Dear Readers:
Healing the foot or leg ulcer (DU) of a patient with diabetes lowers his or her risk of lower-extremity amputation, a frequent precursor of morbidity and mortality.1 Evidence-based management requires
consistent offloading or protection of the DU site, metabolic control, and a moist wound environment1,2 in addition to careful debridement.2,3 Clinicians may choose from a variety of topical modalities. Despite evidence of improved healing relative to placebo or gauze5–7 none of these seem widely accepted. The search for improved topical DU management continues. This month’s Evidence Corner describes recent research on further options to manage these challenging wounds—a thrombin peptide and a silver dressing.
Laura Bolton, PhD, FAPWCA
Adjunct Associate Professor
Department of Surgery, UMDNJ
WOUNDS Editorial Advisory Board Member and Department Editor
Thrombin Peptide Stimulates Diabetic Ulcer Repair
Reference: Fife C, Mader JT, Stone J, et al. Thrombin peptide Chrysalin® stimulates healing of diabetic foot ulcers in a placebo-controlled phase I/II study. Wound Repair Regen. 2007;15(1):23–24.
Rationale: Diabetic ulcers pose a significant healthcare challenge. Advanced therapeutic options for DU, such as bilayered skin equivalents or growth factors cleared by the FDA, do not appear to be widely accepted as standards of care.
Objective: Explore pilot clinical efficacy and safety of a thrombin peptide topically applied to noninfected chronic DUs on the leg, ankle or foot.
Methods: A 4-center, prospective, randomized, double-blind, placebo-controlled pilot study enrolled 60 noninfected patients with metabolically controlled diabetes, a Wagner Grade I-III (without eroded tendon or bone) below-the-knee DU 1–7 cm in diameter, and a wound TcPO2 > 20 mmHg. The study DU in 20 patients in each treatment group received sharp debridement as needed, saline irrigation, and 100 µL of saline containing either 0 (placebo), 1, or 10 µg of the thrombin peptide topically applied twice weekly under a foam dressing for up to 20 weeks. A walker boot with evidence of efficacy was used to offload pressure-bearing ulcers, except for a few patients who used crutches or wheelchairs. Subjects were removed from the study and were deemed “nonhealed” if a clinical infection developed or the study DU condition significantly worsened. The primary healing efficacy endpoint was the percentage of wounds completely closed during 20 weeks, with secondary measures of time to 80% or 100% closure. The primary safety outcomes included adverse events (eg, erythema, edema, pain, and overall condition) assessed biweekly. Hematological assays, wound cultures, and radiographs were obtained and analyzed at weeks 5, 10, 15, and 20.
Results: There were no statistically significant effects of the thrombin peptide on safety or primary or secondary healing end points, with or without excluding patients inadvertently enrolled whose ulcers did not meet the enrollment criteria. Subjects and ulcers were initially comparable in all 3 groups, including subsets of < 10/group in a post-hoc analysis of study foot ulcers (DFU) in which the thrombin peptide increased the percent healed and decreased median healing time (P < 0.05).
Conclusion: Significant data obtained in this pilot study suggest that topical application of the thrombin peptide may benefit DFUs.
Silver Dressing Reduces Diabetic Foot Ulcer Depth
Reference: Jude EB, Apelqvist J, Spraul M, Martini J, the Silver Dressing Study Group. Prospective randomized controlled study of Hydrofiber® dressing containing ionic silver or calcium alginate dressings in non-ischaemic diabetic foot ulcers. Diabetic Med. 2007;24(3):280–288.
Rationale: DFU are at risk of infection, which can delay healing and place patients at risk of lower extremity amputation. A dressing with ionic silver providing a bacterial barrier may benefit DFU.
Objective: Compare clinical efficacy and safety of 2 absorbent fiber dressings, 1 with and 1 without ionic silver, on patients with a DFU.
Methods: A prospective, 18-center, randomized, controlled study enrolled 134 patients with diabetes in metabolic control with adequate lower limb perfusion and a neuropathic or neuroischemic Wagner Grade I or II DFU > 1 cm2 in area. Patients were surgically debrided achieving < 5% slough or eschar at baseline, stratified on enrollment to subsets with or without prescribed antibiotic use to signify clinical infection or risk of infection. Within these subsets each patient was randomly assigned to receive either a primary dressing of a sodium-carboxymethylcellulose dressing containing 1.2% ionic silver (Ag) or a calcium alginate (CA) dressing applied for 8 weeks with a secondary foam dressing and accommodative footwear for nonplantar ulcers or appropriate offloading for plantar ulcers. Efficacy outcomes measured were healing speed (primary), time to healing, proportion healed on study and 8-week percent reduction in ulcer area (secondary), as well as ulcer dimensions and periwound skin condition. Safety was measured as adverse events including infections.
Results: The 2 treatment groups of 67 patients each were comparable at baseline, and on primary or secondary healing, infection and safety outcomes, with 31% of Ag and 22% of CA patients healed during the 8-week study. In the 60 patients in each group with initial and 8-week depth measurements, greater depth reduction occurred in the Ag group (P = 0.04). In the planned stratified analysis of the Ag and CA dressed subsets prescribed antibiotics on study enrollment, more of the 12 Ag-dressed wounds (91.7%) healed or improved on study and fewer deteriorated than the 8 CA-dressed wounds (50%; P = 0.02). These healing outcomes occurred despite mean ulcer durations exceeding 1 year in both groups.
Conclusion: Primary outcomes reported for the 2 groups were comparable. DU depth reduced more during 8 weeks in the Ag group. Subjects prescribed antibiotics on study enrollment experienced more
healing /improvement and less deterioration with the Ag than the CA dressing.
Clinical Perspective
Wide variability in design, analysis, and reporting of DU studies makes it challenging to place them in perspective of the literature. For example, studies vary in design, treatment duration, ulcer characteristics (eg, severity, dimensions, and pre-study duration), as well as patient metabolic control, adherence to therapy protocols, and offloading. studies avoided using traditional gauze control dressings, elevating the quality of DU research. One pauses before drawing a conclusion from unplanned DFU subset analyses in the pilot study by Fife et al. It succeeded in its goal of informing future research on design and sample size issues for Wagner Grade I-III DFU studies, but it was insufficiently powered for statistical significance of clinically meaningful differences. How might one avoid enrolling DUs too small or brief in duration to meet study criteria? The study by Jude et al raises interesting questions. Many other large DFU trials excluded infected wounds or reported < 1 year mean DFU duration. In spite of including potentially infected DFUs with a mean duration of 1.2 years, Jude et al reported 31% of 67 Ag-dressed patients with a DFU healed during 8 weeks—this appears comparable to percentages healed at 20 weeks using good quality standard care and offloading,4 12 weeks with a dermal substitute5 or becaplermin,6 and 10 weeks with a collagen oxidized-regenerated cellulose dressing.7 What is the ideal duration of a DFU study? How long should a DFU last before it is considered “chronic”? Was ionic silver the sole cause of the significant effects? Why do other modalities seem to take longer to heal 31% of Wagner Grade I/II DFU? This study suggests that DFU depth reduction may be a clinically meaningful measure for future use, citing another similar finding. Has research been focusing on wound area reduction, neglecting the biologic fact that many DFU or other deep wounds must fill with granulation tissue before they contract or epithelize? Would a longer study have seen re-epithelization follow depth reduction? Diabetic ulcer literature reminds us to design studies carefully, lest we find what we seek rather than what nature is telling us.
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