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      VOLUME 46 | SUPPLEMENT 1

12. Retinopathy, Neuropathy, and Foot Care:

Standards of Care in Diabetes 2023

Nuha A. ElSayed, Grazia Aleppo, Vanita R. Aroda,

Raveendhara R. Bannuru, Florence M. Brown, Dennis Bruemmer Billy S. Collins, Christopher H. Gibbons, John M. Giurini,

Marisa E. Hilliard, Diana Isaacs, Eric L. Johnson, Scott Kahan, Kamlesh Khunti, Jose Leon, Sarah K. Lyons, Mary Lou Perry,

Priya Prahalad, Richard E. Pratley, Jane Jeffrie Seley, Robert C. Stanton, Jennifer K. Sun, and Robert A. Gabbay, on hehalf of the American Diabetes Association

Diabetes Care 2023;46(Suppl. 1):S203-S215 | https://doi.org/10.2337/dc23-S012

ISSN 0149-5992

12. Retinopathy, Neuropathy, and Foot Care: Standards of Care in Diabetes-2023

Diabetes Care 2023;46(Suppl. 1):5203-5215 I https://doi.org/10.2337/dc23-5012

The American Diabetes Association (ADA) “Standards of Care in Diabetes” in­ cludes the ADA’s current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guide­ lines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee, are responsible for up­ dating the Standards of Care annually, or more frequently as warranted. For a de­ tailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA’s clinical practice recommendations and a full list of Professional Practice Committee members, please refer to Introduction and Methodology. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

For prevention and management of diabetes complications in children and adoles­ cents, please refer to Section 14, “Children and Adolescents.”

DIABETIC R’ETINOPATHY

Diabetic retinopathy is a highly specific vascular complication of both type 1 and type 2 diabetes, with prevalence strongly related to both the duration of diabetes and the level of glycemic control (1). Diabetic retinopathy is the most frequent cause of new cases of blindness among adults aged 20-74 years in developed countries. Glaucoma, cataracts, and other eye disorders occur earlier and more frequently in people with diabetes.

In addition to diabetes duration, factors that increase the risk of, or are associ­ ated with, retinopathy include chronic hyperglycemia (2,3), nephropathy (4), hyper­ tension (5), and dyslipidemia (6). Intensive diabetes management with the goal of achieving near-normoglycemia has been shown in large prospective randomized studies to prevent and/or delay the onset and progression of diabetic retinopathy, reduce the need for future ocular surgical procedures, and potentially improve patient-reported visual function (2,7-10). A meta-analysis of data from cardiovascular outcomes studies showed no association between glucagon-like peptide 1 receptor agonist (GLP-1 RA) treatment and retinopathy per se, except through the association between retinopathy and average AlC reduction at the 3-month and 1-year follow­ up. Long-term impact of improved glycemic control on retinopathy was not studied

Nuha A. EISayed, Grazia Aleppo,

Vanita R. Aroda, Raveendhara R. Bannuru, Florence M. Brown, Dennis Bruemmer, Billy 5. Collins, Christopher H. Gibbons, John M. Giurini, Marisa E. Hilliard,

Diana Isaacs, Eric L. Johnson, Scott Kahan, Kamlesh Khunti, Jose Leon, Sarah K. Lyons, Mary Lou Perry, Priya Prahalad,

Richard E. Pratley, Jane Jeffrie Seley, Robert C. Stanton, Jennifer K. Sun, and Robert A. Gabbay, on behalf of the American Diabetes Association

Disclosure information for each author is available at https://dai.org/10.2337/dc23-SDIS.

Suggested citation: EISayed NA, Aleppo G, Aroda VR, et al., American Diabetes Association. 12. Retinopathy, neuropathy, and foot care: Standards of Care in Diabetes-2023. Diabetes Care 2023; 46(Suppl. 1}:5203-5215

© 2022 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at https://www. diabetesjournals.org/journals/pages/license.

in these trials. Retinopathy status should be assessed when intensifying glucose­ lowering therapies such as those using GLP-1 RAs, since rapid reductions in AlC can be associated with initial worsening of retinopathy (11).

Screening

The preventive effects of therapy and the fact that individuals with prolifera­ tive diabetic retinopathy (PDR) or macu­ lar edema may be asymptomatic provide strong support for screening to detect diabetic retinopathy. Prompt diagnosis allows triage of patients and timely in­ tervention that may prevent vision loss in individuals who are asymptomatic despite advanced diabetic eye disease.

Diabetic retinopathy screening should be performed using validated approaches and methodologies. Youth with type 1 or type 2 diabetes are also at risk for compli­ cations and need to be screened for dia­ betic retinopathy (12) (see Section 14, “Children and Adolescents“). If diabetic retinopathy is evident on screening, prompt referral to an ophthalmologist is recom­ mended. Subsequent examinations for individuals with type 1 or type 2 diabe­ tes are generally repeated annually for individuals with minimal to no retinop­ athy. Exams every 1-2 years may be cost-effective after one or more normal eye exams. In a population with well­ controlled type 2 diabetes, there was little risk of development of significant retinopathy within a 3-year interval af­ ter a normal examination (13), and less frequent intervals have been found in simulated modeling to be potentially ef­ fective in screening for diabetic retinop­ athy in individuals without diabetic retinopathy (14). However, it is impor­ tant to adjust screening intervals based on the presence of specific risk factors for retinopathy onset and worsening retinopathy. More frequent examina­ tions by the ophthalmologist will be re­ quired if retinopathy is progressing or risk factors such as uncontrolled hyperglyce­ mia, advanced baseline retinopathy, or diabetic macular edema are present.

Retinal photography with remote read­ ing by experts has great potential to pro­ vide screening services in areas where qualified eye care professionals are not readily available (15-17). High-quality fun­ dus photographs can detect most clinically significant diabetic retinopathy. Interpreta­ tion of the images should be performed by a trained eye care professional. Retinal

photography may also enhance efficiency and reduce costs when the expertise of ophthalmologists can be used for more complex examinations and for therapy (15,18,19). In-person exams are still nec­ essary when the retinal photos are of unacceptable quality and for follow-up if abnormalities are detected. Retinal pho­ tos are not a substitute for dilated com­ prehensive eye exams, which should be performed at least initially and at yearly intervals thereafter or more frequently as recommended by an eye care profes­ sional. Artificial intelligence systems that detect more than mild diabetic retinopa­ thy and diabetic macular edema, autho­ rized for use by the U.S. Food and Drug Administration (FDA), represent an alter­ native to traditional screening approaches

(20). However, the benefits and optimal utilization of this type of screening have yet to be fully determined. Results of all screening eye examinations should be documented and transmitted to the refer­ ring health care professional.

Type 1 Diabetes

Because retinopathy is estimated to take at least 5 years to develop after the on­ set of hyperglycemia, people with type 1 diabetes should have an initial dilated and comprehensive eye exami­ nation within 5 years after the diagnosis of diabetes (21).

Type 2 Diabetes

People with type 2 diabetes who may have had years of undiagnosed diabetes and have a significant risk of prevalent diabetic retinopathy at the time of diag­ nosis should have an initial dilated and comprehensive eye examination at the time of diagnosis.

Pregnancy

Individuals who develop gestational dia­ betes mellitus do not require eye ex­ aminations during pregnancy since they do not appear to be at increased risk of developing diabetic retinopathy during pregnancy (22). However, individuals of childbearing potential with preexisting type 1 or type 2 diabetes who are plan­ ning pregnancy or who have become pregnant should be counseled on the baseline prevalence and risk of devel­ opment and/or progression of diabetic retinopathy. In a systematic review and meta-analysis of 18 observational studies of pregnant individuals with preexisting

type 1 or type 2 diabetes, the prevalence of any diabetic retinopathy and PDR in early pregnancy was 52.3% and 6.1%, re­ spectively. The pooled progression rate per 100 pregnancies for new diabetic reti­ nopathy development was 15.0 (95% Cl

9.9-20.8), worsened nonproliferative

diabetic retinopathy was 31.0 (95% Cl 23.2-39.2), pooled sight-threatening pro­ gression rate from nonproliferative dia­ betic retinopathy to PDR was 6.3 (95% Cl 3.3-10.0), and worsened PDR was 37.0

(95% Cl 21.2-54.0), demonstrating that close follow-up should be maintained during pregnancy to prevent vision loss

(23). In addition, rapid implementation of intensive glycemic management in the setting of retinopathy is associ­ ated with early worsening of retinop­ athy (24).

A systematic review and meta-analysis and a controlled prospective study dem­ onstrate that pregnancy in individuals with type 1 diabetes may aggravate reti­ nopathy and threaten vision, especially when glycemic control is poor or retinop­ athy severity is advanced at the time of conception (23,24). Laser photocoagu­ lation surgery can minimize the risk of vision loss during pregnancy for individ­ uals with high-risk PDR or center-involved diabetic macular edema (24). Anti-vascular endothelial growth factor (anti-VEGF) med­ ications should not be used in pregnant individuals with diabetes because of the­ oretical risks to the vasculature of the developing fetus.

Treatment

Two of the main motivations for screen­ ing for diabetic retinopathy are to pre­ vent loss of vision and to intervene with treatment when vision loss can be pre­ vented or reversed.

Photocoagulation Surgery

Two large trials, the Diabetic Retinopa­ thy Study (DRS) in individuals with PDR and the Early Treatment Diabetic Reti­ nopathy Study (ETDRS) in individuals with macular edema, provide the strongest support for the therapeutic benefits of photocoagulation surgery. The DRS (25) showed in 1978 that panretinal photo­ coagulation surgery reduced the risk of severe vision loss from PDR from 15.9% in untreated eyes to 6.4% in treated eyes with the greatest benefit ratio in those with more advanced baseline disease (disc neovascularization or vitre­ ous hemorrhage). In 1985, the ETDRS also verified the benefits of panretinal photocoagulation for high-risk PDR and in older-onset individuals with severe

nonproliferative diabetic retinopathy or less-than-high-risk PDR. Panretinal laser photocoagulation is still commonly used to manage complications of dia­ betic retinopathy that involve retinal neovascularization and its complications. A more gentle, macular focal/grid laser photocoagulation technique was shown in the ETDRS to be effective in treating eyes with clinically significant macular edema from diabetes (26), but this is now largely considered to be second-line treatment for diabetic macular edema.

Anti-Vascular Endothelial Growth Factor Treatment

Data from the DRCR Retina Network

(formerly the Diabetic Retinopathy Clini­ cal Research Network) and others dem­ onstrate that intravitreal injections of anti–VEGF agents are effective at re­ gressing proliferative disease and lead to noninferior or superior visual acuity outcomes compared with panretinal la­ ser over 2 years of follow-up (27,28). In addition, it was observed that individuals treated with ranibizumab tended to have less peripheral visual field loss, fewer vitrectomy surgeries for secondary com­ plications from their proliferative dis­ ease, and a lower risk of developing diabetic macular edema. However, a potential drawback in using anti-VEGF therapy to manage proliferative disease is that patients were required to have a greater number of visits and received a greater number of treatments than is typically required for management with panretinal laser, which may not be opti­ mal for some individuals. The FDA has approved aflibercept and ranibizumab for the treatment of eyes with diabetic retinopathy. Other emerging therapies for retinopathy that may use sustained intravitreal delivery of pharmacologic agents are currently under investigation. Anti-VEGF treatment of eyes with non­ proliferative diabetic retinopathy has been demonstrated to reduce subse­ quent development of retinal neovascu­ larization and diabetic macular edema but has not been shown to improve visual outcomes over 2 years of therapy and therefore is not routinely recom­ mended for this indication (29).

While the ETDRS (26) established the

benefit of focal laser photocoagulation surgery in eyes with clinically significant macular edema (defined as retinal edema

located at or threatening the macular center), current data from well-designed clinical trials demonstrate that intravi­ treal anti-VEGF agents provide a more effective treatment plan for center­ involved diabetic macular edema than monotherapy with laser (30,31). Most patients require near-monthly adminis­ tration of intravitreal therapy with anti­ VEGF agents during the first 12 months of treatment, with fewer injections needed in subsequent years to maintain remission from central-involved diabetic macular edema. There are currently three anti­ VEGF agents commonly used to treat eyes with central-involved diabetic macular edema-bevacizumab, ranibizumab, and atlibercept (1)-and a comparative effec­ tiveness study demonstrated that atliber­ cept provides vision outcomes superior to those of bevacizumab when eyes have moderate visual impairment (vision of 20/50 or worse) from diabetic macular edema (32). For eyes that have good vision (20/25 or better) despite diabetic macular edema, close monitoring with initiation of anti-VEGF therapy if vision worsens provides similar 2-year vision outcomes compared with immediate initi­ ation of anti-VEGF therapy (33).

Eyes that have persistent diabetic macu­ lar edema despite anti-VEGF treatment may benefit from macular laser photo­ coagulation or intravitreal therapy with corticosteroids. Both of these therapies are also reasonable first-line approaches for individuals who are not candidates for anti-VEGF treatment due to systemic considerations such as pregnancy.

Adjunctive Therapy

Lowering blood pressure has been shown to decrease retinopathy progression, although tight targets (systolic blood pressure <120 mmHg) do not impart additional benefit (8). In individuals with dyslipidemia, retinopathy progression may be slowed by the addition of feno­ fibrate, particularly with very mild non­ proliferative diabetic retinopathy at baseline (34,35).

NEUROPATHY

Screening

Diabetic neuropathies are a heteroge­ neous group of disorders with diverse clinical manifestations. The early rec­ ognition and appropriate management of neuropathy in people with diabetes is important. Points to be aware of in­ clude the following:

1. Diabetic neuropathy is a diagnosis of exclusion. Nondiabetic neuropa­ thies may be present in people with diabetes and may be treatable.
2. Up to 50% of diabetic peripheral neu­ ropathy may be asymptomatic. If not recognized and if preventive foot care is not implemented, people with dia­ betes are at risk for injuries as well as diabetic foot ulcers and amputations.
3. Recognition and treatment of au-

symptoms, reduce sequelae, and im­ prove quality of life.

Specific treatment to reverse the un­ derlying nerve damage is currently not available. Glycemic control can effec­ tively prevent diabetic peripheral neu­ ropathy (DPN) and cardiac autonomic neuropathy (CAN) in type 1 diabetes (36,37) and may modestly slow their progression in type 2 diabetes (38), but it does not reverse neuronal loss. Treat­ ments of other modifiable risk factors (including lipids and blood pressure) can aid in prevention of DPN progression in type 2 diabetes and may reduce disease progression in type 1 diabetes (39-41). Therapeutic strategies (pharmacologic and nonpharmacologic) for the relief of painful DPN and symptoms of autonomic neurop­ athy can potentially reduce pain (42) and improve quality of life.

Diagnosis

Diabetic Peripheral Neuropathy

Individuals with a type 1 diabetes dura­ tion 2′.5 years and all individuals with type 2 diabetes should be assessed an­ nually for DPN using the medical history and simple clinical tests (42). Symptoms vary according to the class of sensory fi­ bers involved. The most common early symptoms are induced by the involve­ ment of small fibers and include pain and dysesthesia (unpleasant sensations of burning and tingling). The involve­ ment of large fibers may cause numb­ ness and loss of protective sensation (LOPS). LOPS indicates the presence of distal sensorimotor polyneuropathy and is a risk factor for diabetic foot ulceration. The following clinical tests may be used to assess small- and large-fiber func­ tion and protective sensation:

1. Small-fiber function: pinprick and temperature sensation.
2. Large-fiber function: lower-extremity

reflexes, vibration perception, and 10-g monofilament.

1. Protective sensation: 10-g mono­ filament.

These tests not only screen for the presence of dysfunction but also predict future risk of complications. Electrophysi­ ological testing or referral to a neurolo-

tonomic neuropathy may improve gist is rarely needed, except in situations

where the clinical features are atypical or the diagnosis is unclear.

In all people with diabetes and DPN, causes of neuropathy other than diabetes should be considered, including toxins (e.g., alcohol), neurotoxic medica­ tions (e.g., chemotherapy), vitamin B12 deficiency, hypothyroidism, renal disease, malignancies (e.g., multiple myeloma, bronchogenic carcinoma), infections (e.g., HIV), chronic inflammatory demyelinating neuropathy, inherited neuropathies, and vasculitis (43). See the American Diabetes Association position statement “Diabetic Neuropathy” for more details (42).

Diabetic Autonomic Neuropathy

Individuals who have had type 1 diabe­ tes for 2:5 years and all individuals with type 2 diabetes should be assessed an­ nually for autonomic neuropathy (42). The symptoms and signs of autonomic neuropathy should be elicited carefully during the history and physical examina­ tion. Major clinical manifestations of diabetic autonomic neuropathy include resting tachycardia, orthostatic hypoten­ sion, gastroparesis, constipation, diarrhea, fecal incontinence, erectile dysfunction, neurogenic bladder, and sudomotor dysfunction with either increased or decreased sweating. Screening for symp­ toms of autonomic neuropathy includes asking about symptoms of orthostatic in­ tolerance (dizziness, lightheadedness, or weakness with standing), syncope, exer­ cise intolerance, constipation, diarrhea, urinary retention, urinary incontinence, or changes in sweat function. Further testing can be considered if symptoms are present and will depend on the end organ involved but might include cardio­ vascular autonomic testing, sweat testing, urodynamic studies, gastric emptying, or endoscopy/colonoscopy. Impaired coun­ terregulatory responses to hypoglycemia in type 1 and type 2 diabetes can lead to hypoglycemia unawareness but are not directly linked to autonomic neuropathy.

Cardiovascular Autonomic Neuropathy. CAN is associated with mortality independently of other cardiovascular risk factors (44,45). In its early stages, CAN may be completely asymptomatic and detected only by decreased heart rate variability with deep breathing. Advanced disease may be associated with resting tachycardia (>100 bpm) and orthostatic hypoten­ sion (a fall in systolic or diastolic blood

pressure by >20 mmHg or >10 mmHg, respectively, upon standing without an appropriate increase in heart rate). CAN treatment is generally focused on allevi­ ating symptoms.

Gastrointestinal Neuropathies. Gastrointes­ tinal neuropathies may involve any por­ tion of the gastrointestinal tract, with manifestations including esophageal dysmotility, gastroparesis, constipation, diarrhea, and fecal incontinence. Gastro­ paresis should be suspected in individu­ als with erratic glycemic control or with upper gastrointestinal symptoms with­ out another identified cause. Exclusion of reversible/iatrogenic causes such as medi­ cations or organic causes of gastric outlet obstruction or peptic ulcer disease (with esophagogastroduodenoscopy or a barium study of the stomach) is needed before considering a diagnosis of or specialized testing for gastroparesis. The diagnostic gold standard for gastroparesis is the measurement of gastric emptying with scintigraphy of digestible solids at 15-min intervals for 4 h after food intake. The use of ¹³C octanoic acid breath test is an ap­ proved alternative.

Genitourinary Disturbances. Diabetic auto­ nomic neuropathy may also cause geni­ tourinary disturbances, including sexual dysfunction and bladder dysfunction. In men, diabetic autonomic neuropathy may cause erectile dysfunction and/or retrograde ejaculation (42). Female sex­ ual dysfunction occurs more frequently in those with diabetes and presents as decreased sexual desire, increased pain during intercourse, decreased sexual arousal, and inadequate lubrication (46). Lower urinary tract symptoms manifest as urinary incontinence and bladder dys­ function (nocturia, frequent urination, urination urgency, and weak urinary stream). Evaluation of bladder func­ tion should be performed for individuals with diabetes who have recurrent uri­ nary tract infections, pyelonephritis, in­ continence, or a palpable bladder.

Treatment

Glycemic Control

Near-normal glycemic control, imple­ mented early in the course of diabetes, has been shown to effectively delay or prevent the development of DPN and CAN in people with type 1 diabetes (47-50). Although the evidence for the benefit of near-normal glycemic control is not as strong that for type 2 diabetes, some studies have demonstrated a mod­ est slowing of progression without rever­ sal of neuronal loss (38,51). Specific glucose-lowering strategies may have dif­ ferent effects. In a post hoc analysis, par­ ticipants, particularly men, in the Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes (BARI 2D) trial treated with insulin sensitizers had a lower inci­ dence of distal symmetric polyneuropathy over 4 years than those treated with insu­ lin/sulfonylurea (52). Additionally, recent evidence from the Action to Control Car­ diovascular Risk in Diabetes (ACCORD) trial showed clear benefit of intensive glucose and blood pressure control on the preven­ tion of CAN in type 2 diabetes (53).

Lipid Control

Dyslipidemia is a key factor in the development of neuropathy in people with type 2 diabetes and may contrib­ ute to neuropathy risk in people with type 1 diabetes (54,55). Although the ev­ idence for a relationship between lipids

and neuropathy development has be­ come increasingly clear in type 2 diabe­ tes, the optimal therapeutic intervention has not been identified. Positive effects of physical activity, weight loss, and bar­ iatric surgery have been reported in indi­ viduals with DPN, but use of conventional lipid-lowering pharmacotherapy (such as statins or fenofibrates) does not appear to be effective in treating or preventing DPN development (56).

Blood Pressure Control

There are multiple reasons for blood pressure control in people with diabetes, but neuropathy progression (especially in type 2 diabetes) has now been added to this list. Although data from many studies have supported the role of hy­ pertension in risk of neuropathy devel­ opment, a recent meta-analysis of data from 14 countries in the International Prevalence and Treatment of Diabetes and Depression (INTERPRET-DD) study re­ vealed hypertension as an independent risk of DPN development with an odds ratio of 1.58 (57). In the ACCORD trial, intensive blood pressure intervention decreased CAN risk by 25% (53).

Neuropathic Pain

Neuropathic pain can be severe and can impact quality of life, limit mobility, and contribute to depression and social dys­ function (58). No compelling evidence exists in support of glycemic control or lifestyle management as therapies for neuropathic pain in diabetes or predia­ betes, which leaves only pharmaceutical interventions (59). A recent guideline by the American Academy of Neurology rec­ ommends that the initial treatment of pain should also focus on the concurrent treatment of both sleep and mood dis­ orders because of increased frequency of these problems in individuals with DPN (60).

A number of pharmacologic therapies exist for treatment of pain in diabetes. The American Academy of Neurology update suggested that gabapentinoids, serotonin-norepinephrine reuptake inhibi­ tors (SNRls), sodium channel blockers, tricyclic antidepressants (TCAs), and SNRI/ opioid dual-mechanism agents could all be considered in the treatment of pain in DPN (60). These American Academy of Neurology recommendations offer a sup­ plement to a recent American Diabetes Association pain monograph, although

some areas of disagreement exist, particu­ larly around SNRl/opioid dual-mechanism agents (61). A recent head-to-head trial suggested therapeutic equivalency for TCAs, SNRls, and gabapentinoids in the treatment of pain in DPN (62). The trial also supported the role of combination therapy over monotherapy for the treat­ ment of pain in DPN.

Gabapentinoids. Gabapentinoids include

several calcium channel a2-o subunit li­ gands. Eight high-quality studies and seven medium-quality studies support the role of pregabalin in treatment of pain in DPN. One high-quality study and many small studies support the role of gabapentin in the treatment of pain in DPN. Two medium-quality studies suggest that micro­ gabalin has a small effect on pain in DPN

(60). Adverse effects may be more severe in older individuals (63) and may be at­ tenuated by lower starting doses and more gradual titration.

SNRls. SNRls include duloxetine, venla­

faxine, and desvenlafaxine, all selective SNRls. Two high-quality studies and five medium-quality studies support the role of duloxetine in the treatment of pain in DPN. A high-quality study supports the role of venlafaxine in the treatment of pain in DPN. Only one medium-quality study sup­ ports a possible role for desvenlafaxine for treatment of pain in DPN (60). Adverse events may be more severe in older peo­ ple but may be attenuated with lower doses and slower titration of duloxetine. Tapentadol and Tramadol. Tapentadol and tramadol are centrally acting opioid anal­ gesics that exert their analgesic effects through both µ-opioid receptor agonism and norepinephrine and serotonin reuptake inhibition. SNRl/opioid agents are probably effective in the treatment of pain in DPN. However, the use of any opioids for man­ agement of chronic neuropathic pain carries the risk of addiction and should be avoided. Tricyclic Antidepressants. Tricyclic anti­ depressants have been studied for treat­ ment of pain, and most of the relevant data was acquired from trials of ami­ triptyline and include two high-quality studies and two medium-quality stud­ ies supporting the treatment of pain in DPN (60,62). Anticholinergic side effects may be dose limiting and restrict use in individuals 2′.65 years of age.

Sodium Channel Blockers. Sodium channel blockers include lamotrigine, lacosamide, oxcarbazepine, and valproic acid. Five medium-quality studies support the role

of sodium channel blockers in treating pain in DPN (60).

Capsaicin. Capsaicin has received FDA ap­ proval for treatment of pain in DPN using an 8% patch, with one high-quality study reported. One medium-quality study of 0.075% capsaicin cream has been re­ ported. In patients with contraindica­ tions to oral pharmacotherapy or who prefer topical treatments, the use of topical capsaicin can be considered.

Carbamazepine and a-Lipoic Acid. Carba­

mazepine and a-lipoic acid, although not approved for the treatment of painful DPN, may be effective and considered for the treatment of painful DPN (41,54,56).

Orthostatic Hypotension

Treating orthostatic hypotension is chal­ lenging. The therapeutic goal is to mini­ mize postural symptoms rather than to restore normotension. Most patients re­ quire both nonpharmacologic measures (e.g., ensuring adequate salt intake, avoid­ ing medications that aggravate hypoten­ sion, or using compressive garments over the legs and abdomen) and pharmaco­ logic measures. Physical activity and ex­ ercise should be encouraged to avoid deconditioning, which is known to ex­ acerbate orthostatic intolerance, and volume repletion with fluids and salt is critical. There have been clinical studies that assessed the impact of an approach incorporating the aforementioned non­ pharmacologic measures. Additionally, supine blood pressure tends to be much higher in these individuals, often requir­ ing treatment of blood pressure at bed­ time with shorter-acting drugs that also affect baroreceptor activity such as guan­ facine or clonidine, shorter-acting calcium blockers (e.g., isradipine), or shorter­ acting [3-blockers such as atenolol or metoprolol tartrate. Alternatives can in­ clude enalapril if an individual is unable to tolerate preferred agents (64-66). Midodrine and droxidopa are approved by the FDA for the treatment of ortho­ static hypotension.

Gastroparesis

Treatment for diabetic gastroparesis may be very challenging. A low-fiber, low-fat eating plan provided in small frequent meals with a greater proportion of liquid calories may be useful (67-69). In addi­ tion, foods with small particle size may improve key symptoms (70). With­ drawing drugs with adverse effects on

gastrointestinal motility, including opioids, anticholinergics, tricyclic antidepressants, GLP-1 RAs, and pramlintide, may also improve intestinal motility (67,71). How­ ever, the risk of removal of GLP-1 RAs should be balanced against their potential benefits. In cases of severe gastroparesis, pharmacologic interventions are needed. Only metoclopramide, a prokinetic agent, is approved by the FDA for the treatment of gastroparesis. However, the level of evidence regarding the benefits of meto­ clopramide for the management of gas­ troparesis is weak, and given the risk for serious adverse effects (extrapyramidal signs such as acute dystonic reactions, drug-induced parkinsonism, akathisia, and tardive dyskinesia), its use in the treat­ ment of gastroparesis beyond 12 weeks is no longer recommended by the FDA. It should be reserved for severe cases that are unresponsive to other thera­ pies (71). Other treatment options in­ clude domperidone (available outside the U.S.) and erythromycin, which is only effective for short-term use due to tachy­ phylaxis (72,73). Gastric electrical stimula­ tion using a surgically implantable device has received approval from the FDA, although its efficacy is variable and use is limited to individuals with severe symp­ toms that are refractory to other treat­ ments (74).

Erectile Dysfunction

In addition to treatment of hypogonadism if present, treatments for erectile dys­ function may include phosphodiester­ ase type 5 inhibitors, intracorporeal or intraurethral prostaglandins, vacuum devices, or penile prostheses. As with DPN treatments, these interventions do not change the underlying pathol­ ogy and natural history of the disease process but may improve a person’s qual­ ity of life.

FOOT CARE

Foot ulcerations and amputations are common complications associated with diabetes. These may be the consequences of several factors, including peripheral neuropathy, peripheral arterial disease (PAD), and foot deformities. They rep­ resent major causes of morbidity and mortality in people with diabetes. Early recognition of at-risk feet, preulcerative lesions, and prompt treatment of ulcer­ ations and other lower-extremity com­ plications can delay or prevent adverse outcomes.

Early recognition requires an under­

standing of those factors that put peo­ ple with diabetes at increased risk for ulcerations and amputations. Factors that are associated with the at-risk foot include the following:

1. • Poor glycemic control
   • Peripheral neuropathy/LOPS
   • PAD
   • Foot deformities (bunions, hammer- toes, Charcot joint, etc.)
   • Preulcerative corns or calluses
   • Prior ulceration
   • Prior amputation
   • Smoking
   • Retinopathy
   • Nephropathy (particularly individuals on dialysis or posttransplant)

Identifying the at-risk foot begins with a detailed history documenting diabetes control, smoking history, exercise toler­ ance, history of claudication or rest pain, and prior ulcerations or amputations. A thorough examination of the feet should be performed annually in all people with diabetes and more frequently in at-risk individuals (75). The examination should include assessment of skin integrity, as­ sessment for LOPS using the 10-g mono­ filament along with at least one other neurological assessment tool, pulse ex­ amination of the dorsalis pedis and pos­ terior tibial arteries, and assessment for foot deformities such as bunions, ham­ mertoes, and prominent metatarsals, which increase plantar foot pressures and increase risk for ulcerations. At-risk individuals should be assessed at each visit and should be referred to foot care specialists for ongoing preventive care and surveillance. The physical examina­ tion can stratify patients into different categories and determine the frequency of these visits (76) (Table 12.1).

Evaluation for Loss of Protective Sensation

The presence of peripheral sensory neu­ ropathy is the single most common com­ ponent cause for foot ulceration. In a multicenter trial, peripheral neuropathy was found to be a component cause in 78% of people with diabetes with ulcer­ ations and that the triad of peripheral sensory neuropathy, minor trauma, and foot deformity was present in >63% of participants (77). All people with dia­ betes should undergo a comprehensive foot examination at least annually, or

more frequently for those in higher-risk categories (75,76).

LOPS is vital to risk assessment. One of the most useful tests to determine LOPS is the 10-g monofilament test. Studies have shown that clinical exami­ nation and the 10-g monofilament test are the two most sensitive tests in iden­ tifying the foot at risk for ulceration

(78). The monofilament test should be performed with at least one other neu­ rologic assessment tool (e.g., pinprick, temperature perception, ankle reflexes, or vibratory perception with a 128-Hz tuning fork or similar device). Absent monofilament sensation and one other abnormal test confirms the presence of LOPS. Further neurological testing, such as nerve conduction, electromyography, nerve biopsy, or intraepidermal nerve fi­ ber density biopsies, are rarely indicated for the diagnosis of peripheral sensory neuropathy (42).

Evaluation for Peripheral Arterial Disease

Initial screening for PAD should include a history of leg fatigue, claudication, and rest pain relieved with dependency. Physical examination for PAD should include assessment of lower-extremity pulses, capillary refill time, rubor on dependency, pallor on elevation, and ve­ nous filling time (75,79). Any patient ex­ hibiting signs and symptoms of PAD should be referred for noninvasive arte­ rial studies in the form of Doppler ultra­ sound with pulse volume recordings. While ankle-brachia! indices will be calculated, they should be interpreted carefully, as they are known to be inac­ curate in people with diabetes due to

noncompressible vessels. Toe systolic blood pressure tends to be more accurate. Toe systolic blood pressures <30 mmHg are suggestive of PAD and an inability to heal foot ulcerations (80). Individuals with abnormal pulse volume recording tracings and toe pressures <30 mmHg with foot ulcers should be referred for immediate vascular evaluation. Due to the high prevalence of PAD in people with dia­ betes, it has been recommended by the Society for Vascular Surgery and the American Pediatric Medical Associa­ tion in their 2016 guidelines that all people with diabetes >50 years of age should undergo screening via noninva­ sive arterial studies (79,81). If nor­ mal, these should be repeated every 5 years (79).

Patient Education

All people with diabetes (and their families), particularly those with the aforementioned high-risk conditions, should receive general foot care edu­ cation, including appropriate manage­ ment strategies (82-84). This education should be provided to all newly diag­ nosed people with diabetes as part of an annual comprehensive examination and to individuals with high-risk conditions at every visit. Recent studies have shown that while education improves knowl­ edge of diabetic foot problems and self­ care of the foot, it does not improve behaviors associated with active participa­ tion in their overall diabetes care and to achieve personal health goals (85). Evi­ dence also suggests that while patient and family education are important, the knowledge is quickly forgotten and needs to be reinforced regularly (86).

Table 12.1-lnternational Working Group on the Diabetic Foot risk stratification system and corresponding foot screening frequency Category Ulcer risk Characteristics Examination frequency* 0 Very low No LOPS and No PAD Annually
1	Low	LOPS or PAD	Every 6-12 months
2	Moderate	LOPS + PAD, or LOPS + foot deformity, or PAD + foot deformity	Every 3-6 months
3 High LOPS or PAD and one or more of the following: Every 1-3 months History of foot ulcer Amputation (minor or major) End-stage renal disease Adapted with permission from Schaper et al. (76). LOPS, loss of protective sensation; PAD, peripheral artery disease. *Examination frequency suggestions are based on expert opinion and patient-centered requirements.

Individuals considered at risk should understand the implications of foot de­ formities, LOPS, and PAD; the proper care of the foot, including nail and skin care; and the importance of foot inspec­ tions on a daily basis. Individuals with LOPS should be educated on appropriate ways to examine their feet (palpation or visual inspection with an unbreakable mirror) for daily surveillance of early foot problems. Patients should also be educated on the importance of refer­ rals to foot care specialists. A recent study showed that people with diabetes and foot disease lacked awareness of their risk status and why they were be­ ing referred to a multidisciplinary team of foot care specialists. Further, they ex­ hibited a variable degree of interest in learning further about foot complica­ tions (87).

Patients’ understanding of these issues

and their physical ability to conduct proper foot suNeillance and care should be as­ sessed. Those with visual difficulties, physi­ cal constraints preventing movement, or cognitive problems that impair their ability to assess the condition of the foot and to institute appropriate responses will need other people, such as family members, to assist with their care.

The selection of appropriate footwear and footwear behaviors at home should also be discussed (e.g., no walking barefoot, avoiding open-toed shoes). Therapeutic footwear with custom-made orthotic devices have been shown to re­ duce peak plantar pressures (84). Most studies use reduction in peak plantar pressures as an outcome as opposed to ulcer prevention. Certain design features of the orthoses, such as rocker soles and metatarsal accommodations, can reduce peak plantar pressures more significantly than insoles alone. A systematic review, however, showed there was no signifi­ cant reduction in ulcer incidence after

18 months compared with standard insoles and extra-depth shoes. Fur­ ther, it was also noted that evidence to prevent first ulcerations was non­ existent (88).

Treatment

Treatment recommendations for people with diabetes will be determined by their risk category. No-risk or low-risk individuals can often be managed with

education and self-care. People in the moderate- to high-risk category should be referred to foot care specialists for further evaluation and regular surveil­ lance as outlined in Table 12.1. This in­ cludes individuals with LOPS, PAD, and/ or structural foot deformities, such as Charcot foot, bunions, or hammertoes. Individuals with any open ulceration or unexplained swelling, erythema, or in­ creased skin temperature should be re­ ferred urgently to a foot care specialist or multidisciplinary team.

Initial treatment recommendations should include daily foot inspection, use of moisturizers for dry, scaly skin, and avoidance of self-care of ingrown nails and calluses. Well-fitted athletic or walking shoes with customized pressure­ relieving orthoses should be part of ini­ tial recommendations for people with increased plantar pressures (as demon­ strated by plantar calluses). Individuals with deformities such as bunions or hammertoes may require specialized footwear such as extra-depth shoes. Those with even more significant de­ formities, as in Charcot joint disease, may require custom-made footwear.

Special consideration should be given to individuals with neuropathy who pre­ sent with a warm, swollen, red foot with or without a history of trauma and without an open ulceration. These indi­ viduals require a thorough workup for possible Charcot neuroarthropathy (89). Early diagnosis and treatment of this condition is of paramount importance in preventing deformities and instability that can lead to ulceration and amputa­ tion. These individuals require total non­ weight-bearing and urgent referral to a foot care specialist for further manage­ ment. Foot and ankle X-rays should be performed in all individuals presenting with the above clinical findings.

There have been a number of devel­

opments in the treatment of ulcerations over the years (90). These include negative-pressure therapy, growth fac­ tors, bioengineered tissue, acellular ma­ trix tissue, stem cell therapy, hyperbaric oxygen therapy, and, most recently, topi­ cal oxygen therapy (91-93). While there is literature to support many modalities currently used to treat diabetic foot wounds, robust randomized controlled trials (RCTs) are often lacking. How­ ever, it is agreed that the initial treat­ ment and evaluation of ulcerations

include the following five basic prin­ ciples of ulcer treatment:

• Offloading of plantar ulcerations
• Debridementofnecrotic,nonviable tissue
• Revascularization of ischemic wounds when necessary
• Management of infection: soft tissue or bone
• Use of physiologic, topical dressings

However, despite following the above principles, some ulcerations will become chronic and fail to heal. In those situa­ tions, advanced wound therapy can play a role. When to employ advanced wound therapy has been the subject of much discussion, as the therapy is often quite expensive. It has been determined that if a wound fails to show a reduc­ tion of 50% or more after 4 weeks of appropriate wound management (i.e., the five basic principles above), consid­ eration should be given to the use of advanced wound therapy (94). Treat­ ment of these chronic wounds is best managed in a multidisciplinary setting.

Evidence to support advanced wound

therapy is challenging to produce and to assess. Randomization of trial partici­ pants is difficult, as there are many variables that can affect wound heal­ ing. In addition, many RCTs exclude certain cohorts of people, e.g., individu­ als with chronic renal disease or those on dialysis. Finally, blinding of participants and clinicians is not always possible. Meta-analyses and systematic reviews of obseNational studies are used to deter­ mine the clinical effectiveness of these modalities. Such studies can augment for­ mal RCTs by including a greater variety of participants in various clinical settings who are typically excluded from the more rigidly structured clinical trials.

Advanced wound therapy can be cat­

egorized into nine broad categories (90) (Table 12.2). Topical growth factors, acel­ lular matrix tissues, and bioengineered cellular therapies are commonly em­ ployed in offices and wound care cen­ ters to expedite healing of chronic, more superficial ulcerations. Numerous clinical reports and retrospective studies have demonstrated the clinical effectiveness of each of these modalities. Over the years, there has been increased evidence to support the use of these modalities.

Nonetheless, use of those products or agents with robust RCTs or system­ atic reviews should generally be pre­ ferred over those without level 1 evidence (Table 12.2).

Negative-pressure wound therapy was

first introduced in the early to mid- 1990s. It has become especially useful in wound preparation for skin grafts and flaps and assists in the closure of deep, large wounds (95,96). A variety of types exist in the marketplace and range from electrically powered to mechanically

powered in different sizes depending upon the specific wound requirements.

Electrical stimulation, pulsed radio­ frequency energy, and extracorporeal shockwave therapy are biophysical mo­ dalities that are believed to upregulate growth factors or cytokines to stimulate wound healing, while low-frequency non­ contact ultrasound is used to debride wounds. However, most of the studies advocating the use of these modalities have been retrospective observational or poor-quality RCTs.

Hyperbaric oxygen therapy is the de­ livery of oxygen through a chamber, ei­ ther individual or multiperson, with the intention of increasing tissue oxygena­ tion to increase tissue perfusion and neovascularization, combat resistant bac­ teria, and stimulate wound healing. While there had been great interest in this modality being able to expedite healing of chronic diabetic foot ulcers (DFUs), there has only been one positive RCT published in the last decade that re­ ported increased healing rates at 9 and 12 months compared with control subjects (97). More recent studies with significant design deficiencies and par­ ticipant dropouts have failed to provide corroborating evidence that hyperbaric oxygen therapy should be widely used for managing nonhealing DFUs (98,99). While there may be some benefit in prevention of amputation in selected chronic neuroischemic ulcers, recent stud­ ies have shown no benefit in healing DFUs in the absence of ischemia and/ or infection (93,100).

Topical oxygen therapy has been studied rather vigorously in recent years, with several high-quality RCTs and at least five systematic reviews and meta­ analyses all supporting its efficacy in healing chronic DFUs at 12 weeks (19,20,30-34,91,92,101-105). Three

types of topical oxygen devices are available, including continuous-delivery, low-constant-pressure, and cyclical­ pressure modalities. Importantly, topical oxygen therapy devices provide for home-based therapy rather than the need for daily visits to specialized cen­ ters. Very high participation with very few reported adverse events combined with improved healing rates makes this therapy another attractive option for ad­ vanced wound care.

If DFUs fail to heal despite appropriate wound care, adjunctive advanced thera­ pies should be instituted and are best managed in a multidisciplinary manner. Once healed, all individuals should be enrolled in a formal comprehensive prevention program focused on reducing the incidence of recurrent ulcerations and subsequent amputations (75,106,107).

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8. Frykberg RG, Franks PJ, Edmonds M, et al.; TWO2 Study Group. A multinational, multicenter, randomized, double-blinded, placebo-controlled trial to evaluate the efficacy of cyclical topical wound oxygen (TWO2) therapy in the treatment

of chronic diabetic foot ulcers: the TWO2 study. Diabetes Care 2020;43:616-624

1. Boulton AJM, Armstrong DG, Li:indahl M, et al. New Evidence-Based Therapies far Complex Diabetic Foot Wounds. Arlington, VA, American Diabetes Association, 2022
2. Sheehan P, Jones P, Caselli A, Giurini JM, Veves A. Percent change in wound area of diabetic foot ulcers over a 4-week period is a robust predictor of complete healing in a 12-week prospective trial. Diabetes Care 2003;26:1879- 1882
3. Blume PA, Walters J, Payne W, Ayala J, Lantis J. Comparison of negative pressure wound therapy using vacuum-assisted closure with advanced moist wound therapy in the treatment of diabetic foot ulcers: a multicenter randomized controlled trial. Diabetes Care 2008;31:631-636
4. Argenta LC, Morykwas MJ, Marks MW, DeFranzo AJ, Molnar JA, David LR. Vacuum­ assisted closure: state of clinic art. Plast Reconstr Surg 2006;117(Suppl. ):1275-1425
5. Li:indahl M, Katzman P, Nilsson A, Hammarlund

C. Hyperbaric oxygen therapy facilitates healing of chronic foot ulcers in patients with diabetes. Diabetes Care 2010;33:998-1003

1. Santema KTB, Stoekenbroek RM, Koelemay MJW, et al.; DAMO2CLES Study Group. Hyperbaric oxygen therapy in the treatment of ischemic lower- extremity ulcers in patients with diabetes: results of the DAMO₂CLESmulticenter randomized clinical trial. Diabetes Care 2018;41:112-119
2. Fedorko L, Bowen JM, Jones W, et al. Hyperbaric oxygen therapy does not reduce indications for amputation in patients with diabetes with nonhealing ulcers of the lower limb: a prospective, double-blind, randomized controlled clinical trial. Diabetes Care 2016;39: 392-399
3. Lalieu RC, Brouwer RJ, Ubbink DT, Hoencamp R, Bol Raap R, van Hulst RA. Hyperbaric oxygen therapy for nonischemic diabetic ulcers: a sys­ tematic review. Wound Repair Regen 2020;28: 266-275
4. Niederauer MQ, Michalek JE, Liu Q, Papas KK, Lavery LA, Armstrong DG. Continuous diffusion of oxygen improves diabetic foot ulcer healing when compared with a placebo control: a randomised, double-blind, multicentre study. J Wound Care 2018;27(Suppl. 9):530- 545
5. Serena TE, Bullock NM, Cole W, Lantis J, Li L, Moore S, et al. Topical oxygen therapy in the treatment of diabetic foot ulcers: a multicentre, open, randomised controlled clinical trial. J Wound Care 2021;30(Suppl. 5):57-514
6. Sun XK, Li R, Yang XL, Yuan L. Efficacy and safety of topical oxygen therapy for diabetic foot ulcers: an updated systematic review and meta­ analysis. Int Wound J. 5 May 2022 [Epub ahead of print]. DOI: 10.1111/iwj.13830
7. Frykberg RG.Topical wound oxygen therapy

in the treatment of chronic diabetic foot ulcers. Medicina (Kaunas) 2021;57:917

1. Sethi A, Khambhayta Y, Vas P. Topical oxygen therapy for healing diabetic foot ulcers: a systematic review and meta-analysis of randomised control trials. Health Sci Rep 2022;3:100028
2. van Netten JJ, Price PE, Lavery LA, et al.; International Working Group on the Diabetic Foot. Prevention of foot ulcers in the at-risk patient with diabetes: a systematic review. Diabetes Metab Res Rev 2016;32(Suppl. 1):84-98
3. Frykberg RG, Vileikyte L, Boulton AJM,

Armstrong DG. The at-risk diabetic foot: time to focus on prevention. Diabetes Care 2022;45: e144-e145

 

Clinical Research

Featured

Reduced Hospitalizations and Amputations in Patients with Diabetic Foot Ulcers Treated

with Cyclical Pressurized Topical Wound Oxygen Therapy: Real-World Outcomes

Jessica Izhakoff Yellin,¹ Julia A. Gaebler,¹ Frank F. Zhou,¹

Timothy Niecko,² Olivia Novins,¹ Amelia Ockert,¹ Darcy Krzynowek,¹ Matthew G. Garoufalis,³ Aliza M. Lee,⁴ and Robert G. Frykberg^5,*^,i

¹Health Advances LLC, Newton, Massachusetts, USA.

²Niecko Health Economics LLC, Tierra Verde, Florida, USA.

³Department of Podiatry, Jesse Brown VA Medical Center, Chicago, Illinois, USA.

⁴Department of Podiatry, Salem Veterans Affairs Medical Center, Salem, Virginia, USA.

⁵Department of Podiatry, Diabetic Foot Consultants, Midwestern University, Glendale, Arizona, USA.

ⁱORCID ID (https://orcid.org/0000-0001-9095-303X).

Background: This study sought to examine the real-world impact of multi- modality cyclical-pressure topical wound oxygen therapy (TWO2) on hospital- izations and amputations in patients with diabetic foot ulcer (DFU) compared with patients without TWO2.

Methods: We conducted a retrospective review of deidentified patient medi- cal records at 2 U.S. Veterans Affairs hospitals between January 2012 and January 2020. DFU patients were assigned to TWO2 or NO TWO2 cohorts based on their treatment records. Patients received appropriate standard of care and may have received other advanced wound treatments, including skin substitutes, negative pressure wound therapy, and growth factors. Pri- mary study outcomes were patients requiring hospitalization and/or ampu- tation within 360 days of initial wound documentation.

Findings: Among unmatched cohorts of 202 patients with DFU (91 TWO2, 111 NO TWO2), 6.6% and 12.1% of TWO2 patients had hospitalizations and amputations, respectively, compared with 54.1% and 41.4% of NO TWO2 patients within 360 days ( p < 0.0001, p < 0.0001), representing 88% and 71% reductions. Among propensity score-matched cohorts of 140 DFU patients (70 TWO2, 70 NO TWO2), compared with NO TWO2, 82% fewer TWO2 patients were hospitalized (7.1% vs. 40.0%, p < 0.0001) and 73% fewer TWO2 patients had amputations (8.6% vs. 31.4%, p = 0.0007). Logistic regression among matched cohorts demonstrated nearly ninefold and fivefold higher risk of hospitalization and amputation, respectively, for NO TWO2 versus TWO2.

Interpretation: This retrospective cohort study demonstrates that treating pa- tients with DFU with TWO2 is associated with significant reductions in hospi- talizations and amputations in the real-world setting.

Keywords: diabetic foot ulcers, topical oxygen therapy, amputations, hospitalizations

Robert G. Frykberg, DPM, MPH

Submitted for publication July 15, 2021.

Accepted in revised form October 19, 2021.

*Correspondence: Department of Podiatry, Diabetic Foot Consultants, 15411 N. Tepic Lane,

Fountain Hills, AZ 85268, USA

(e-mail: [email protected]).

ª Jessica Izhakoff Yellin et al., 2021; Published by Mary Ann Liebert, Inc. This Open Access article is distributed under the terms of the Creative Commons License [CC-BY] (http:// creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduc- tion in any medium, provided the original work is properly cited.

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 af- ter 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 frequen- tly recur.² While a number of adjunctive thera- pies are available for use, the quality of evidence about their respective efficacy rates is regarded to be low, due primarily to small and poorly de- signed 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 pro- cess of healing a wound.¹¹ Nonetheless, efficacy results from studies of hyperbaric oxygen ther- apy and topical oxygen therapy (TOT) vary, and conclusions regarding effectiveness are inconsis- tent.^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 pro- prietary dressing devices, (2) low constant pressure devices in a contained chamber, and (3) the device used in this study, incorporating cyclically pres- surized (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, repre- sentative 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 hospi- talizations and amputations in a large, real-world, representative patient population.

METHODS

Study population

We used deidentified data collected retrospec- tively from patient medical records at two U.S. Veterans Affairs (VA) hospitals. The period of review was January 2012 through January 2020. Patients were identified through a primary diag- nosis of diabetic, ischemic, venous, pressure, and multimorbid wounds (total N = 246). Only patients with a primary diagnosis of DFU (either alone or multimorbid with other wounds) were included in the analysis (N = 202). The protocol was approved by the Institutional Review Board at each facility. Patient medical records were reviewed for de- mographic information such as age, sex, and eth- nicity, wound characteristics, including Wagner classification, wound duration, area, and addi- tional clinical characteristics, including prior amputation, type 1 or 2 diabetes, neuropathy, car- diovascular disease (CVD), peripheral arterial dis- ease (PAD), venous disease, pain level, and stage of kidney disease.

Therapeutic interventions

We evaluated the impact of treating chronic DFU with home-based multimodality cyclical pres- sure topical wound oxygen therapy (TWO2), (AOTI Ltd., Galway, Ireland), on hospitalizations and amputations. As is common in clinical practice, study participants may have also received addi- tional adjunctive therapies, including negative pressure wound therapy (NPWT), skin substitutes (SS), and/or growth factors (GF). This study fo- cused on the impact of TWO2 in the real-world setting to corroborate the recent positive find- ings from the aforementioned strictly controlled randomized trial of TWO2 versus sham-treated controls.¹⁵

To evaluate the effectiveness of TWO2, we developed two comparison groups. Comparison #1 (C1) compared patients who had ever received TWO2 (TWO2) with those who had never received TWO2 (NO TWO2). Patients in each cohort may have received treatment with additional adjunc- tive therapies, so TWO2 was considered additive to adjunctive treatment in C1. Comparison #2 (C2) compared patients who had received only TWO2 and no other adjunctive wound care therapies (TWO2 ONLY) with those receiving SS, NPWT, and/or GF, but not TWO2 (OTHER TX ONLY), thus evaluating the impact of TWO2 in lieu of other adjunctive treatments. Patients in each co- hort received appropriate SOC irrespective of any adjunctive therapies, including TWO2.

Study outcomes

The primary study outcomes were defined as patients with one or more wound-related hospi- talization or amputation within a 1-year analysis period. Medical records were reviewed for presence of wound-related hospitalization or amputation at 90, 180, and 360 days after first documentation of the wound. The presence of a first hospitali- zation or amputation at any time point before or at 360 days classified a patient as having had a hospitalization or amputation within 360 days. Because the study outcomes were patients with wound-related hospitalizations and amputations, no patient was counted for more than one hospi- talization or amputation if multiple such episodes occurred.

Statistical analysis

Missing data for demographics and clinical characteristics was imputed by the single imputa- tion hot-deck method. This method uses observed values from the sample to impute (fill-in) missing values. In instances of missing outcomes data, we applied the last observation carried forward (LOCF) method, which is a common statistical approach to account for missing follow-up obser- vations.¹⁶ We assumed that any patient without follow-up data suggesting a hospitalization or amputation during the 360-day period was cate- gorized as not hospitalized or not amputated.

Baseline demographics and clinical character- istics were assessed by chi-square test for cate- gorical and t-tests for continuous variables. In cases where cell size was small (<5) for categorical assessments chi-square may not be a valid test, thus Fisher’s exact test was used.

When using an observational study design, such as a retrospective cohort study, subjects are not ran- domized to a treatment or control group. Confounding can occur when some of the covariates are related to both the treatment and the outcome. Consequently, there can be systematic differences between the treated subjects and the control subjects.

In the presence of confounding, statistical ap- proaches are required to remove the effects of confounding when estimating the effect of the treatment. Propensity score matching minimizes the effects of confounding by achieving more bal- anced covariates in the absence of a randomized study design.^17,18 We, therefore, applied propen- sity score matching by means of a greedy algori- thm to match TWO2 patients to NO TWO2 patients in a 1:1 ratio. Cohorts were matched on age, sex, ethnicity, wound severity, prior amputation, use of offloading, and use of NPWT, SS, or GF.

In addition, the study dichotomous outcomes of wound-related hospitalization versus no hospitali- zation, and amputation versus no amputation were assessed by logistic regression within the matched cohorts for C1 (NO TWO2 vs. TWO2). The logistic model calculated odds ratios (ORs), 95% confidence intervals (CIs), and p-values for the study treat- ment arms (NO TWO2 vs. TWO2). Statistical tests were two-sided, and significance level was set at p < 0.05. Analyses were performed using SAS soft- ware version 9.4.

Role of the funding source

The funders of the study had no role in study design, data analysis, data interpretation, or writ- ing of the report, but did help coordinate data col- lection. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.

RESULTS

Study population

A total of 202 patients with DFU were identified. For C1, 91 DFU patients qualified as ever receiving TWO2 (TWO2), and 111 patients qualified as never receiving TWO2 (NO TWO2). During the 1-year analysis time frame, patients in each cohort may have been treated with other advanced wound care treatments, including SS, NPWT, and GF. For C2, 58 DFU patients received only TWO2 and no other adjunctive wound care therapies (TWO2 ONLY), and 34 patients received only SS, NPWT, and/or GF, but not TWO2 (OTHER TX ONLY).

Table 1 presents demographic and clinical char- acteristics of unmatched and matched cohorts. For C1, unmatched cohorts of TWO2 versus NO TWO2 were similar on most characteristics, including the use of adjunctive therapies, although statistically significant differences were present for wound se- verity ( p < 0.0001), prior amputation ( p = 0.011), pain level ( p = 0.011), and stage of kidney disease ( p < 0.0001). For C2, unmatched cohorts of TWO2 ONLY versus OTHER TX ONLY were also simi- lar on most characteristics, differing on use of adjunctive therapies, as well as wound severity ( p = 0.0005), pain level ( p = 0.026), stage of kidney disease ( p = 0.0008), and HbA1c ( p = 0.038).

Similarly, C1 is tabulated after application of propensity score matching for age, sex, ethnicity, wound severity, prior amputation, use of offload- ing, and use of NPWT, SS, or GF. After propensity score matching, the TWO2 (n = 70) and NO TWO2 (n = 70) cohorts were well matched on all demogra- phics and clinical characteristics, except for kid- ney disease ( p < 0.0001) and HbA1c ( p = 0.0093).

TWO2 NO TWO2   TWO2 ONLY OTHER TX ONLY   TWO2 NO TWO2   N = 91 N = 111 p N = 58 N = 34                  p   N = 70 N = 70 p Patient demographics Age (years), mean (SD)   66.9 (9.9)   67.0 (8.7)   0.93   67.7 (11.2)   65.9 (6.5)             0.33     67.5 (9.7)   67.7 (8.4)   0.89 Sex, male, n (%) 89 (97.8) 107 (96.4) 0.69             58 (100.0) 34 (100.0)           NA 68 (97.1) 69 (98.6) 1.0 Ethnicity, n (%)     0.092 0.084     0.61 White 51 (56.0) 49 (44.1) 33 (56.9) 13 (38.2) 37 (52.9) 34 (48.6)   Non-White 40 (44.0) 62 (55.9) 25 (43.1) 21 (61.8) 33 (47.1) 36 (51.4)   Wound characteristics Wound classification, n (%)       <0.0001   0.0005       1.0 Wagner 1 39 (42.9) 38 (34.2) 29 (50.0) 8 (23.5) 30 (42.9) 30 (42.9)   Wagner 2 45 (49.5) 39 (35.1) 27 (46.6) 15 (44.1) 33 (47.1) 33 (47.1)   Wagner 3 5 (5.5) 25 (22.5) 1 (1.7) 8 (23.5) 5 (7.1) 4 (5.7)   Wagner 4 2 (2.2) 9 (8.1) 1 (1.7) 3 (8.8) 2 (2.9) 3 (4.3)   Presenting area (cm2), mean (SD) 3.8 (6.8) 3.9 (7.1) 0.95            3.2 (5.2) 7.2 (11.1)           0.056 3.3 (6.7) 3.6 (7.8) 0.80 Wound duration (days), mean (SD) 175.3 (241.7) 166.9 (240.8) 0.81        195.6 (271.0) 267.4 (316.1)         0.27 194.8 (269.8) 188.6 (261.4) 0.89 Use of other treatments                   Used offloading devices, n (%) 81 (89.0) 97 (87.4) 0.72             51 (87.9) 30 (88.2)           1.0 61 (87.1) 61 (87.1) 1.0 Used NPWT, n (%) 2 (2.2) 9 (8.1) 0.12               0 (0.0) 9 (26.5)        <0.0001 2 (2.9) 2 (2.9) 1.0 Used SS, n (%) 31 (34.1) 25 (22.5) 0.068             0 (0.0) 25 (73.5)        <0.0001 19 (27.1) 19 (27.1) 1.0 Used GF, n (%) 24 (26.4) 22 (19.8) 0.27               0 (0.0) 22 (64.7)        <0.0001 16 (22.9) 14 (20.0) 0.68 Other clinical characteristics               Prior amputation, n (%) 41 (45.1) 31 (27.9) 0.011           21 (36.2) 11 (32.4)           0.71 20 (28.6) 20 (28.6) 1.0 Type 1 diabetes, n (%) 5 (5.5) 4 (3.6) 0.73               5 (8.6) 0 (0.0)             0.15 2 (2.9) 2 (2.9) 1.0 Type 2 diabetes, n (%) 86 (94.5) 107 (96.4) 53 (91.4) 34 (100.0) 68 (97.1) 68 (97.1)   Neuropathy, n (%) 88 (96.7) 107 (96.4) 1.0              56 (96.6) 33 (97.1)           1.0 67 (95.7) 67 (95.7) 1.0 Cardiovascular disease, n (%) 69 (75.8) 79 (71.2) 0.46             45 (77.6) 27 (79.4)           0.84 51 (72.9) 51 (72.9) 1.0 Peripheral artery disease, n (%) 72 (79.1) 90 (81.1) 0.73             50 (86.2) 26 (76.5)           0.23 55 (78.6) 54 (77.1) 0.84 Peripheral edema, n (%) 22 (24.2) 31 (27.9) 0.55             14 (24.1) 9 (26.5)           0.80 15 (21.4) 18 (25.7) 0.55 Venous disease, n (%) 36 (39.6) 36 (32.4) 0.29             27 (46.6) 12 (35.3)           0.29 28 (40.0) 27 (38.6) 0.86 Pain level, mean (SD) 1.4 (2.3) 2.4 (3.3) 0.011          1.5 (2.1) 3.0 (3.5)             0.026 1.5 (2.4) 2.4 (3.3) 0.093 Kidney disease stage, n (%)     <0.0001 0.0008     <0.0001 Normal 1 (1.1) 19 (17.1) 0 (0.0) 4 (11.8) 1 (1.4) 15 (21.4)   Stage I/II 23 (25.3) 24 (21.6) 15 (25.9) 6 (17.7) 18 (25.7) 11 (15.7)   Stage III 45 (49.5) 31 (27.9) 32 (55.2) 8 (23.5) 36 (51.4) 21 (30.0)   Stage IV/V 12 (13.2) 16 (14.4) 5 (8.6) 7 (20.6) 9 (12.9) 11 (15.7)   Dialysis 10 (11.0) 21 (18.9) 6 (10.3) 9 (26.5) 6 (8.6) 12 (17.1)   Diabetes duration (years), mean (SD) 17.4 (9.9) 18.0 (9.0) 0.66          17.5 (11.5) 18.9 (7.1)             0.48 17.4 (9.8) 17.4 (8.8) 0.99 HbA1c, mean (SD) 8.0 (1.7) 8.6 (2.2) 0.053          7.9 (1.8) 8.8 (2.1)             0.038 7.8 (1.7) 8.7 (2.5) 0.0093

Table 1. Baseline demographics and clinical characteristics of unmatched and matched cohorts

Unmatched Cohorts                                                       Propensity Score Matched Cohorts Comparison #1 (C1)          Comparison #2 (C2)                                                                      Comparison #1 (C1)

 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.

GF, growth factors; NPWT, negative pressure wound therapy; SD, standard deviation; SOC, standard of care; SS, skin substitutes.

Most of the matched patients were male (97.1% TWO2, 98.6% NO TWO2), and approximately half of patients were white (52.9% TWO2, 48.6% NO TWO2). Many patients also had prior amputa- tion (28.6% TWO2, 28.6% NO TWO2). A large

proportion of patients in each cohort also had CVD (72.9% TWO2, 72.9% NO TWO2), PAD (78.6%

TWO2, 77.1% NO TWO2), and venous disease (40.0% TWO2, 38.6% NO TWO2). On average,

patients in each cohort had a mean diabetes dura- tion of 17.4 years. Average wound duration was similar in the matched cohorts at 194.8 days for TWO2 and 188.6 days for NO TWO2 patients.

During the 12-month observation period, we only had one mortality in the NO TWO2 cohort. There were no instances of mortality in the TWO group.

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%

41. 41.4%, p < 0.0001), respectively, within 360 days

(Fig. 1).

 

TWO2 NO TWO2     TWO2 ONLY OTHER TX ONLY     TWO2 NO TWO2   N = 91 N = 111 p   N = 58 N = 34 p   N = 70 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

Table 2. Patients with hospitalization and amputation across cohorts

Unmatched Cohorts                                                         Propensity Score–Matched Cohorts Comparison #1 (C1)   Comparison #2 (C2)                                                                       Comparison #1 (C1)

 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 hospitali- zation 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).

Outcomes for matched cohorts

Within matched cohorts, TWO2 patients still experienced reduced hospitalizations and ampu- tations versus NO TWO2 within 360 days (Table 2). Compared with NO TWO2, 82% fewer TWO2 patients  were  hospitalized  (7.1%  vs.  40.0%, p < 0.0001) and 73% fewer TWO2 patients had an amputation (8.6% vs. 31.4%, p = 0.0007) (Fig. 1).

Regression models in matched cohorts

Logistic regression models were conducted on the dichotomous study outcomes (hospitalization vs. no hospitalization, and amputation vs. no am- putation) within matched cohorts of NO TWO2 and TWO2 patients. The models demonstrated a nearly ninefold greater risk of wound-related hospitalization (OR: 8.667; 95% CI: 3.101, 24.219; p < 0.0001) and nearly fivefold greater risk of amputation (OR: 4.887; 95% CI: 1.840–12.985;

p = 0.0015) for NO TWO2 patients compared with TWO2 within 360 days (Table 3).

DISCUSSION

This study demonstrates the real-world effec- tiveness of cyclical pressurized topical wound oxygen therapy in reducing wound-related hospi- talizations and amputations for patients with DFU compared with patients who did not receive this intervention. Both amputations and hospitaliza- tions 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 am- putation 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 fre- quent 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 ad- junctive therapies (NPWT, SS, and GF). For C1 (TWO2 vs. NO TWO2), the use of TWO2 was addi- tive 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 mean- ingful 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 signifi- cant 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 alterna tive to other advanced wound care modalities.

To our knowledge, few other studies have evalu- ated the impact of adjunctive modalities, including TOT, on near-term hospitalizations and amputa- tions. In a retrospective uncontrolled chart re- view evaluating the impact of another type of TOT device on a variety of wound types, the over- all amputation rate for patients treated with TOT was 2.4%.²¹ Although lower than observed for pa- tients in this study (9–14% across cohorts treated with TWO2), comparisons are difficult to make due to the heterogeneity of woundtypes in theformerstudy. Furthermore, while our average DFU duration was *6 months, the majority of all wounds in the Copeland study were 3 months or less in dura- tion.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

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.

Table 3. Logistic regression models for matched cohorts

 

		Comparison #1 (C1)
	OR	95% CI	p
Hospitalization (NO TWO2 vs. TWO2)	8.667	(3.101, 24.219)	<0.0001
Amputation (NO TWO2 vs. TWO2)	4.887	(1.840, 12.985)	0.0015

Study outcomes were assessed through logistic regression models for propensity score–matched cohorts in Comparison #1 (C1). 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. Propensity score matching was performed on the fol- lowing 9 factors; age, sex, ethnicity, wound severity, prior amputation, use of offloading, use of NPWT, use of SS, use of GF.

CI, confidence interval; OR, odds ratio.

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 signifi- cant reduction in hospitalizations and amputations, also at 12 months, in a large, real-world patient pop- ulation with background use of adjunctive therapies. Taken together, the value of TWO2 is clearly dem- onstrated 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 amputa- tion 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 Inter- estingly, these data are derived from years over- lapping 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 amputa- tion 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 fac- tors 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 of- ten 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 am- putation. 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 man- age missing data, we used the LOCF method and conservatively assumed that any patient without follow-up data suggesting a hospitalization or am- putation during the 360-day period was cate- gorized as not hospitalized or not amputated. Similarly, due to the nature of medical records, we did not collect data on mortality or level of ampu- tation, as neither was reliably captured within the medical records.

Second, medical records do not capture or ac- count for compliance with prescribed treatments. While patient compliance with TWO2 (and NPWT) is therefore unknown, this uncertainty is also re- flective of and generalizable to a real-world popu- lation of patients with DFU. Third, our study does not evaluate wound healing, but rather mea- sures 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 pa- tients 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 demon- strates 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 nine- fold increased association with need for hospitali- zation 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 adjunc- tive treatments, is associated with significantly re- duced frequency of wound-related hospitalization and amputation for patients afflicted with DFU. Hospitalizations and amputations are not only con- cerning 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 re- quest 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 publica- tion, for proposals that set out to achieve aims specified in a methodologically and scientifically sound protocol, and where any mandated VHA ap- proval requirements are met.

AUTHORS’ CONTRIBUTIONS

J.I.Y., J.A.G., D.K., F.Z., O.N., and A.O. contributed to the conception, design, and analysis of the study. J.I.Y wrote the article. T.N. performed the statistical analysis and contributed to the article and study design. M.G.G. and A.M.L. conducted and oversaw the retrospective data collection at each of the VA sites. J.A.G, D.K., F.Z., O.N., A.O., R.G.F.,

M.G.G., and A.M.L. contributed to the discussion and critically reviewed and provided edits to the article. J.I.Y., J.A.G., R.G.F., M.G.G., and A.M.L. are the guarantors of this work. All authors had full access to the full data in the study and accept responsibility to submit for publication.

ACKNOWLEDGMENTS AND FUNDING SOURCES

The authors would like to thank Despi Herodo- tou (Director of Clinical Development, AOTI) for her help with data collection. This study was spon- sored by AOTI Ltd. (Galway, Ireland). Health Ad- vances received consultative reimbursement from AOTI, and T.N. received consultative reimburse- ment from Health Advances for his independent performance of the statistical analysis. R.G.F. has received research funding from and is a consultant for AOTI. M.G.G. has received research funding and is a consultant for AOTI. A.M.L. has received research funding from AOTI.

AUTHOR DISCLOSURE AND GHOSTWRITING

No other potential conflicts of interest relevant to this article were reported.

ABOUT THE AUTHORS

Jessica Izhakoff Yellin, AB, is a Director at Health Advances, a strategy consulting firm focused exclusively on the health care industry. Julia A. Gaebler, PhD was a Partner at Health Advances. Frank F. Zhou, BA, Olivia Novins, BA, Amelia Ockert, BA, were all Analysts at Health Advances, and Darcy Krzynowek, BA is a Vice President of Health Advances. Timothy Niecko, MS, is Pre- sident, Niecko Health Economics LLC, Matthew G. Garoufalis, DPM is a Podiatrist atthe Jesse Brown VA Medical Center, Chicago, Illinois, Aliza M. Lee, DPM is a Podiatrist at the Salem Veterans Affairs Medical Center, Salem, Virginia, Robert G. Fryk- berg, DPM, MPH, FFPM(Glasg), FRSM is the Medical Director of DM Prevent Diabetic Foot and Wound Centers, and former Chief of the Podiatry section at the Phoenix Veterans Affairs Medical Center in Phoenix, Arizona. He holds Faculty ranks as Adjunct Professor, Midwestern University Pro- gram in Podiatric Medicine as well as Honorary Professor of Podiatric Medicine at NUI Galway.

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3. Armstrong DG, Swerdlow MA, Armstrong AA, Conte MS, Padula WV, Bus Five year mor- tality and direct costs of care for people with diabetic foot complications are comparable to cancer. J Foot Ankle Res [Internet] 2020 Mar 24 [cited 2021 Mar 18];13. Available from: https:// www.ncbi.nlm.nih.gov/pmc/articles/PMC7092527/
4. Driver VR, Fabbi M, Lavery LA, Gibbons The costs of diabetic foot: the economic case for the limb salvage team. Journal of Vascular Surgery 2010;52(3, Supplement):17S–22S.
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6. Rice JB, Desai U, Cummings AKG, Birnbaum HG, Skornicki M, Parsons NB. Burden of Diabetic Foot Ulcers for Medicare and Private Dia- betes Care 2014;37:651–658.
7. Hingorani A, LaMuraglia GM, Henke P, et The management of diabetic foot: a clinical practice guideline by the Society for Vascular Surgery in collaboration with the American Podiatric Medical Association and the Society for Vascular Medi- cine. J Vasc Surg 2016;63(2 Suppl):3S–21S.
8. Schaper NC, Netten JJ van, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes/Metabolism Research and Reviews 2020;36(S1):e3266.
9. Vas P, Rayman G, Dhatariya K, et Effectiveness of interventions to enhance healing of chronic foot ulcers in diabetes: a systematic review. Diabetes/Metabolism Research and Reviews 2020;36(S1):e3284.
10. Aldana PC, Khachemoune Diabetic Foot Ulcers: appraising Standard of Care and Reviewing New Trends in Management. Am J Clin Dermatol 2020; 21:255–264.
11. Gottrup F, Dissemond J, Baines C, et Use of Oxygen Therapies in Wound Healing. J Wound Care 2017;26(Sup5):S1–S43.
12. Fedorko L, Bowen JM, Jones W, et Hyperbaric Oxygen Therapy Does Not Reduce Indications forAmputation in Patients With Diabetes With Nonhealing Ulcers of the Lower Limb: a Pro- spective, Double-Blind, Randomized Controlled Clinical Trial. Diabetes Care 2016;39:392–399.

13. Gordillo GM, Sen Evidence-based recom- mendations for the use of topical oxygen therapy in the treatment of lower extremity wounds. Int J Low Extrem Wounds 2009;8:105–111.
14. Smet GHJ de, Kroese LF, Menon AG, et Oxygen therapies and their effects on wound healing. Wound Repair and Regeneration 2017;25:591–608.
15. Frykberg RG, Franks PJ, Edmonds M, et A Mul- tinational, Multicenter, Randomized, Double-Blinded, Placebo-Controlled Trial to Evaluate the Efficacy of Cyclical Topical Wound Oxygen (TWO2) Therapy in the Treatment of Chronic Diabetic Foot Ulcers: the TWO2 Study. Diabetes Care 2020;43:616–624.
16. Molenberghs G, Kenward Missing Data in Clinical Studies. John Wiley & Sons; 2007. 529 p.
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18. Grip ET, Svensson A-M, Miftaraj M, et Real- World Costs of Continuous Insulin Pump Therapy and Multiple Daily Injections for Type 1 Diabetes: a Population-Based and Propensity-Matched Co- hort From the Swedish National Diabetes Regis- ter. Diabetes Care 2019;42:545–552.
19. Margolis DJ, Malay DS, Hoffstad O, et al. Economic burden of diabetic foot ulcers and am- Diabetic Foot Ulcers Data Points #3 (prepared by the University of Pennsylvania DEcIDE Center, under Contract No HHSA29020 0500411). 2011 Jan;AHRQ Publication No. 10(11)- EHC009-2-EF.
20. Franklin H, Rajan M, Tseng C-L, Pogach L, Sinha A, Mph M. Cost of lower-limb amputation in U.S. veterans with diabetes using health services data in fiscal years 2004 and 2010. J Rehabil Res Dev 2014;51:1325–1330.
21. Copeland K, Purvis A Retrospective Chart Review of Chronic Wound Patients Treated with Topical Oxygen Therapy. Adv Wound Care (New Rochelle) 2017;6:143–152.
22. Niederauer MQ, Michalek JE, Liu Q, Papas KK, Lavery LA, Armstrong Continuous diffusion of oxygen improves diabetic foot ulcer healing when compared with a placebo control: a randomised, double-blind, multicentre study. J Wound Care 2018;27(Sup9):S30–S45.

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28. Frykberg RG, Attinger C, Smeets L, Koller A, Bal A, Kavarthapu Surgical strategies for prevention of amputation of the diabetic foot. Journal of Clinical Orthopaedics and Trauma 2021;17:99–105.
29. Geiss LS, Li Y, Hora I, Albright A, Rolka D, Gregg Resurgence of Diabetes-Related Nontrau- matic Lower-Extremity Amputation in the Young and Middle-Aged Adult U.S. Population. Diabetes Care 2019;42:50–54.
30. Ferreira L, Carvalho A, Carvalho Short-term predictors of amputation in patients with diabetic foot ulcers. Diabetes & Metabolic Syndrome: clinical Research & Reviews 2018;12:875–879.

 

Clinical Research

Featured

THE JOURNAL OF CLINICAL AND APPLIED RESEARCH AND EDUCATION

Diabetes Care

In This Issue of

Diabetes Care          By Max Bingham, PhD

 

Global Mechanisms Proposed for Cardioprotective Effects of SGLT2 Inhibitors

The beneficial effects of sodium–glucose cotransporter 2 inhibitors (SGLT2i) in type 2 diabetes are mostly attributed to their ability to enhance glucose excretion and lower hyperglycemia. But they can also promote positive cardiovascular outcomes. Less clear is quite how they manage to achieve the effects, and although many hypothetical mechanisms exist, they only partly explain what might be going on. Avogaro et al. (p. 501) attempt to bring the different strands of evidence to- gether and propose a hypothesis that suggests SGLT2i might modify the trajectory of cell responses to high glucose levels from one of defense to dormancy. They suggest this might be the mechanism that explains the cardiac and renal protective effects of SGLT2i treatments. On that basis they call for dedicated studies to test the hypothesis to ultimately gather the support needed for human studies. They explain that high blood glucose is effectively a toxic environment that likely shifts cell responses to a state of defense characterized by immune responses, anabolic metabolism, inflam- mation, adiposity, and also cardiovascular events. In contrast, they suggest that switching to a dormancy program would curtail many of these issues and that evidence suggests that SGLT2i may actually be able to force this switch—effectively explaining the positive cardiorenal outcomes of

the trials. They acknowledge that most of the cited evidence comes from animal studies but suggest that, together with the more limited human data, the evidence points towards SGLT2i having a dormancy effect at a cellular level. Commenting further, author Angelo Avogaro told us: “There is still a lot to be understood about what SGLT2i do to humans beyond their glycosuric effects. Many hypotheses have been proposed, but we found it fascinating that they may switch the milieu of the cells to a state similar to that observed in mammalian animals during hibernation. If this is the case, this evolutionary hypothesis should be rigorously tested in future studies.”

Oxygen Therapy Improves Diabetic Ulcer Wound Healing: RCT Data

Treating diabetic foot ulcers for 12 weeks with a topical wound oxygen therapy in addition to standard care increases the likelihood that they heal, according to Frykberg et al. (p. 616). Specifically, they found that the therapy resulted in a >4.5-fold increased likelihood of healing compared with placebo and notably could be administered at home by patients. The results come from a double-blind randomized controlled trial (RCT) that compared an oxygen treatment ap- proach (Topical Wound Oxygen [TWO2]) or placebo (circulating air) delivered via a device called a HyperBox (AOTI Ltd., Galway, Ireland). Both approaches were applied on top of standard care for wounds, which were long-standing and had not healed prior to the trial. The company-sponsored trial was stopped early (as planned) after the active treatment showed clear success in healing wounds compared with placebo. Seventy-three individuals had been enrolled up to that point.

The primary outcome was the percentage of ulcers achieving 100% healing at 12 weeks. The authors found that the active treatment had a closure rate of nearly 42%, while the placebo had a closure rate of 13.5%. This resulted in an odds ratio of ~4.5, which was statistically significant, and it increased to 6.0 once ulcer grade was accounted for. Additionally, more than half of ulcers were closed at 12 months after the active treatment but only about one-quarter following placebo. Quality of life measures also improved more following the active treatment. There were high compliance rates in both groups, and no device-related adverse events were experienced in either group. Commenting further, author Robert Frykberg told us: “We believe that in this rather robust double-blinded RCT we have clearly demonstrated the positive effects of cyclical, pressurized topical oxygen therapy in the healing of chronic diabetic foot ulcers. Accordingly, we now have the evidence required to recommend the use of this therapy as an adjunct to good standard care for the management of difficult-to-heal diabetic foot ulcers.”

Avogaro et al. Reinterpreting cardiorenal protection of renal sodium–glucose cotransporter 2 inhibitors via cellular life history reprogramming. Diabetes Care 2020;43:501–507

Kaplan-Meier curve showing the separation between placebo (SC

+ Sham) and active therapy (SC + TWO2) study groups throughout the 12-week trial. SC, standard care.

Frykberg et al. A multinational, multicenter, randomized, double- blinded, placebo-controlled

trial to evaluate the efficacy of cyclical Topical Wound Oxygen (TWO2) therapy in the treatment of chronic diabetic foot ulcers: the TWO2 study. Diabetes Care 2020;43:616–624

A Multinational, Multicenter, Randomized, Double-Blinded, Placebo-Controlled Trial to Evaluate the Efficacy of Cyclical Topical Wound Oxygen (TWO2) Therapy in the Treatment of Chronic Diabetic Foot Ulcers: The TWO2 Study

Robert G. Frykberg,¹ Peter J. Franks,² Michael Edmonds,³ Jonathan N. Brantley,⁴ Luc Te´ot,⁵ Thomas Wild,⁶

Matthew G. Garoufalis,⁷ Aliza M. Lee,⁸ Janette A. Thompson,⁹ Ge´rard Reach,¹⁰ Cyaandi R. Dove,¹¹ Karim Lachgar,¹² Dirk Grotemeyer,¹³ and Sophie C. Renton,¹⁴ on behalf of the TWO2 Study Group*

OBJECTIVE

Topical oxygen has been used for the treatment of chronic wounds for more than 50 years. Its effectiveness remains disputed due to the limited number of robust high-quality investigations. The aim of this study was to assess the efficacy of multimodality cyclical pressure Topical Wound Oxygen (TWO2) home care therapy in healing refractory diabetic foot ulcers (DFUs) that had failed to heal with standard of care (SOC) alone.

RESEARCH DESIGN AND METHODS

Patients with diabetes and chronic DFUs were randomized (double-blind) to either active TWO2 therapy or sham control therapydboth in addition to optimal SOC. The primary outcome was the percentage of ulcers in each group achieving 100% healing at 12 weeks. A group sequential design was used for the study with three predetermined analyses and hard stopping rules once 73, 146, and ultimately 220 patients completed the 12-week treatment phase.

RESULTS

At the first analysis point, the active TWO2 arm was found to be superior to the sham arm, with a closure rate of 41.7% compared with 13.5%. This difference in outcome produced an odds ratio (OR) of 4.57 (97.8% CI 1.19, 17.57), P 5 0.010. After adjustment for University of Texas Classification (UTC) ulcer grade, the OR increased to 6.00 (97.8% CI 1.44, 24.93), P 5 0.004. Cox proportional hazards modeling, also after adjustment for UTC grade, demonstrated >4.5 times the likelihood to heal DFUs over 12 weeks compared with the sham arm with a hazard ratio of 4.66 (97.8% CI 1.36, 15.98), P 5 0.004. At 12 months postenrollment, 56% of active arm ulcers were closed compared with 27% of the sham arm ulcers (P 5 0.013).

CONCLUSIONS

This sham-controlled, double-blind randomized controlled trial demonstrates that, at both 12 weeks and 12 months, adjunctive cyclical pressurized TWO2 therapy was superior in healing chronic DFUs compared with optimal SOC alone.

¹Diabetic Foot Consultants, Midwestern Univer- sity, Glendale, AZ

²Centre for Research and Implementation of Clinical Practice, London, U.K.

³King’s College Hospital, London, U.K.

⁴McGuire Veterans Affairs Medical Center, Richmond, VA

⁵Montpellier University Hospital, Montpellier, France

⁶Medical Center Dessau, Brandenburg Medical School Theodor Fontane, Dessau, Germany ⁷Edward Hines Jr. VA Hospital, Chicago, IL ⁸Salem Veterans Affairs Medical Center, Salem, VA

⁹Washington DC Veterans Affairs Medical Center, Washington, DC

¹⁰Hoˆpital Avicenne and Paris 13 University, Bobigny, France

¹¹Advanced Foot & Ankle Center, Las Vegas, NV ¹²Hoˆpital Simone Veil, Eaubonne, Paris, France ¹³Hoˆpitaux Robert Schuman – Hoˆpital Kirchberg,

Luxembourg City, Luxembourg

¹⁴Northwick Park Hospital, London, U.K.

Corresponding author: Robert G. Frykberg, rgfdpm@ diabeticfoot.net

Received 8 March 2019 andaccepted 3 September 2019

Clinical trial reg. no. NCT02326337, clinicaltrials.gov.

This article contains Supplementary Data online at https://care.diabetesjournals.org/lookup/suppl/ doi:10.2337/dc19-0476/-/DC1.

*A complete list of the TWO2 Study Group collaborators, Steering Committee, and Data Monitoring Committee can be found in the Supplementary Data online.

This article is featured in a podcast available at https://www.diabetesjournals.org/content/ diabetes-core-update-podcasts.

© 2019 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More infor- mation is available athttps://www.diabetesjournals.org/content/license.

See accompanying article, p. 515.

With the growing worldwide prevalence of diabetes there has been a resultant increase in the incidence of diabetic foot ulcerations (DFUs) with attendant mor- bidity, mortality, and health care costs (1–3). Common diabetes comorbidities including peripheral neuropathy, defor- mity, and peripheral arterial disease (PAD) are among a number of well- established risk factors for DFUs (2,4). These person-level conditions when combined with numerous underlying cellular or metabolic and ulcer-related factors (hypoxia, inflammation, biobur- den, etc.) will quite frequently lead to impaired wound healing and to possible amputation (5,6).

Over the last decade it has become clear that basic standards of care for DFUs mandate rigorous attention to proper de- bridement and off-loading (7–9). While a number of new adjunctive therapies have become available, including growth fac- tors, cellular and acellular tissues, topical negative pressure, oxygen therapies, etc., most therapies suffer from inadequately designed or nongeneralizable studies that cannot attest to their efficacy, safety, and cost-benefit (1,10,11).

Oxygen is an essential component in the wound-healing cascade. Energy me- tabolism (ATP synthesis), reactive oxygen species generation, redox signaling, H₂O₂ production, antioxidant generation, col- lagen synthesis, deposition of extracel- lular matrix, VEGF gene expression, and angiogenesis are among processes de- pendent on a sufficient supply of oxygen for their activities (12–15).

Hyperbaric oxygen therapy (HBOT) has been studied extensively for its efficacy in healing DFUs and amputation preven- tion, but despite several recent random- ized clinical trials, the results remain inconsistent regarding its effectiveness in healing DFUs (10,16–19). Topical ox- ygen therapies (TOTs), used in clinical practice for .50 years, supply oxygen directly to the hypoxic wound surface without the potential complications posed by HBOT (13,15,20,21). Despite long-standing clinical evidence support- ing the effectiveness of topically applied oxygen for chronic wounds, hyperbaric oxygen proponents have raised concerns about such benefits without systemic hyperoxygenation (22).

To study the effect of topically admin- istered oxygen on cutaneous wounds, Fries et al. (23) conducted a controlled porcine dermal wound-healing experi- ment. They found that topical oxygen increased the wound tissue partial pres- sure of oxygen (PO₂) levels 10-fold after 4 min and that repeated treatments ac- celerated wound closure compared with control (air-exposed) wounds. Histological examination showed a stronger presence of VEGF, signs of improved angiogenesis, and more advanced remodeling with bet- ter quality collagen. Their findings sug- gest several biological mechanisms for the enhanced healing found in other topical oxygen studies. While numerous reports have similarly suggested the po- tential benefits of topical oxygen in heal- ing chronic wounds, its effectiveness in healing DFUs remains disputed due to a combination of poorly designed studies, inconsistent results, and the paucity of ro- bust investigations through randomized controlled clinical trials (RCTs) (15,24–26). In recognition of the need for more rigorous studies of this therapy, a ran- domized, double-blinded, sham-controlled clinical trial was designed to explore the efficacy of cyclical pressurized Topical Wound Oxygen (TWO2) therapy in heal- ing refractory DFUs that had failed to heal with optimal standard of care (SOC) alone. We herein present the results of the TWO2 diabetic foot ulcer study.

RESEARCH DESIGN AND METHODS

Study Design

The TWO2 study was designed as a pro- spective, multinational, multicenter, double- blinded, placebo-controlled, randomized clinical trial with 17 diabetic foot centers participating across the U.S., U.K., France, Germany, and Luxembourg. The protocol was approved by the governing institu- tional review or local ethics board of each of the participating centers throughout the U.S. and Europe. The study was per- formed in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines of the International Conference on Harmonization. Written informed con- sent was provided by all participants prior to performance of study procedures. An independent data monitoring committee and a study steering committee were established to monitor the conduct and analysis of the study.

Sample Size and Design Rationale Limited information was available on RCTs looking at the efficacy of cyclical pressurized topical oxygen for healing DFUs. Aburto and Frye (27), in a ran- domized study of topical oxygen, dem- onstrated better healing in DFU patients after 90 days (90% vs. 40%) compared with the control group. Blackman et al.

(20) enrolled 28 patients with DFUs and obtained a similar result (82.4% vs. 45.5%). In combining the results of these two studies, the control group achieved a healing rate of 9 of 21 (42.8%), and in the active group healing occurred in 23 of 27 (85.2%). Using these figures, we would anticipate a tentative expected control rate of 43%, and it was proposed that a conservative estimate of difference be- tween groups would be half that experi- enced in these trials at 21%. In order to address the unknown outcomes, we used a group sequential design with three predetermined analysis points. With three analyses, the level of signif- icance needed to be adjusted to maintain the integrity of the analysis. The Pocock stopping boundary method requires a more stringent P value threshold (P , 0.022) at each of the three analysis points to achieve an overall probability of P ,0.05 at the final evaluation. For achieve- ment of a minimal level of significance between study arms, it was calculated that 110 patients would be required in each study arm (n 5 220). The resultant analyses would therefore be performed after one-third (73), two-thirds (146), and finally all (220) enrolled patients completed the active phase of the study. Since analysis would be exclusively of the intention-to-treat (ITT) cohort, all pa- tients would be analyzed as per the 12-week primary end point (healed vs. unhealed). Furthermore, no up-rating of this sample size was made to take into consideration patients lost to follow-up.

Patients

Inclusion criteria for participation in the trial were as follows: patients with type 1 or 2 diabetes with nonhealing, full-thickness, University of Texas Clas- sification (UTC) grade 1 or 2 DFU measuring $1 cm² and ,20 cm² post- debridement. All ulcers included were to be between 4 weeks and 1 year in duration and to have been receiving stan- dard care for at least 4 weeks. Patients with modest limb ischemia were per- mitted with an ankle brachial index (ABI) .0.7. To account for falsely elevated ABI measurements (7), we performed a secondary confirmatory measurement of distal perfusion adjacent to or distal to the index ulcer in all patients, in- cluding a transcutaneous oxygen pres- sure (TcPO₂) .30 mmHg, skin perfusion pressure .30 mmHg, toe pressure .30 mmHg, or a Duplex ultrasound showing biphasic waveforms below the knee. Detailed study enrollment cri- teria can be found in Table 1.

Randomization

Patients were randomly assigned in a 1:1 ratio double blinded to either the SOC plus sham therapy (SC1Sham) arm or to an SOC plus active TWO2 therapy (SC1TWO2) arm. The randomization list of 220 codes in A or B format was generated by the blinded statistician using a random permuted block design, with blocks of 2, 4, 6, and 8. Study arm allocation was randomly assigned by a centralized study coordinator for each patient at the randomization visit.

Interventions

All patients were recruited as outpatients in participating wound care centers. At the screening visit and after obtaining informed consent, the pa- tient’s wound was sharply debrided and digitally photographed. All patients were then provided with the same study foam dressings and hydrogel (Kendall; Covidien), instructions, and the study off- loading device (Optima Diab; Salvatelli srl, Civitanova Marche, Italy). After a run-in period of 2 weeks, patients re- turned for their randomization visit. Only if the wound area reduction was ,30% were patients subsequently random- ized double-blind into either the active (SC1TWO2) or sham (SC1Sham) study arm.

The U.S. Food and Drug Administration– cleared, CE-marked TWO2 therapy device (HyperBox; AOTI Ltd., Galway, Ireland) operates by inflation of a single- use extremity chamber over the pa- tient’s limb; then, humidified oxygen is cycled between 10 mb and 50 mb within the chamber. A 10 liters per minute oxygen concentrator was used to provide the oxygen supply rather than oxygen cylinders.

Both the active and sham devices looked and operated identically. How- ever, the sham device did not deliver pressurized oxygen into the extremity chamber, even though values displayed on the device controls looked as if this was being performed. The sham treatment therefore consisted only of unrestricted nonpressurized ambient room air in the nonocclusive extremity chamber.

Delivery, installation, and training on the use of the blinded study device was performed by blinded home equipment providers. No study-related procedures or treatments were provided by these representatives. Patients treated them- selves at home for 90 min daily five times per week with either the allo- cated TWO2 or sham therapy. Dressing changes were performed at home by either the patient or their personal care- giver. No study therapy was done at the study centers.

Patients visited a local study center weekly for the duration of the study for wound assessment, debridement, and digital wound photographs. Patients re- corded therapy and off-loading compli- ance daily on diary cards that were verified at each study visit. Additionally, therapy hours were verified by the TWO2 device itself. The active treatment phase was continued until the ulcer healed or for a maximum of 12 weeks.

 

Data Collection and Outcome

Measures

The treatment phase of the study was 12 weeks. The randomization visit mea- surement after debridement served as the index (baseline) measurement. If mul- tiple ulcers were present, the largest area ulcer at the baseline visit was designated the index ulcer. Weekly digital wound im- ages were transmitted electronically and were assessed for area changes and clo- sure confirmation by a single blinded cen- tral assessor using automated CE-marked wound measurement software (MOWA; Healthpath srl, Rome, Italy).

Once a wound was initially determined to be closed by the blinded study site investigator, that visit served as the first of two confirmatory visits. Wound clo- sure (complete epithelialization) was confirmed at the second closure visit 2 weeks later (28). Upon completion of the 12-week treatment phase, patients entered the posttreatment follow-up period for an additional 38 weeks, whereby they returned for wound clo- sure assessment and quality of life (QOL) questionnaires.

The maximum duration for participa- tion in the study was 54 weeks. During the follow-up phase, patients without healed ulcers received standard care according to their clinician’s recommen- dation and were asked not to participate in another wound care trial.

The primary study end point was the percentage of ulcers in each group achieving 100% healing at 12 weeks. Secondary end points included wound area reduction, 12-month in- cidence of both recurrence and com- plete healing, incidence of amputation, Cardiff Wound Impact Schedule (CWIS) QOL assessment, and adverse events (1,28,29).

 

Table 1—Inclusion/exclusion criteria Inclusion criteria Males and females aged between 18 and 89 years	Exclusion criteria Evidence of gangrene on any part of affected limb
Documented diagnosis of type 1 or 2 diabetes	Documented evidence of osteomyelitis on any part of affected limb
Foot ulcer at or below ankle with duration .4 weeks to ,1 year • If the index ulcer is postamputation, date of surgery must be .30 days • If .1 ulcer is present, largest is considered as the study index ulcer • Index ulcer must be $1 cm from any other ulcers present on the foot	Index ulcer has exposed bone Active Charcot foot on the study limb Uncontrolled diabetes: HbA1c .12% (108 mmol/mol) Renal dialysis or creatinine .2.5 mg/dL (221 mmol/L)
Ulcer size $1 and #20 cm2 after debridement at start of run-in period	Known immune insufficiency
Ulcer of UTC grade 1A, 1B, 1C, 1D, 2A, 2B, 2C, or 2D	Active treatment for malignancy (not specific to study limb)
ABI .0.7 with a TcPO2 .30 mmHg, skin perfusion .30 mmHg, toe pressure .30 mmHg, or Duplex ultrasound with biphasic waveforms below the knee	Chronic steroid use or immunosuppressive agents within the last 3 months or anticipated to require them during the duration of the study
No planned revascularization procedure or vascular surgery within the last or next 30 days	Subject participated in another investigational device, drug, or biological trial within last 30 days
Subject and caregiver willing and able to comply with all specified care and visit requirements	Index ulcer exhibits signs of severe clinical infection that requires hospitalization or immediate surgical intervention
Subject has a reasonable expectation of completing the study	Subject is pregnant at the time of screening
Subject completed 2-week run-in period with ,30% wound size reduction	Subject has had a deep vein thrombosis within the last 30 days Subject has received growth factor therapy, autologous platelet-rich plasma gel, bilayered cell therapy, dermal substitute, extracellular matrix, etc., within the screening period

97.8% CIs. For all other analyses, statis- tical significance was assessed at the two-sided 5% level (P , 0.05) with 95% CIs provided as appropriate. The stat- istician conducting all analyses was blinded to treatment allocation (with groups identified as A and B) until results had been finalized.

RESULTS

Between November 2014 and December 2017, 136 patients were screened for the study. Of these, 63 patients (46%) were excluded from randomization for not meeting the inclusion criteria. Thirty- four patients (25%) returned from the 2-week run-in with wound size reduc- tions $30%, 10 (7%) had ABI values or second vascular assessments out of range, and 19 (14%) either were not willing to comply fully with the protocol or had other laboratory values out of range. Therefore, 73 patients were ran- domized into the active phase of the study (see Fig. 1).

At baseline, 65 patients (89%) had type 2 diabetes and 8 patients (11%) had type 1 diabetes. Fourteen index ulcers (39%) in the active arm, compared with six index ulcers (16%) in the sham arm, were assessed to be UTC grade 2 (penetrating to tendon or capsule). Conversely, 22 ulcers (61%) in the active arm, compared with 31 ulcers (84%) in the sham arm, were assessed to be UTC grade 1 wounds (P 5 0.038). Additionally, 10 patients (28%) in the active arm, compared with 4 patients (11%) in the sham arm, had a previous diagnosis of PAD (P 5 0.066). Seventeen patients (47%) in the active arm had a history of prior amputations on the index limb in contrast to eight (22%) in the sham arm (P 5 0.018) (see Table 2).

Primary Outcome

At the first ITT analysis point of 73 pa- tients, the independent data monitoring committee recommended that enroll- ment should conclude per the predeter- mined stopping rules, as the active arm was shown to be superior to the sham arm for the primary outcome. In the ac- tive arm 15 wounds (41.7%) completely healed versus 5 wounds (13.5%) in the sham arm at 12 weeks [Pearson x² 5 7.27 (1 df), P 5 0.007]. The difference in outcome produced an OR of 4.57 (97.8% CI 1.19, 17.57), P 5 0.010. Examination of the potential confounding by other baseline variables revealed that UTC ul- cer grade substantially changed the OR in favor of the TWO2 group (OR 5 6.00 [97.8% CI 1.44, 24.93], P 5 0.004). The active TWO2 arm showed .3.5 times the likelihood to completely heal over 12 weeks compared with the sham arm with an HR of 3.64 (97.8% CI 1.11, 11.94), P 5 0.013. With inclusion of the UTC ulcer grade into the model, the HR increased to 4.66 (97.8% CI 1.36, 15.98), P 5 0.004. The Kaplan-Meier curve shown in Fig. 2 clearly shows the separation between groups throughout the active phase of the study. The patients then entered into the follow-up phase of the study where they were assessed for index ulcer re- currence, healing, and QOL changes for 12 months post enrollment (see Table 3).

Table 2—Baseline characteristics Sham TWO2 (n 5 37) Age, years, mean (SD)                             61.9 (9.5)		Active TWO2 (n 5 36) 64.6 (10.3)	Total (n 5 73) 63.3 (9.9)	P 0.21
Sex, male, n (%)	31 (84)	32 (89)	63 (86)	0.53
Race, n (%)
White/Hispanic	24 (65)	26 (72)	50 (68.5)	0.90*
Black	5 (14)	5 (14)	10 (14)
Asian	1 (2.7)	2 (5.6)	3 (4.1)
American Indian	1 (2.7)	0 (0)	1 (1.4)
Not reported	6 (16.2)	3 (8.3)	9 (12.3)
Type 2 diabetes, n (%)	33 (89)	32 (89)	65 (89)	0.97
BMI (kg/m2), mean (SD)	31.2 (7.6)	30.8 (5.9)	31 (6.8)	0.85
Wound area (cm2), mean (SD)	3.22 (2.54)	3.02 (2.66)	3.13 (2.57)	0.74
Wound perimeter (cm), mean (SD)	6.85 (4.18)	6.22 (2.85)	6.54 (3.55)	0.45
Ulcer duration (days), mean (SD)	174.6 (94)	160.3 (96)	166.4 (95)	0.53
Wound classification, n (%)
UTC grade 1A	27 (73)	20 (56)	47 (64)
UTC grade 1B	2 (5.4)	1 (2.8)	3 (4.1)
UTC grade 1C	2 (5.4)	1 (2.8)	3 (4.1)
UTC grade 2A	4 (10.8)	9 (25)	13 (17.8)	0.04**
UTC grade 2B	0 (0)	1 (2.8)	1 (1.4)
UTC grade 2C	2 (5.4)	4 (11.1)	6 (8.2)
Neuropathic foot, n (%)	29 (78)	28 (78)	57 (78)	0.95
Charcot deformity, n (%)	3 (8.1)	1 (2.8)	4 (5.4)	0.32
Ulcer location, n (%)				0.32
Dorsal foot	5 (13.5)	8 (22.2)	13 (17.8)
Leg below malleoli	4 (10.8)	1 (2.8)	5 (6.8)
Pedal foot	22 (59.5)	18 (50)	40 (54.8)
Toe	6 (16.2)	9 (25)	15 (20.5)
Previous history of lower-extremity amputation, n (%)	8 (21.6)	17 (47.2)	25 (34.3)	0.02
Comorbidities, n (%)
Hypertension	30 (81)	28 (78)	58 (79)	0.73
Cardiovascular disease	9 (24.3)	13 (36.1)	22 (30.1)	0.27
PAD	4 (10.8)	10 (27.8)	14 (19.2)	0.07
Venous disease	1 (2.7)	2 (5.6)	3 (4.1)	0.54
Renal disease	6 (16.2)	10 (27.8)	16 (21.9)	0.23
Neurologic disease	31 (83.8)	28 (77.8)	59 (80.8)	0.52
Peripheral edema	1 (2.7)	3 (8.3)	4 (5.4)	0.29
Hyperlipidemia	25 (67.6)	23 (63.9)	48 (65.8)	0.74
Smoker, n (%)	10 (27)	13 (36)	23 (31.5)	0.41
Peripheral arterial circulation parameters Mean ABI (SD) Mean toe systolic blood pressure (SD), mmHg	1.00 (0.23)	1.07 (0.23)	1.03 (0.23)	0.20
	83.00 (32.75)	84.50 (30.55)	83.77 (30.63)	0.84
Blood work values, mean (SD) Prealbumin, mmol/L                          4.29 (1.45)         4.44 (0.93)         4.36 (1.18)       0.61 CRP, nmol/L                                         140 (173)          65.7 (96.2)          99.6 (139)       0.05 Creatinine, mmol/L                           105.2 (30.1)       113.2 (81.3)         108.7 (61)       0.57 HbA1c, %                                             8.14 (1.49)         8.43 (1.75)         8.25 (1.64)       0.46 HbA1c, mmol/mol                                65 (16.3)            69 (19.1)            67 (17.9)        0.46 All comparisons are nonsignificant except for values in boldface type. *Due to low frequency in each cell, white race was compared with all other races combined. **Due to low frequency in UTC categories, UTC I was compared with UTC II.

Secondary Outcome Measures

Ulcer Recurrence

At 12 months postenrollment, only 1 of 15 healed ulcers (6.7%) in the active arm recurred, compared with 2 of 5 healed ulcers (40%) in the sham arm, falling just short of statistical sig- nificance (P 5 0.070). In total, 20 (56%) active arm (SC1TWO2) ulcers were closed at 12 months postenrollment compared with 10 (27%) of the sham arm (SC1SHAM) ulcers [x² (1 df) 5 6.13, P 5 0.013].

Wound Area Reduction

Of the patients with open ulcers at the end of the 12-week active phase, the mean (SD) absolute reduction in ulcer area from baseline was 1.97 (2.75) cm² for the active arm compared with 0.40 (1.75) cm² for the sham arm [t (df) 52.12 (35), P 5 0.041].

For the patients with larger open ulcers .4 cm² at the end of the active phase, the mean (SD) absolute reduction in ulcer area from baseline was 4.12 (1.51) cm² for the active arm compared with a 1.34 (1.18) cm² increase for the sham arm [t (df) 5 2.85 (8), P 5 0.021].

QOL

The wound care–focused CWIS QOL in- dex improved during the study for pa- tients whose ulcers healed across all functional domains. This positive in- crease was observed in both full and partial responders. The greatest im- provement was seen for the well-being component, with mean (SD) score dif- ference between baseline and the end of 12-week treatment in the active arm of 9.1 (13.9) compared with 20.1 (16.9) in the sham arm [t (df) 5 2.18 (53), P 5 0.033].

TWO2 Therapy and Off-loading Compliance

Therapy compliance in both the active and sham arms was high, with 94% and 96% completing treatments, respectively. Off-loading device compliance in both the active and sham arms was also high, with 97% and 99% using the off-loading .75% of the time.

Adverse

Events During the study, there were equal num- bers of serious adverse events (10) and adverse events (8) experienced in both study arms. There were no TWO2 device– related adverse events reported. Two index limb amputations (5%) occurred in the active arm compared with three index limb amputations (8%) in the sham arm.

CONCLUSIONS

TOT has been reported to improve heal- ing of DFUs in several earlier prospec- tive randomized studies (20,27,30,31). However, these studies suffered from methodological weaknesses, such as a lack of blinding, uncontrolled SOC, or in- appropriate analyses of the ITT populations.

The present TWO2 study has demon- strated, in a randomized, sham-controlled trial, that cyclical pressurized TOT ad- junctive to optimal SOC is significantly superior to standard care alone in heal- ing recalcitrant DFUs within a 12-week home-based treatment period. To this end, trial enrollment was terminated at the first predetermined analysis point, since the primary end point had been achieved after the initial 73 randomized patients had completed their 12-week treatment phase.

Despite the loss of 25% of patients in the 2-week run-in period prior to random- ization, a four-and-a-half–fold increased likelihood of healing was achieved at 12 weeks in patients allocated to the active TWO2 therapy. With adjustment for UTC ulcer grade, this effect increased even further. A very high degree of com- pliance with treatment and off-loading was demonstrated in both groups. Clin- ically, the durability of healing as mea- sured by index ulcer recurrence at 12 months was sixfold better than that in the sham group and that seen in other studies (2). Of interest, and distinct from other topical oxygen studies, this RCT allowed for patients with up to UTC grade 2 ulcers with modest degrees of ischemia. Although not statistically significant, nearly 28% of patients ran- domized to the active therapy had a prior history of PAD compared with just 10% in the control group. How- ever, despite double-blinded random- ization, a significant 47% of active therapy patients had a history of lower- extremity amputations compared with just 22% in the sham arm.

This study is consistent with results reported in several previous studies us- ing topical oxygen in DFU (20,30–32) and venous leg ulcers (33,34), as well as animal studies (23). Several other re- views of this approach have also sug- gested mechanisms of action and putative benefits of topically applied oxygen in the management of chronic wounds (13,15,24,26). Blackman et al. (20), in a prospective open-label study, examined the clinical efficacy of TWO2 therapy in healing DFU patients in a community wound care clinic. Patients were allocated to topical oxygen or oth- erwise treated with advanced moist wound therapy. At 12 weeks, 82.4% of the ulcers in the TWO2 therapy arm and 45.5% in the control arm healed completely (P 5 0.04). Median time to complete healing was 56 days in the active and 93 days in the control arm (P 5 0.013). Another unblinded comparative study investigated the benefits of con- tinuous diffusion of oxygen compared with variable standard care for DFUs (31). Notwithstanding methodological weak- nesses, they found significantly faster rates of healing in the topical oxygen group compared with the standard care group and most notably in deeper ulcers. A more recent randomized placebo- controlled trial using a continuous dif- fusion of oxygen device for only UTC grade 1A ulcers reported a higher pro- portion of healed DFUs (32.4% vs. 16.7%, P 5 0.033) and a faster time to closure (P 50.015) in the active group at 12 weeks (30). This study was also planned with a group sequential design; however, their interim analysis end point was not met, and their ITT analysis did not include 35% of randomized patients who were subsequently removed from the trial.

Strengths and Limitations

This TWO2 study followed the guidance for wound-healing therapies put forth by the U.S. Food and Drug Administration (28) as well as subsequent publications from leading authorities calling for more robustly designed sham-controlled RCTs (1,29,35). Nonetheless, and despite ran- domization of known and unknown po- tential confounders between groups, it does have limitations. One is the rela- tively small number of patients included in the primary end point analysis of our ITT population, although the group was similar in size to those of other wound care RCTs (2,36). In a group sequential design study, predetermined hard stop- ping rules are put in place that in our case were met at the first analysis point of 73 patients. At that point, the primary outcome was achieved by finding signif- icantly more patients in the active group had healed compared with the sham- treated group (41.7% vs. 13.5%, P 5 0.007). This approach is used when the magnitude of the treatment effect is uncertain, as it allows for stopping a trial once a wide treatment effect is proven. This also ethically ensures that patients are not further randomized to an inferior arm. In our study, a large margin of effect (68%) and relative performance ratio (309%) were achieved.

Table 3—Summary of the results: ITT analysis
Sham TWO2       Active TWO2	Pearson x2 or OR or
(n 5 37)             (n 5 36)	HR (97.8% CI), P value
Primary outcome
Ulcers completely healed at 12 weeks, n (%)                                                   5 (13.5)               15 (41.7)	x2 7.27 (1 df), P 5 0.007
By randomized treatment group, univariate	OR 4.57 (1.19, 17.57), P 5 0.010
	HR 3.64 (1.11, 11.94), P 5 0.013
After adjustment for UT grade	OR 6.00 (1.44, 24.93), P 5 0.004
	HR 4.66 (1.36, 15.98), P 5 0.004
Margin of effect/relative performance                                                                         68%/309%
Secondary outcomes
Healing durability
Ulcer recurrence at 12 months, n (%)                                                          2 (40.0)                 1 (6.7)	P 5 0.070
Ulcers closed at 12 months, n (%)                                                                 10 (27)                 20 (56)	P 5 0.013
Margin of effect/relative performance                                                                     52%/207%
Healing trajectories
Absolute change in ulcer area over 12 weeks, cm2                                   0.40 (1.75)           1.97 (2.75)	P 5 0.041
Absolute change in ulcer area in ulcers .4 cm2 over 12 weeks, cm2        21.34 (1.18)         4.12 (1.51)	P 5 0.021
Time to complete wound closure, weeks                                                     6.3 (1.9)               8.2 (4.2)	P 5 0.350
QOL
CWIS well-being improvement between baseline and week 12               20.1 (16.9)           9.1 (13.9)	P 5 0.033
CWIS social life improvement between baseline and week 12                  4.1 (12.4)            7.9 (16.9)	P 5 0.340
CWIS physical symptom improvement between baseline and week 12          4.6 (11.8)            12.1 (23.2)	P 5 0.130
Index limb amputations, n (%)                                                                             3 (8)                     2 (5)	P 5 0.668
TWO2 therapy and off-loading compliance
Used TWO2 therapy device 5 days/week, 90 min/day, n (%)                      35 (96)                 34 (94)	P 5 0.978
Used off-loading device .75% of the time, n (%)                                        36 (99)                35 (97)	P 5 0.984
Safety analysis Incidence of serious adverse events, n                                                                 10                        10 Wound infection                                                                                                  2                          3 Osteomyelitis                                                                                                       5                          2 Hypoglycemic event                                                                                            1                          0 Urinary tract infection                                                                                         0                          2 Significant necrotic tissue                                                                                   1                          0 Cardiovascular event                                                                                           0                          1 UTC grade 2 ulceration                                                                                       0                          1 Severe maceration/dermatitis                                                                             1                          0 Pneumonia                                                                                                           0                          1 Incidence of adverse events, n                                                                               8                          8 UTC grade 1 ulceration                                                                                       0                          3 Ulcer decline                                                                                                        0                          2 Minor infection                                                                                                    1                          1 Minor osteomyelitis                                                                                             0                          1 Minor necrotic tissue                                                                                          1                          0 Cellulitis                                                                                                                1                          0 Swelling/edema                                                                                                   1                          1 Maceration                                                                                                          2                          0 Dermatitis                                                                                                            1                          0 Contusion                                                                                                             1                          0 Incidence of adverse device events                                                                        0                          0 Data are means (SD) unless otherwise indicated. Boldface type indicates significant differences.	P 5 0.943                   P 5 0.950

The quality of DFU studies is often measured by the results obtained in the control groups. In our sham-treated control group, 13.5% of patients achieved complete ulcer healing within the 12-week outcome period. This rate is similar to that of some studies and lower than others (17,30,37,38). Interestingly, a recent topical oxygen RCT reported an active group healing rate lower than ours at 32.4% and a similar control healing rate (30). For the more chronic ulcers, their placebo arm healing rate dropped to 13.2%. Despite the large margin of effect between our active and sham groups, we attribute our osten- sibly low sham healing rate to the chronicity of the ulcers, complexity of the patients, and the control of, rather than a failure of, SOC treatment. In this regard, the average duration of ulcers enrolled in the trial was .5 months, with a nonsignificant 14-day longer duration in the control group. After the 2-week run-in period, 25% of enrolled patients were excluded from randomi- zation due to a reduction in wound area $30%. The study off-loading device, itself proven to be as efficacious as gold standard total contact casting (39), may have enabled progress toward healing that excluded patients likely to heal with such standard care alone. This allowed only patients with wounds more difficult to heal (true SOC failures) to be random- ized into this trial. Since there was a very high degree of compliance with both blinded treatments and off-loading throughout the study, we have no reason to believe that the control group healing result was due to any shortcoming in the SOC protocol.

Our sham therapy itself provided nothing more than nonpressurized room air that was free to circulate within the extremity chamber. Room air cannot conceivably be detrimental to the control patients or have a negative impact on ability to heal. Even at the 12-month follow-up evaluation point, long after the active therapy had ended, there was still a clear separation between study groups, with the sham control patients achieving a healing rate of only 27%. Analysis for predictors of healing at 12 weeks resulted only in the treatment effect and UTC ulcer grade being signif- icant. Furthermore, we found no difference in compliance with the therapy or off- loading between study groups. In the ab- sence of otherwise explanatory data to account for the control healing rate, we are left with our presumption that those randomized into the study had ulcers that were truly hard to heal and that the dif- ference in healing rates between active and sham groups was indeed a treatment effect.

The mean age of our study population was ;63 years old, which mirrors that seen in other DFU studies. Eighty-six percent of our study patients were men, likely resulting somewhat from the fact that one-half of the U.S. study sites were Veterans Affairs wound care clinics. Multiple studies have shown DFUs to be more prevalent in men than women to a degree similar to that seen in this RCT (4,10,38). With no significant differences in covariates seen between the two study groups, our findings support the premise that these results are generalizable to simi- larly afflicted patient populations.

Conclusion

The results of the TWO2 study demon- strate that cyclical pressurized TOT in conjunction with both optimal off-loading and good standard wound care can heal significantly more DFUs at 12 weeks compared with optimal SOC alone. In fact, we found a .4.5-fold increased likelihood of healing within this time period for our actively treated patients. This therapy was safe, without compli- cations, and provided more durable heal- ing for those who had wound closure during active treatment. Uniquely, the therapy has additional benefit in that it can be administered by the patient at home without the expense and difficul- ties of daily travel to a specialized center. In contrast to recently reported systemic HBOT studies (16,18,40), this robust double-blinded, sham-controlled trial provides evidence to support use of this adjunctive cyclical pressurized TOT for chronic DFUs.

Acknowledgments. The authors thank all study patients, clinic personnel, study coordinators, and colleagues who assisted with patient referrals.

Duality of Interest. This study was sponsored by AOTI Ltd. (Galway, Ireland). The sponsor incurred all costs for the study including all institutional fees, monitoring, data warehousing, statistical services, and the provision of study devices and supplies. R.G.F. received research support from thesponsorduringtheconductofthestudy while employed at the Phoenix VA Healthcare System and has received subsequent speaking honoraria. P.J.F., M.E., J.N.B., L.T., T.W., M.G.G., A.M.L., J.A.T.,

G.R., C.R.D., K.L., D.G., and S.C.R. all received research support from the sponsor during the study. No other potential conflicts of interest relevant to this article were reported.

Aside from delivery and home setup of study devices, no sponsor employee or agent participated in any aspect of patient care or study treatments.

Author Contributions. R.G.F. assisted with the conception, design, and analysis of the study and wrote the manuscript. P.J.F. provided the sta- tistical design, performed the analyses, and assisted with writing the manuscript. M.E., J.N.B., L.T., T.W., M.G.G., A.M.L., J.A.T., G.R.,

C.R.D., K.L., D.G., and S.C.R. contributed to the discussion and critically reviewed and provided edits to the manuscript. R.G.F. and P.J.F. are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Prior Presentation. Parts of this study were presented as a late-breaking abstract at the 78th Scientific Sessions of the American Di- abetes Association, Orlando, FL, 22–26 June 2018.

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