Patients suffering from chronic diabetic foot ulcers (DFUs) could experience at least a fourfold increase in healing over standard of care with 12 weeks of home-based topical wound oxygen (TWO2) therapy, investigators have shown in a sham-controlled, double-blind trial they describe as "groundbreaking."
TWO2DFU compared an active home-based topical wound oxygen treatment (HyperBox, AOTI) with an identical sham device in patients with long-standing DFUs that had not healed after an optimal period of standard of care.
The company-funded trial was ended early after active treatment showed remarkable success in the first 73 patients, report Robert G. Frykberg, DPM, MPH, Diabetic Foot Consultants, Midwestern University, Glendale, Arizona, and colleagues, in their article published online October 16 in Diabetes Care.
Not only did the treatment improve healing, but quality of life also improved, even if patients only had a partial healing response.
The research "emphatically demonstrates, utilizing one of the most robust protocols ever developed for the wound care space, that cyclical pressurized TWO2 therapy should be considered a front-line adjunctive treatment option for DFUs that have failed to heal with standard care alone," said Frykberg in a company press release. Frykberg has received research support and speaker honoraria from AOTI.
He believes that the "ease of use and homecare application of this approach" help with patient compliance "and offer enormous cost-saving potential" versus other options for this kind of hard-to-heal ulcer, including hyperbaric oxygen.
"Not Revolutionary but a Great Adjunct to Good Care"
Approached for comment, David G. Armstrong, MD, PhD, professor of clinical surgery at the University of Southern California, Los Angeles, told Medscape Medical News that the results are "pleasantly surprising."
"If you were to have asked me maybe just a couple of years ago if I thought topical oxygen on a wound, or on anything, would have any kind of effect, I think I was on record as saying that, unless someone's legs had gills on them...I'm not sure how something like this could work," he said.
Armstrong, who was not involved in the current study and has no conflicts of interest, added that, based on these results and those of other studies, including one he was principal investigator on in 2018, "it looks like I was wrong."
Taken together, studies published so far suggest that, although it has "some real promise," topical oxygen is not "revolutionary," he observed.
Nevertheless, "it's going to be a great adjunct to very good care, and I think there might be therapies like this that will be added on that could create...an environment for healing."
Diabetic Foot Ulcer Amputation "Every 20 Seconds"
Frykberg and colleagues say that the increase in the prevalence of diabetes, compounded by comorbidities such as peripheral neuropathy, deformity, and peripheral arterial disease, has led to an increase in the occurrence of DFUs. These, in turn, increase the risk of morbidity and mortality, and have substantial healthcare costs.
Armstrong explained that, around the world, there is a DFU every 1.2 seconds, of which around half become infected, resulting in a DFU-related amputation, "give or take, every 20 seconds."
The 5-year survival for an individual with a DFU is "only about 50%," and that for someone who gets a foot amputated is 20% to 30%.
"So this problem now, in terms of its complexity, its real costs, and its cost in dollars, is comparable to a significant cancer," Armstrong added.
Although standard care, with debridement and off-loading, is effective when rigorously applied, a series of adjunctive therapies have been investigated, including oxygen therapy.
Oxygen is an "essential component" of wound healing, the authors note, with multiple steps in the healing cascade requiring a "sufficient supply."
This led to numerous studies examining the efficacy of approaches such as hyperbaric oxygen therapy (HBOT) in healing diabetic foot ulcers and preventing amputation. However, the results of these trials have been inconsistent.
And although topical oxygen therapy has been used in clinical practice for more than 50 years, with a growing body of clinical evidence supporting its use in chronic wounds, its effectiveness is still questioned.
Patients Treated Themselves at Home
Frykberg and coauthors conducted their prospective, multinational, placebo-controlled randomized clinical trial of patients with type 1 or 2 diabetes from 17 centers in Europe and the United States who had nonhealing, full thickness DFUs.
The ulcers were all grade 1 or 2 on the University of Texas Classification and measured ≥ 1 cm2 and < 20 cm2 following debridement. Patients had had the ulcers for between 4 weeks and 1 year, and had been receiving standard care for at least 4 weeks.
Following a 2-week run-in, patients were randomized double-blind (1:1) to standard care plus active TWO2 or an identical sham therapy, which looked and was operatively identically, apart from the delivery of oxygen.
After training, patients treated themselves at home for 90 minutes, five times per week for 12 weeks or until the wound healed, with dressing changes performed at home by the patient or their caregiver.
Patients visited their local study center weekly for wound assessment, debridement, and photography, during which diary cards recording therapy delivery and daily off-loading compliance were verified.
In total, 73 patients were enrolled. The intention-to-treat analysis demonstrated that active treatment (n = 37) was superior to sham treatment (n = 36) for the primary outcome of percentage of users in each group achieving 100% healing at 12 weeks.
At 12 weeks, 41.7% of wounds in the active arm had completely healed versus just 13.5% in the sham arm (P = .007), for an odds ratio of 4.57 (P = .010).
After adjusting for a number of factors, including ulcer grade at baseline, active TWO2 was associated with a hazard ratio of 4.66 for complete healing at 12 weeks versus sham therapy (P = .004).
Following treatment, patients were followed further, for a maximum of 38 weeks, at which point wound closure assessment and quality of life questionnaires were administered.
Only one (6.7%) of the 15 healed ulcers in the active arm recurred at 12 months, compared with two (40.0%) of five healed ulcers in the sham arm (P = .070).
At 12 months post-enrollment, 56% of active ulcers in the TWO2 group were closed compared with 27% of those in the sham group (P = .013).
Two patients in the active arm and three in the sham arm underwent index limb amputations.
Patients whose ulcers healed also showed marked improvements in quality of life on the Cardiff Wound Impact Schedule, although partial responders also experienced improvements.
Patients were highly compliant with both therapies. No adverse events were reported.
TWO2 a Good Option for Ulcers for Which Treatment Has Stalled
Frykberg told Medscape Medical News that, in his opinion, TWO2 "should be made available for all chronic foot ulcers that are stalled and are not healing with standard care."
"You would never use an advanced therapy such as this on an acute wound initially, unless that wound had already failed a number of other treatments," he said. "Generally, you try well-accepted standard wound care for 4 weeks or so before you start considering advanced therapies, which is what this is."
Armstrong broadly agrees with that assessment, underlining that, "most of the time, if you have a noninfected, nonischemic wound, I think that if we do a good job of debridement of the wound and we protectively offload it, then many of them are going to heal."
Hyperbaric vs Topical Oxygen Therapy
Frykberg said TWO2 has suffered as a treatment in recent years because "hyperbaric oxygen proponents have been vehemently opposed to the efficacy of topical oxygen, feeling as though there's no way that topically applied oxygen could have an effect on a wound, since it isn't systemically administered, from the inside out."
He explained that the current study was designed to "address all the prior weaknesses of topical oxygen trials," with the benchmark of achieving results at least as good as those seen with hyperbaric oxygen.
However, the study "far surpassed" that level.
Frykberg said that what is crucial for him is that TWO2 is a safe, home-based therapy, so patients can administer it "while they're reading, while they're watching...TV; they're very comfortable, and there are no risks."
In contrast, hyperbaric oxygen therapy requires patients "to travel to a specialized hyperbaric center five times a week for 40 to 60 days," in addition to which it is carried out in a chamber, which has its own risks.
"Now, with this trial, in concert with several other different trials on topical oxygen, I think it's going to change the landscape" of DFU management, said Frykberg.
Diabetes Care. Published online October 16, 2019. Abstract
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Cite this: Topical Oxygen Shines in Hard-to-Heal Diabetic Foot Ulcers - Medscape - Oct 31, 2019.