Improving Venous Ulcer Outcomes

Reference: Mikosinski J, Di Landro A, Kasztalska-Kazmierczak K, Soriano E, Caverzasio C, Binelli D, Falissard B, Dereure O. Efficacy and safety of a hyaluronic acid-containing cream in the treatment of chronic, venous, or mixed-origin leg ulcers: a prospective, multicenter randomized controlled trial. Wounds. 2021;33(11):285–295. doi:10.25270/wnds/100521.01

Rationale: Patients with chronic wounds have been successfully treated with a 0.2% HA cream for more than 20 years. Longer-term 20-week healing outcomes for patients with venous or mixed venous-arterial ulcers treated with this topical HA cream remain to be studied in RCTs.

Objective: A prospective, multicenter, double-blind RCT explored the effects of topical 0.2% HA cream compared with a similar cream without HA as an adjunct to gauze wound dressings used within a standardized protocol of care, including cleansing and compression applied to venous or mixed arterial-venous ulcers.

Methods: The RCT was conducted June 2017 to April 2019 in 29 chronic leg ulcer centers in Poland using standards set forth in the Declaration of Helsinki, with ethics review board approval and written informed patient consent. Adults 18 years of age or older with a history of superficial or deep vein thrombosis, lower leg edema, and at least 1 venous or mixed venous-arterial ulcer measuring 5 cm² to 40 cm² in area were randomly assigned to be treated with topical HA or control cream. All patients were treated and evaluated by those unaware of which patients received the HA cream. Ulcers were included if less than half the ulcer area was covered with necrotic tissue and the ulcer had been present for 2 months to 4 years. Subjects were excluded if they were receiving a topical antimicrobial or antiseptic agent or high-dose corticosteroid, cytostatic, or other medication that may delay healing. Study nurses treated each patient’s target ulcer at home daily with HA or control cream covered with a gauze dressing and kept study diaries to confirm adherence to daily treatments and monitor oral analgesics taken by each patient. Standard elastic compression socks or bandages were worn during the day and removed at night. Study investigators rated periulcer edema, purpura, erythema, oozing, or maceration on a 4-point scale from none (0) to severe (3) and collected ulcer area data from standardized digital photography after target ulcer cleansing and debridement during 8 clinic visits on day 0 and after study treatment weeks 4, 8, 12, 16, and 20. Optional unscheduled data collection visits were arranged if the study nurse thought the wound may heal at an interval of less than 4 weeks after a scheduled visit. A final follow-up visit confirmed complete wound closure 3 weeks after healing or at study week 23 for patients whose target ulcer was unhealed at week 20. The primary efficacy endpoint was complete ulcer healing (ie, 100% reepithelialization of the wound area centrally assessed at 20 weeks or before and confirmed 3 weeks later). Secondary outcomes were percent of patients whose target ulcers healed on study, target ulcer area reduction from baseline, periulcer skin condition, analgesics used, adherence to treatment, target ulcer infection rates, time to target VLU healing, and patient-reported pain assessed using a visual analogue scale at each clinic visit. Safety outcomes were incidence and severity of adverse events and treatment-emergent adverse events (TEAEs) on study. A sample size of 84 subjects per group was estimated based on a calculation of a 90% power to detect as statistically significant (α ≤ .05), a clinically important difference of 23 percentage points between the percent of patients healed in the HA group compared with the control group. Healing time was calculated using the Cochrane-Mantel-Haenszel χ² test, stratified by ulcer size into VLUs measuring less than or equal to 20 cm² or greater than 20 cm².

Results: The 2 groups were comparable at baseline on ulcer and patient characteristics, though there was less purpura and erythema at baseline in the periulcer skin of the subjects in the control group. There were 85 patients receiving HA and 83 patients in the control group who received at least 1 study treatment included in the safety analysis, with 70 HA and 74 control patients completing the primary study endpoint with almost 100% adherence to protocol. More HA-treated patients (31.3%) healed the target VLU within 20 weeks and were confirmed 3 weeks later (primary endpoint) compared with 14.8% of the control group (P =.009). Median time to complete healing of the target VLU was 12 weeks for the HA group or 16 weeks for the patients in the control group. Healing differences persisted from study week 8 through week 20 (P <.05), sustained for the full analysis set and for subsets of ulcers measuring less than or equal to 20 cm² or greater than 20 cm². Target VLU area at baseline and duration were strong predictors of VLU healing within 20 weeks (P <.01). Ulcer pain reduced similarly by over 50% in both groups compared with pretreatment pain levels, with no significant differences observed between groups in infection incidence, analgesic use, or as a result of concomitant pentoxifylline use. Safety outcomes were similar for both groups.

Authors’ Conclusions: Adding topical HA to a protocol of care that included standardized elastic compression improved healing outcomes of VLUs and mixed venous-arterial ulcers in a double-blind RCT.

Reference: Bavaresco T, de Fátima Lucena AF. Low-laser light therapy in venous ulcer healing: a randomized clinical trial. [Article in English, Portuguese.] Rev Bras Enferm. 2021;75(3):e20210396. doi:10.1590/0034-7167-2021-0396

Rationale: Low-level laser monochromatic coherent light therapy (LLLT) has been reported to improve chronic or acute wound pain and healing outcomes, with mixed results on patients with a VLU.¹⁰

Objective: The authors conducted an RCT comparing healing effects of a standardized protocol including diet, exercise, compression, and patient-appropriate wound dressings with vs without adjunct LLLT.

Methods: With institutional ethics board approval, using appropriate patient consent, an RCT enrolling patients able to attend clinic appointments for 16 weeks was conducted at a Brazilian university hospital outpatient nursing service. Patients who were obese or those with a circumferential VLU were excluded. All participants were 18 years of age or older with an open venous ulcer (VU) receiving care from 2016 to 2018. Low-level laser monochromatic coherent light therapy at a wave length of 660 nm was applied once weekly to the wound bed at a power level of 30 mW and at an energy level of 1 to 3 joules per cm². All patients received standardized protocols including leg elevation, diet, elastic compression, exercise, and patient-appropriate absorptive, moisture-retentive, or antimicrobial dressings. Patient demographic, clinical, and ulcer data were collected and compared at baseline. Complete wound healing was compared for the LLLT (n = 20 with 42 VU) and control (n = 20 with 39 VU) groups using Kaplan-Meier analysis. Wound scores were documented using standardized Nursing Outcomes Classification measures and compared at study weeks 1 and 16 using t tests for continuous variables and Fisher’s exact test for categorical variables. including wound area, granulation, odor, maceration, exudate, scarring, and periwound edema, with P <.05 indicating statistical significance.

Results: The 2 groups were comparable at baseline on most patient and wound characteristics except that a greater percent of LLLT patients were female and LLLT-treated VU were initially more severe. The LLLT-treated VU improved more during the 16 weeks of study than the control group VU in wound area, granulation tissue, scarring, and exudate measures (P <.03). Kaplan-Meier analysis indicated that during 16 weeks, 58% of LLLT-treated ulcers healed compared with 36% in the control group (P <.031). The percent of patients healed in each group, the recognized standard for reporting comparative healing, was not reported.

Authors’ Conclusions: Application of LLLT to VU as an adjunct to standardized best practices improved VLU healing.

These 2 studies^8,9 show room for improvement of VLU outcomes. A close look at the laser research⁹ suggests caution in interpreting healing improvement analyzed on a “per ulcer” basis rather than the percent of patients healed, the recognized standard for healing analysis. The meticulous double-blind study of topical 2% HA cream effects on VLU healing⁸ showed 1 of 2 ways to provide a moist wound healing environment sufficient to double the 20-week percent of VLUs healed compared with those dressed with gauze by adding a hygroscopic agent like hydrogel, honey, or HA to attract and hold moisture at the wound-dressing interface. The other way is to use dressings like hydrocolloid or foam dressings or bioengineered skin, with a moisture vapor transmission rate after 1 day in place on the wound of less than or equal to 35 g/m² per hour to seal wound moisture over the wound.¹¹ One wonders if the HA effect was due to moist wound healing or did the HA cream reverse the delayed healing and increased pain and infection rates¹² resulting from gauze dressing use? Could other hygroscopic agents like honey¹³ or hydrogels¹⁴ similarly favor healing? The healing outcomes of VLUs improved quickly once effective compression was validated as mm Hg of pressure applied and clinically used. Additional items to consider would include whether consistently defined clinical use of validated moist wound healing interventions would further improve VLU outcomes when used with effective compression as well as whether patients with VLUs receiving optimal compression heal even faster if dressed primarily with a hygroscopic agent (eg, HA, hydrogel, or honey) sealed beneath a secondary moisture-retentive dressing (eg, hydrocolloid or film-covered foam dressing or bioengineered skin). Until these items have more definitive answers with blind-evaluated RCTs, it is difficult to tell whether clinicians are optimizing clinical outcomes for individuals with a VLU.