknowledge that HbA1c levels were ∼7–10% higher in our NO TWO2 cohorts (Table 1). Nonetheless, glycohemoglobin levels have long been found to be an inconsistent risk factor for DFU healing as well as risk for amputation. Accordingly, the aforementioned meta-analysis on risk factors for amputation confirmed that HbA1c level in DFU patients does not affect the incidence of amputation. ²⁶

Our study has several limitations inherent to any retrospective cohort analysis. First, we lacked control over the data at the time of documentation. For instance, the analysis could be impacted by missing data over the observation period. To manage missing data, we used the LOCF method and conservatively assumed that any patient without follow-up data suggesting a hospitalization or amputation during the 360-day period was categorized as not hospitalized or not amputated. Similarly, due to the nature of medical records, we did not collect data on mortality or level of amputation, as neither was reliably captured within the medical records.

Second, medical records do not capture or account for compliance with prescribed treatments. While patient compliance with TWO2 (and NPWT) is therefore unknown, this uncertainty is also reflective of and generalizable to a real-world population of patients with DFU. Third, our study does not evaluate wound healing, but rather measures outcomes in the form of hospitalizations and amputations. Fourth, the medical records follow individual patients, not specific wounds. So, it is possible that a single patient could have additional wounds that contribute to the outcomes of analysis.

Finally, treatment selection was based on the clinical judgment of the wound care physician at the time of treatment, which cannot be ascertained through a retrospective chart review, although patients at both treatment facilities had access to all treatments, including TWO2.

This study also demonstrates the benefit of TWO2 across a spectrum of DFU severities. Although most of the patients in this study were categorized as Wagner 1 and 2 upon documentation of their wounds, 20% of analyzed patients (41 of 202) were classified as Wagner 3 and 4 with more severe wounds, reflecting the real-world composition of this VA patient population.

With all severities considered, TWO2 demonstrates a statistically significant benefit over NO TWO2 in reduced incidence of hospitalization and amputation. Specifically, we found a nearly fivefold increased association with amputation and ninefold increased association with need for hospitalization in those patients who did not receive TWO2 compared with those who did.

Conclusion

The results of this study demonstrate that home-based cyclical pressurized topical wound oxygen therapy, when used with or without other adjunctive treatments, is associated with significantly reduced frequency of wound-related hospitalization and amputation for patients afflicted with DFU. Hospitalizations and amputations are not only concerning patient outcomes affecting both morbidity and mortality, they are also costly complications that contribute to the significant overall cost burden of DFU on health care resources. ^4,5 By inference, therefore, cyclical pressurized topical wound oxygen therapy would likely be associated with important quality of life and health economic benefits.

Data Sharing

The study protocol will be made available on request from the corresponding author. Deidentified individual participant data that underlie the results reported in this article will be made available with requests accepted immediately after publication, for proposals that set out to achieve aims specified in a methodologically and scientifically sound protocol, and where any mandated VHA approval requirements are met.