The Use of Pulsed Radio Frequency Energy Therapy in Treating Lower Extremity Wounds: Results of a Retrospective Study of a Wound Registry

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1 FEATURE The Use of Pulsed Radio Frequency Energy Therapy in Treating Lower Extremity Wounds: Results of a Retrospective Study of a Wound Registry Robert G. Frykberg, DPM, MPH; Vickie R. Driver, DPM, MS; Lawrence A. Lavery, DPM, MPH; David G. Armstrong, DPM, PhD; and Richard A. Isenberg, MD Abstract Pulsed radio frequency energy (PRFE) has been shown to stimulate cultured epidermal cells in vitro, inciting a cascade of cytokines, cyclins, growth factors, and other gene products associated with wound healing. A retrospective, descriptive study was conducted to evaluate the effect of PRFE on healing lower extremity wounds. Using data from a patient registry of 510 wounds in 413 patients, information was abstracted on patients with lower extremity wounds treated with PRFE for at least 4 weeks between 2005 and 2008 and who were evaluated 4 weeks after the start of treatment; wound size reduction was calculated. Patients with peripheral vascular disease, renal disease, poor glucose control, immune-compromise, large or deep wounds were not excluded. Of the 128 wounds (in 113 patients) that met the eligibility criteria, 35 were diabetic foot ulcers (DFUs), 42 were venous leg ulcers (VLUs), 34 were Stage II to Stage IV pressure ulcers (PUs), and 27 were other types of chronic wounds. Most patients were men (91%), receiving outpatient care (70%), and elderly (mean age 67 ± 11 years, median 64, range 41 89). Mean wound duration before starting PRFE was 29 ± 86 months (median 10, range 1 756). Mean percent reduction in wound area after 4 weeks was 49% ± 6% for pressure (P <0.0001), 38% ± 6% for diabetic (P <0.0001), 44% ± 5% for venous (P <0.0001), and 39% ± 9% for wounds of various other etiologies (P = ). The median wound reduction rate was 0.08 cm 2 /day (range ). A considerable percentage of wounds reached >50% reduction in size at 4 weeks (DFU 40%, VLU 43%, PU 59%), suggesting that a large proportion of these PRFEtreated wounds wound have healed with ongoing therapy. Additional studies to evaluate the safety, effectiveness, and efficacy of this treatment modality in the management of chronic wounds are warranted. Key Words: retrospective descriptive study, wounds, wound registry, pulsed radio frequency energy, percent area wound reduction Index: Ostomy Wound Management 2011;57(3):22 29 Potential Conflicts of Interest: Dr. Driver and Dr. Armstrong stated they have nothing to disclose. Dr. Frykberg is a consultant/paid advisory board member, Dr. Isenberg is an employee, and Dr. Lavery provided data analysis and manuscript preparation for Regenesis Biomedical, Inc., Scottsdale, AZ. Chronic lower extremity wounds pose a major problem for healthcare providers and patients. They place the patient at risk for deep infection and sepsis and are frequently associated with a high degree of morbidity, mortality, and impaired quality of life. In persons with diabetes mellitus (DM), foot and leg wounds are the most common precipitating event leading to lower extremity amputation. 1 In the growing US population of people with DM, the lifetime risk of foot ulceration is 15% to 25% 2,3 ; 7% to 20% of these lesions will subsequently require amputation. 1 Results of a retrospective Dr. Frykberg is Chief of Podiatry and Residency Director, Carl C. Hayden VA Medical Center, Phoenix, AZ. Dr. Driver is a Associate Professor of Surgery, Boston University School of Medicine and Boston Medical Center, Boston, MA. Dr. Lavery is Professor of Plastic Surgery, University of Texas Southwestern Medical Center, Dallas, TX. Dr. Armstrong is Professor of Surgery, University of Arizona College of Medicine, Tucson, AZ. Dr. Isenberg is Vice President of Clinical and Regulatory Affairs, Regenesis Biomedical, Inc., Scottsdale, AZ. Please address correspondence to: Richard A. Isenberg, MD, 1435 N. Hayden Road, Scottsdale, AZ 85257; isenberg@regenesisbio.com. 22 OSTOMY WOUND MANAGEMENT MARCH

2 chart-review study 4 have shown that lower extremity amputation is associated with a 5-year survival of 40% overall and 25% in the elderly. Venous ulcers and pressure ulcers occurring in people without DM also may cause considerable morbidity. 5-7 In a recent review of biomedical device therapeutics in wound healing, Rizzi et al 8 suggest that advanced therapies to heal chronic wounds may provide an opportunity to reduce morbidity and mortality. One such therapy is pulsed radio frequency energy (PRFE), which has been shown to stimulate cultured epidermal cells in vitro, inciting a cascade of cytokines, cyclins, growth factors, and other gene products associated with wound healing. 9 The use of PRFE to stimulate cell activity in chronic wounds is gaining attention. Its potential clinical utility has been reported in a recent series of case studies in the treatment of a variety of dermal ulcers PRFE has been used to improve wound healing for several decades In 1964, Cameron 14 studied postoperative wound healing in a randomized controlled study of 100 general surgical patients and found accelerated healing and shortened hospital stays. In 1981, Goldin 15 reported accelerated healing in a 67-patient randomized controlled study of skin graft patients treated preand postoperatively with PRFE. Improved healing outcomes were reported in the 1990s in randomized, controlled studies 16,17 and case series 18,19 of pressure ulcers treated with PRFE. In a 1991 randomized controlled trial (RCT), Muirhead 22 reported accelerated healing among young women with pre-tibial lacerations. Provant Therapy System (Regenesis Biomedical Inc, Scottsdale, AZ) is a device that emits a nonthermal, nonionizing radio frequency signal with a carrier frequency of MHz from a flat spiral antenna placed adjacent to the wound (see Figure 1). The device delivers a 42-µsec pulse delivered 1,000 times per second and generates an electromagnetic field thought to be responsible for the therapeutic effect. The electromagnetic field is continuously monitored and regulated to ensure consistent dosing. Waveform, energy, and treatment parameters were optimized in in vitro cell growth studies 23 involving dermal fibroblasts and epithelial cells. PRFE delivered via this device is FDA-cleared for adjunctive treatment of postoperative pain and edema in superficial soft tissue and is currently under investigation in trials intended to demonstrate effectiveness in wound healing. The purpose of this retrospective, descriptive study was to evaluate the effect of using PRFE on healing chronic lower extremity wounds. Methods and Procedures Data set: wound registry. The registry, established and maintained by Regenesis Biomedical, Inc. (Scottsdale, AZ) contains data collected by clinicians during the course of normal clinical care at 100 geographically diverse US medical facilities 41 wound clinics, 25 skilled nursing facilities, 21 long-term acute care hospitals, eight nursing homes, five spinal cord injury units, and three other types of facilities. PULSED RADIO FREQUENCY ENERGY THERAPY Ostomy Wound Management 2011;57(3):22 29 Key Points To evaluate outcomes of care after 4 weeks using pulsed radio frequency energy (PRFE), a retrospective analysis of 113 patient records (138 chronic wounds) was conducted. Almost half (46%) of all wounds exhibited a reduction in size of >50%, suggesting a healing trajectory. Studies including control groups are warranted to ascertain the effectiveness and efficacy of this treatment modality. Figure 1. Provant Therapy System (Regenesis Biomedical, Inc., Scottsdale, AZ) Four facilities have more than one type of medical care setting that submitted patient information to the registry. The registry includes data acquired serially on 413 patients with 510 wounds treated with the PRFE system from 2005 through All clinicians submitting data to the registry had been trained on proper use of the device according to the manufacturer s instructions. Clinicians submitted case data on one to six consecutive patients, which represented their initial experience with the PRFE system. For the most part, these were patients whose chronic wounds had failed to respond to standard care such as debridement, offloading, a moist wound healing environment, and the application of more advanced modalities such as negative pressure wound therapy (NPWT), platelet-derived growth factors, or bioengineered skin equivalents. Data entry was consecutive with no inclusion or exclusion criteria. Patients were not excluded on the basis of comorbidity, wound type, wound history, or prior medical history. The database includes information on the following variables: patient age and gender; and wound age, type, stage MARCH 2011 OSTOMY WOUND MANAGEMENT 23

3 FEATURE Table 1. Patient and wound demographics Number of wounds Number of patients a Patient age (years) b Site of care c Wound clinic Other settings Initial wound age (months) b Initial wound surface area (cm 2 ) b Number (%) of wounds per patient Percent male patients a Some patients had wounds of more than one type b Mean + SD (Median), Range c n (%) Diabetic ± 8 (62) (91%) 3 (9%) 22 ± 24 (13) ± 9.1 (3.0) Analysis subset demographics by wound type Pressure Venous Other ± 14 (73) (21%) 22 (79%) 9 ± 10 (5) ± 24.4 (6.0) (for pressure ulcers), location, and surface of routine medical practice, informed Table 2. Distribution by wound area (cm 2 ). The latter was calculated based type consent requirements were waived. All on manual measurements of wound data were de-identified per HIPAA regulations length (greatest measurement at 12 to 6 o clock) and width (greatest measurement Wound type n (%) before submission to the registry. A review of the data set suggested that at 3 to 9 o clock), collected weekly. Foot Diabetic foot ulcer 35 (25%) the 4-week time point provided the most wounds in patients with diabetes are classified as pressure ulcers or diabetic ulcers istry; patients often missed early and/or Venous ulcer 42 (30%) complete set of data contained in the reg- Pressure ulcer 34 (25%) Not Staged 6 (4%) at the discretion of the clinician. subsequent follow-up time points. Thus, Stage II 10 (7%) Wound treatment and PRFE therapy. Stage III 6 (4%) for the purpose of this study, only data of Patients were treated by their clinicians in Stage IV 12 (9%) patients with lower extremity wounds accordance with the guidelines and standards Other 27 (20%) that were at least 4 weeks old, were of their institution. For the most part, no changes were made to ongoing Surgical Trauma 6 (4%) 7 (5%) treated for at least 4 weeks with PRFE, and had data available for analysis at the wound management other than the implementation of PRFE therapy. Treatment Other 12 (9%) included in the analysis subset. Wounds Arterial 2 (1%) 4-week follow-up visit were retrieved and was self-administered at home by community-based patients and administered under nursing supervision to facility-based patients. Patients were treated for 30 minutes, twice daily, by placing the treatment applicator adjacent to the dressings covering their wound in accordance with the instructions for use provided by the manufacturer. Data retrieval and analysis. IRB approval was obtained for this nonsignificant risk device study in accordance with the Code of Federal Regulations 21CFR Because this was a retrospective study of existing data collected during the course treated for less than 4 weeks, regardless of outcome, were excluded, as were all wounds without 4- week follow-up visit data, regardless of treatment duration. For the purposes of this analysis, limb wounds located distal to the acetabulofemoral joint were considered lower extremity ulcers. Descriptive statistics were used to summarize demographic data. The number of patients reported is the number of unique patients, although a patient could contribute more than one wound to the study. 24 OSTOMY WOUND MANAGEMENT MARCH ± 12 (72) (78%) 7 (22%) 45 ± 99 (11) ± 59.0 (12.0) ± 9 (62) (83%) 4 (17%) 43 ± 145 (6) ± 27.0 (8.6) Total population ± 11 (64) (83%) 4 (17%) 29 ±86 (10) ± 27.0 (8.6) (83%) 15 (13%) 2 (2%) 2 (2%) 91%

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5 FEATURE Table 3. Outcomes by wound type Percent reduction in wound surface area at 4 weeks (PWAR) a,b Proportion of wounds achieving 50% reduction at 4 weeks (50% PWAR) Wound healing trajectory at 4 weeks (cm 2 per day) a Diabetic 38%±6 (42%) 100% to -56% 40% a Mean±SD (Median) Range b P < for diabetic, pressure, and venous wounds; P = for other :wounds Healing was evaluated by analyzing percent reduction in wound surface area calculated as follows: (1-[initial wound area - final wound area]/initial wound area) x 100%. Wound healing trajectory was defined as: (initial wound area-final wound area)/number of days of treatment. Because some patients had more than one wound, percent reduction in wound area was analyzed using repeated measures analysis of variance. Results Of the 413 patients in the registry, 113 patients (27%) with 138 wounds met the inclusion criteria for this study. These patients received care at 52 medical facilities; 70% of wounds were in ambulatory patients treated in outpatient wound clinics. Patients ranged in age from 41 to 89 years (see Table 1) The majority (91%) were male. Overall median wound age was 10 months (range 1 to 756 months). Of the 138 wounds, 35 were classified as diabetic ulcers, 42 were venous ulcers, 34 were pressure ulcers, and 27 were of other origin (see Table 2). Among the pressure ulcers, 10 were Stage II, six were Stage III, 12 were Stage IV, and six were not staged or deemed unstageable (see Table 1). Most diabetic and pressure ulcers were located on the foot; whereas, all venous ulcers involved the leg. Wounds ranged widely in terms of initial surface area. Half of all wounds had an initial area >7.6 cm 2. Venous leg ulcers were the largest in the subset, with a median area of 12.0 cm 2 (see Table 1). The overall mean percent wound area reduction (PWAR) for the population at 4 weeks of therapy was 41% ± 5 (P <0.0001). Median PWAR for the population was 45%. Overall, 46% of wounds reduced >50% in size after 4 weeks. A somewhat higher percentage of pressure ulcers (59%) reached 50% PWAR at 4 weeks, compared to 40% and 43%, respectively, for diabetic and venous ulcers (see Table 3, Figure 2). A few of the wounds in each category increased in size as indicated by negative wound healing trajectories.the mean wound healing trajectory for the overall population was cm 2 /day ± 0.65; median was cm 2 /day. Discussion Calculating changes in PWAR is a practical approach to assessing wound response to care. Post hoc analysis of RCT data Analysis subset outcomes by wound type Pressure 49% ± 6 (58%) 100% to -386% -0.07±0.10 (-0.03) -0.34±0.60 (-0.08) -0.43±0.99 (-0.15) -0.24±0.37 (-0.11) Median Wound Surface Area (cm 3 ) Before PRFE has demonstrated that wound area reduction at 1 and 4 weeks of therapy is a robust predictor of complete wound healing For instance, Lavery et al 24 evaluated PWAR in a post hoc analysis of RCT data from a study assessing NPWT in patients with diabetes and foot amputation wounds. Change in wound area of at least 15% at 1 week and 60% at 4 weeks was strongly associated with complete wound healing at 16 weeks in persons that received either NPWT or control. Likewise, Sheehan et al 25 evaluated data from a study of oxidized regenerated cellulose with collagen dressing in a 12-week RCT of patients with diabetic foot ulcers. The overall median wound area reduction at 4 weeks was 53%. Among patients with wound area reduction of 53% or more at 4 weeks, 58% eventually healed; however, in patients with less than this benchmark, only 9% healed (P <0.01). The use of PWAR as a measure to predict healing thereby avoiding long-term use of ineffective treatments has been established for various types of wounds and may be a useful surrogate end-point in clinical studies. The results of the current study are comparable to the outcomes reported in prospective clinical studies using more stringent exclusion 26 OSTOMY WOUND MANAGEMENT MARCH % At Week 4 PRFE * p-value < p-value = Venous 44% ± 5 (44%) 100% to -117% 43% Reduction in Surface Area Diabetic Venous Pressure 6.0 Other 39% ± 9 (43%) 100% to -43% 44% Figure 2. Reduction in wound surface area following 4 weeks of PRFE therapy. 2.0 Other

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7 FEATURE criteria for patients with comorbid conditions and suggest that a high proportion of wounds would have healed using the PRFE treatment modality. It is worth noting that most RCTs exclude patients with risk factors for poor healing such as poor glucose control, large and deep wounds, and persons who are immune-compromised. The PRFE registry did not exclude the latter high-risk patients, and as such represents a more real-world population. In this analysis of lower extremity wounds, diabetic wounds decreased in surface area by a mean of 38% ± 6% and a median of 42% in 4 weeks, somewhat less than the mean PWAR among wounds that healed in the Sheehan analysis. Nonetheless, 40% of diabetic wounds reached Sheehan s surrogate endpoint of ~50% PWAR at 4 weeks, suggesting that a large percentage of these wounds would likely heal within 12 weeks with PRFE. The median reduction in venous ulcer surface area at 4 weeks with PRFE (44%, mean 44% ± 5%) was comparable to the median PWAR of 58% reported by Gelfand 30 for venous ulcers that healed by 24 weeks in his retrospective study of 29,189 patients. In that study, wounds that reached 28.8% PWAR in 4 weeks had a positive predictive value of healing at 24 weeks of 0.80 and a negative predictive value was In the PRFE registry, 43% of venous ulcers demonstrated a 50% PWAR (an extent of healing considerably greater than the cutoff point) at 4 weeks, suggesting that a large proportion of venous ulcers would be expected to heal within 24 weeks with the PRFE therapy. Lundeberg 31 evaluated the use of electrical stimulation in 64 patients with venous ulcers in a 12-week randomized clinical trial. At the end of the study, the average PWAR was 61% in patients in the active and 41% in the placebo arm of the study. In a similar study, Stiller 32 reported an average PWAR of 47% PWAR in the active therapy group compared to a 49% increase in wound area in the sham therapy group. For pressure ulcers, the mean PWAR in the PRFE registry was 49% ± 6% (median 58%). Feedar 33 evaluated 47 patients with 67 Stage II through Stage IV pressure ulcers for 4 weeks. The mean PWAR in the control arm of the study was 34% and the active treatment arm (electrical stimulation) was 56%. This analysis examined only those lower extremity wounds that had data available at 4 weeks of PRFE therapy and excluded all other wounds in the registry. Overall, 138 out of 254 (54%) of the total lower extremity wound population was included in the analysis. An analysis of the population of excluded wounds revealed no significant differences when compared to included wounds in terms of patient demographics, initial wound age, wound type, site of care, or the outcome parameters of PWAR, 50% PWAR, and wound healing trajectory. It is worth noting that this analysis also excluded seven wounds that had completely healed before 4 weeks. As such, the findings here may understate the true effectiveness of PRFE in advancing wound healing. Limitations Retrospective study designs and the use of data from any registry are subject to certain limitations. Because few eligibility criteria are defined, internal validity is minimized and external validity is maximized. Proper and careful statistical methodologies to control potential sources of bias that threaten internal validity were taken, yet can be considered a weakness compared to the standard RCT. 34,35 Data were collected from multiple centers that use a variety of operational definitions, adjunctive wound therapies, and tools and techniques to measure the size and determine the severity of wounds. Potential confounding variables such as adherence with therapy, presence of peripheral arterial occlusive disease or other patient comorbidities, and wound depth were not available and could not be used to further explore wound outcomes. Although selection bias in this registry is more likely to be in favor of more severe than less severe wounds, the 4- week outcomes were close to those reported by others. Conclusion In this registry population of patients with lower extremity wounds, 4 weeks of PRFE treatment was associated with a marked decrease in wound size. The average decrease was close to that reported for other treatment modalities in published clinical trials. Applying the surrogate endpoint analysis recently published for diabetic and venous ulcers, these results suggest that a high proportion of PRFE-treated wounds would have reached full closure with ongoing PRFE therapy. Additional studies to evaluate the safety, effectiveness, and efficacy of this treatment modality in the management of chronic wounds are warranted. Acknowledgements The authors thank Teresa Nelson, MS, Technomics Research, LLC (Medina, MN) for statistical support in the preparation of this report. References 1. Frykberg RG, Zgonis T, Armstrong DG, et al. Diabetic foot disorders. A clinical practice guideline (2006 revision). J Foot Ankle Surg. 2006;45(5 suppl):s1 S Singh N, Armstrong DG, Lipsky BA. Preventing foot ulcers in patients with diabetes. JAMA. 2005;293(2): Reiber GE. The epidemiology of diabetic foot problems. Diabet Med. 1996;13 suppl 1:S6 S Frykberg RG, Arora S, Pomposelli FB Jr, LoGerfo F. Functional outcome in the elderly following lower extremity amputation. J Foot Ankle Surg, 1998;37(3): Kerstein MD, Gahtan V. Outcomes of venous ulcer care: results of a longitudinal study. Ostomy Wound Manage. 2000;46(6): Hess CT. Management of the patient with a venous ulcer. 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