Research Papers

The First CMS-Sanctioned, Pragmatic, Randomized, Controlled Trial in Wound Care

Gude W, Hagan D, Abood F, Clausen P. Aurix Gel Is an Effective Intervention for Chronic Diabetic Foot Ulcers: A Pragmatic Randomized Controlled Trial. Adv Skin Wound Care. 2019;32(9):416-426.

Background: Autologous platelet-rich plasma products can significantly vary with respect to platelet concentration, the presence of additional cellularity, and the use of additives. Therefore, the utility of each formulation for treating chronic wounds needs to be established.

Objective: To establish the efficacy of up to 12 weeks of treatment with Aurix hematogel for healing diabetic foot ulcers against usual and customary care including any wound modality in 129 patients using a Medicare Coverage with Evidence Development paradigm.

Methods: This pragmatic randomized controlled trial was conducted in 28 real-world outpatient wound care sites using an inclusive design that included participants with various health risks, comorbidities (eg, peripheral arterial disease, smoking), and any wound severity (Wagner 1-4).

Results: Kaplan-Meier analysis showed a significant (log-rank P = .0476) time-to-heal advantage, with 48.5% of wounds healing with Aurix hematogel compared with 30.2% with usual and customary care. A higher percentage of healing was observed for Aurix across all wound severities (Wagner grade 1-4). Subgroup analysis revealed a significant healing advantage for Aurix when treating wounds accompanied by peripheral arterial disease and a demonstrated advantage for smokers.

Conclusions: This first Coverage with Evidence Development study in wound care demonstrates the effectiveness of Aurix for treating diabetic foot ulcers in Medicare beneficiaries.

Read the full study here.

Prospective, Randomized, Blinded, Multi-Center, Controlled Trial

Driver, V. R., Hanft, J., Fylling, C. P., Beriou, J. M., & AutoloGel Diabetic Foot Ulcer Study Group. (2006). A prospective, randomized, controlled trial of autologous platelet-rich plasma gel for the treatment of diabetic foot ulcers. Ostomy Wound Manage, 52(6), 68-87.

Abstract

Non-healing diabetic foot ulcers are a common cause of amputation. Emerging cellular therapies such as platelet-rich plasma gel provide ulcer management options to avoid loss of limb. The purpose of this prospective, randomized, controlled, blinded, multicenter clinical study was to evaluate the safety and efficacy of autologous platelet-rich plasma gel for the treatment of non-healing diabetic foot ulcers. One hundred, twenty-nine (129) patients were screened; 72 completed a 7-day screening period and met the study inclusion criteria. Patients were randomized into two groups — the standard care with platelet-rich plasma gel or control (saline gel) dressing group — and evaluated biweekly for 12 weeks or until healing. Healing was confirmed 1 week following closure and monitored for another 11 weeks. An independent audit led to the exclusion of 32 patients from the final per-protocol analysis because of protocol violations and failure to complete treatment. In this group, 13 out of 19 (68.4%) of the platelet-rich plasma gel and nine out of 21 (42.9%) of the control wounds healed. After adjusting for wound size outliers (n = 5), significantly more platelet-rich plasma gel (13 out of 16, 81.3%) than control gel (eight out of 19, 42.1%) treated wounds healed (P = 0.036, Fisher’s exact test). Kaplan-Meier time-to-healing also was significantly different between groups (log-rank, P = 0.0177). No treatment-related serious adverse events were reported and bovine thrombin used in the preparation of PRP did not cause Factor V inhibition. When used with good standards of care, the majority of non-healing diabetic foot ulcers treated with autologous platelet-rich plasma gel can be expected to heal.

Systematic Review of PRP Literature Which Includes AutoloGel PRP Gel

Carter, MJ, Fylling, CP, Parnell, LKS. (2011) Use of Platelet Rich Plasma Gel on Wound Healing: A Systematic Review and Meta-Analysis. www.eplasty.com, OpenAccess Journal of the Journal of Plastic Surgery. September 15, 2011.
Objective: Autologous platelet rich plasma is an advanced wound therapy used in hard-to-heal acute and chronic wounds. To better understand the use and clinical outcomes of the therapy, a systematic review of the published literature in cutaneous wounds was performed.

Methods: Electronic and hand searches for randomized controlled trials and comparative group studies using platelet rich plasma therapy in cutaneous wounds and published over the last 10 years was conducted. Eligible studies compared the
treatment to standard care or other interventions. All citations were screened and eligible studies were assessed for validity, quality, and bias using accepted scoring methods. The primary outcomes were effect of platelet rich plasma and control wound care on wound healing and related healing measurements. Secondary outcomes related to healing such as infection, pain, exudate, adverse events, and quality of life were also considered. The meta-analysis utilized appropriate statistical methods to determine the overall treatment effect on chronic and acute wound healing and infection.

Results: The search terms resulted in 8577 citations and after removing duplicates and screening for protocol eligibility, a total of 24 papers were used. The meta-analysis of chronic wound studies revealed platelet rich plasma therapy is significantly favored for complete healing. The meta-analysis of acute wounds with primary closure studies demonstrated that presence of infection was reduced in platelet rich plasma treated wounds.

Conclusions: This systematic review and meta-analysis of platelet rich plasma therapy in cutaneous wounds showed complete and partial wound healing was improved compared to control wound care.

Observational Study

de Leon J, Driver VR, Fylling CP, Carter MJ, Anderson C, Wilson J, et al. (2011) The clinical relevance of treating chronic wounds with an enhanced near-physiological concentration of platelet rich plasma (PRP) gel. Advances in Skin and Wound Care. 24(8), 357-368.

Objective: This study investigated clinical outcomes in chronic nonhealing wounds following the short-term use of an enhanced, near-physiological concentration of platelet-rich plasma (PRP) gel (AutoloGel System, Cytomedix, Inc, Gaithersburg, Maryland).

Design: Study design was a large, observational case series using a multicenter registry database (all wounds included), which compared different populations within the database.

Setting: Thirty-nine centers contributed to the registry, including long-term acute-care centers, outpatient clinics, a durable medical equipment company, a home health agency, and a long-term-care center.

Patients: The target population included 285 chronic wounds (patient n = 200). Wound etiologies included diabetic, pressure, or venous ulcer; dehisced, surgical, or traumatic wound; and wounds of other etiologies.

Intervention: Therapeutic, PRP gel is produced from patient blood utilizing autologous platelets and plasma that contribute growth factors, cytokines, and chemokines, in a fibrin matrix.

Main measures: Area and volume of the wound and the linear total of undermining and sinus tracts/tunneling were calculated. Clinical relevance was determined by analyzing outcomes in wounds that responded to treatment.

Main results: A positive response occurred in 96.5% of wounds within 2.2 weeks with 2.8 treatments. In 86.3% of wounds, 47.5% area reduction occurred, and 90.5% of wounds had a 63.6% volume reduction. In 89.4% undermined and 85.7% of sinus tracts/tunneling wounds, 71.9% and 49.3% reductions in linear total were observed, respectively.

Frykberg, R. G., Driver, V. R., Carman, D., Lucero, B., Borris-Hale, C., Fylling, C. P., et al. (2010). Chronic wounds treated with a physiologically relevant concentration of plateletrich plasma gel: a prospective case series. Ostomy Wound Manage, 56(6), 36-44.

Chronic wounds are characterized by a long inflammatory phase that hinders regenerative wound healing. The purpose of this prospective case series was to evaluate how a physiologically relevant concentration of an autologous platelet-rich plasma (PRP) gel affects initial wound healing trajectories of chronic, non-healing wounds of various etiologies and in different care settings. Using convenience sampling methods, 49 patients (average age: 60.6 years, SD 14.7) with 65 non-healing wounds (mean duration 47.8 weeks, range 3 to 260) at eight long-term acute care (LTAC) hospitals and three outpatient foot or wound clinics who were prescribed PRP gel for their non-healing wound were enrolled. The majority of patients had low albumin, hematocrit, and/or hemoglobin levels. After wound assessments and measurements were obtained and the gel prepared, a skin barrier was applied to the periwound skin and the gel applied and protected with cover dressings. The most common wounds were pressure ulcers (n = 21), venous ulcers (n = 16) and diabetic foot ulcers (n = 14). Mean wound area and volume were 19 cm2 (SD 29.4) and 36.2 cm3 (SD 77.7), respectively. Following a mean of 2.8 (SD 2.4) weeks with 3.2 (SD 2.2) applications, reductions in wound volume (mean 51%, SD 43.1), area (39.5%, SD 41.2), undermining (77.8%, SD 28.9), and sinus tract/tunneling (45.8%, SD 40.2) were observed. For all wound etiologies, 97% of wounds improved. The results of this study suggest the application of this PRP gel can reverse non-healing trends in chronic wounds.

Comparison Study: Run In Treatment vs AutoloGel Treatment

Sakata J, Sasaki S, Handa K, Uchino T, Sasaki T, Higashita R, Tsuno N, Hiyoshi T, Imakado S, Morimoto S, Rinoie C, Saito N. A retrospective, longitudinal study to evaluate healing lower extremity wounds in patients with diabetes mellitus and ischemia using standard protocols of care and platelet-rich plasma gel in a Japanese wound care program. Ostomy Wound Manage. 2012;58(4):36-49.

Abstract

Chronic wounds, especially in patients with diabetes mellitus (DM), are a major health challenge in Japan. The goal of wound care centers (WCCs) in Japan is to facilitate healing and prevent lower extremity amputations (LEAs) using standardized protocols of patient and wound care. The standard treatment algorithm includes a complete patient and wound assessment, history, physical exam, and a variety of diagnostic tests that determine the need for infection control intervention, revascularization, excision and debridement, growth factor/platelet rich plasma (PRP) gel therapy, skin graft/ flap, wound protection, and education.

All patient and wound data are entered in a secure central database for all WCCs. To evaluate the outcomes of standard care regimens compared to the use of a topical PRP gel treatment in patients with a variety of complex wounds, a retrospective, longitudinal study was conducted. Wound outcomes from 39 patients with 40 chronic, non-healing, lower extremity wounds were evaluated between two time periods: between first presentation at the WCC (T1)
and after using standard topical treatments (T2) and between T2 and after using the PRP gel treatment (T3). Patient average age was 66.8 years (SD: 10.60) and mean wound duration was 99.7 days before treatment (SD: 107.73); and the majority of patients (85%) had DM. Wounds were classified as ischemic diabetic (n = 24), diabetic (n = 10), ischemic (n = 5), and pressure ulcer (n = 1). DFUs were Wagner lll (77%) and lV (23%). Of those, 60% were in patients with arteriosclerotic obliterans (ASO). Infection (abscess, cellulitis, osteomyelitis, and/or gangrene) was present in all wounds and treated using debridement, antibiotic therapy, and surgery as deemed appropriate. During the first treatment period (T1 to T2) of 75.3 days, which included revascularization and/or debridement along with standard of care, none of the wounds healed and the average wound area, depth, and volume increased. Following topical PRP gel treatment, 83% of wounds healed within 145.2 days (T2 to T3) (P = 0.00002). Only one patient required an LEA. The results of this study suggest that good healing outcomes and a low amputation rate can be obtained with a protocol of supportive care (including revascularization procedures) and the PRP gel treatment. Prospective controlled studies comparing the use of this PRP gel to other advanced treatments are warranted.

Carter, M., Fylling, C., Li, W., De Leon, J., Driver, V., Serena, T., et al. (2011). A statistical analysis of a wound outcomes registry using run-in data: clinical impact of platelet rich plasma gel on healing trajectory. Int Wound J. 2011; 8:638–650.
Randomized controlled trials in chronic wounds typically exclude patients with comorbidities and confounding factors. Well-designed observational studies can provide complementary clinical evidence that randomized trials cannot address. This study determined if wound care registry outcomes could be an alternative data source and if the results would be robust and valid. Changes in wound area and depth were hypothesized to be different between run-in therapies and platelet-rich plasma (AutoloGel™, Cytomedix, Inc) treatment. From a treatment registry of 285 chronic wounds, 46 had run-in and post-treatment data. Seven chronic wound categories were identified. Mean wound age at study start was 52·4 weeks. General linear model repeated measures showed a credible and robust data set. Statistically significant differences for wound area and depth were observed between run-in and post-treatment period at multiple time points. Wound area and depth ≥50% reduction were analyzed using Kaplan–Meier methods. During run-in, 15% of wound area improved compared to 28% post-treatment and 11% of wound depth improved during run-in compared to 39% post-treatment. Significant clinical outcomes indicated many previously non-responsive wounds began actively healing in response to platelet-rich plasma therapy, indicating that registry data can be used as a complementary source of evidence.