Advanced Wound Care Therapies for Non-Healing Diabetic, Venous, and Arterial Ulcers: A Systematic Review
Chronic ulcers (i.e., ulcers that are unresponsive to initial therapy or that persist despite appropriate care) are estimated to affect more than six million people in the United States. The incidence is expected to increase as the population ages, and as the number of individuals with diabetes escalates. Lower extremity ulcers, especially those attributed to either diabetes, venous disease, or arterial disease comprise a substantial proportion of chronic ulcers. A wide range of standard treatment approaches to achieve ulcer healing are used (e.g., off-loading, compression, leg elevation, etc.) based on patient and ulcer factors and provider preferences. While many ulcers heal within several weeks, a substantial proportion does not heal or become worse. These chronic ulcers can result in considerable morbidity and healthcare costs.
The purpose of this review was to synthesize the evidence on therapies for non-healing diabetic, venous, and arterial lower extremity ulcers, recognizing that a non-healing ulcer is likely a result of multiple factors and comorbid conditions. Investigators at the VA Evidence-Based Synthesis Program Center in Minneapolis, MN summarized the available research literature — published from 1995 through August 2012 — identifying 68 articles representing 64 randomized controlled trials (RCTs). Focusing on FDA-approved therapies, studies were grouped according to ulcer type. Investigators used data from this review to address the following key questions.
What are the efficacy and harms of therapies for diabetic ulcers? Is efficacy dependent on ancillary therapies? Does efficacy differ according to patient demographics, comorbid conditions, treatment compliance, or activity level?
Thirty-five trials of nine different advanced wound care therapies used for the treatment of diabetic ulcers provided information on primary and secondary outcomes. Most studies compared advanced wound care therapies to standard care, placebo or sham treatments, with few reporting comparative effectiveness findings versus other advanced wound care therapies.
- Advanced wound care therapies using platelet-rich plasma or ozone oxygen therapy did not improve diabetic ulcer healing compared to standard care (2 studies) or another advanced care therapy (1 study).
- Other therapies provided mixed results. For example, four studies compared collagen products to standard care, with only one study reporting significantly better healing in the collagen group (70% vs 46%). Pooled results from 2 studies of one biological skin equivalent (Apligraf) showed significantly improved healing (55% vs 34%), while results from 3 studies of another skin equivalent (Dermagraft) were not significant. And while pooled results from studies of platelet-derived growth factor showed improvement in the percentage of ulcers healed compared to placebo or standard care (58% vs 37%; 7 studies), the strength of evidence was low due to high heterogeneity of results between studies.
- One good quality study provided moderate strength evidence that negative pressure wound therapy (NPWT) significantly improved healing more than standard care (43% vs 29%). In addition, three fair quality studies of hyperbaric oxygen therapy (HBOT) reported significantly better healing with HBOT (52% to 66%) compared to sham therapy or standard care (0% to 29%).
- There was no benefit in time to healing for collagen, biological dressings, or silver products. Investigators found mixed but generally negative results for biological skin equivalents, platelet-derived growth factors, platelet-rich plasma, and negative pressure wound therapy.
- No studies reported on return to daily activities.
- The most commonly reported secondary outcomes were ulcers infected during treatment and ulcer recurrence. No study reported a benefit for any of the advanced therapies reviewed.
- Fewer amputations were reported in three studies (one each of a biological skin equivalent, negative pressure wound therapy, and HBOT — all compared to standard care), while five studies reported no difference.
- Few studies reported other secondary outcomes of interest, including revascularization or surgery, pain or discomfort, hospitalization, need for home care, or quality of life.
- No significant differences between treatment groups were seen in all-cause mortality, though studies were not designed to assess this outcome.
What are the efficacy and harms of therapies for venous ulcers? Is efficacy dependent on ancillary therapies? Does efficacy differ according to patient demographics, comorbid conditions, treatment compliance, or activity level?
Investigators identified 20 trials of nine different advanced ulcer care therapies for patients with venous ulcers; 16 of these studies compared an advanced therapy to standard therapy.
- For collagen, platelet-rich plasma, intermittent pneumatic compression therapy, and HBOT, no eligible studies reported a significant improvement in the number of ulcers healed compared to standard care, placebo, or sham therapy.
- For biological dressings, investigators found low strength of evidence of improved healing compared with standard care (55% vs 34% healed).
- Apligraf significantly increased healed ulcers compared to compression bandaging in one trial (63% vs 49%). In two trials, Dermagraft was not significantly better than compression bandaging.
- Two trials that compared electromagnetic therapy (EMT) to sham treatment for ulcer healing found mixed results.
- Few studies reported time to ulcer healing. Two studies of Apligraf found shorter time to ulcer healing, as did the study comparing a keratinocyte product to standard care. Two other keratinocyte studies reported no significant differences in time to ulcer healing, as did a study comparing a silver dressing to a non-silver dressing. However, strength of evidence was low for these comparisons.
- Only studies of EMT reported patient activity levels; one finding no difference between treatment groups and one noting improvements pre- to post-treatment.
- The most commonly reported secondary outcomes were ulcers infected during treatment (8 studies), ulcer recurrence (7 studies), and pain (9 studies).
- A collagen treatment study reported fewer infected ulcers in the collagen group compared to standard care. No other study reported a difference between treatment groups.
- A biological dressing study reported fewer recurring ulcers in the treatment group compared to standard care. No other differences were reported.
- One EMT study reported a significant reduction in pain from baseline to 30 days in patients receiving EMT. Other studies reporting pain found no differences between treatment groups.
- No studies reported amputation, revascularization or other surgery, time to recurrence, or need for home care.
- Two studies reported hospitalization, and one reported quality of life with no difference between treatment arms in the studies.
- No significant differences were observed in all-cause mortality, study withdrawals due to adverse events, or allergic reactions to treatment.
What are the efficacy and harms of therapies for arterial ulcers? Is efficacy dependent on ancillary therapies? Does efficacy differ according to patient demographics, comorbid conditions, treatment compliance, or activity level?
- For arterial ulcers, one small, fair quality study found that a biological skin equivalent may improve the incidence and rate of complete ulcer healing when used on ischemic foot ulcers following revascularization surgery. Other outcomes did not differ significantly from standard care.
- Investigators found no RCTs that included any of the other therapies of interest exclusively in patients with arterial lower extremity ulcers.
- In seven studies of mixed ulcer types, collagen and biological dressings were found to improve ulcer healing; silver products and negative pressure wound therapy did not.
- There were mixed results for time to ulcer healing and, overall, no differences between investigational treatment and either standard care (5 studies) or another advanced care therapy (2 studies) on other outcomes. The studies were of poor to fair quality.
- One good quality study of ulcers associated with partial foot amputation showed a benefit of NPWT with respect to healed ulcers and time to healing. There were significantly more infections in the NPWT group, but the incidence of other adverse events did not differ between the NPWT and standard care groups.
Advanced wound care therapies for the treatment of chronic lower extremity ulcers generally did not improve wound healing or other clinical outcomes, beyond standard care in patients with venous or diabetic ulcers. The certainty and generalizability of review conclusions is limited due to the selective nature of patients and wounds enrolled, the small number of studies and patients, inconsistency of findings, and limited data reporting. Little high-quality data exists on arterial ulcers or on the comparative effectiveness of different advanced wound care products.
This review highlights several future research needs. Few studies directly compared two advanced therapies, and studies comparing treatments against standard controls were often few in number and small in size. Additional randomized trials of advanced wound care therapies vs standard care are needed to replicate or refute current findings. Moreover, comparative effectiveness research is needed to evaluate the relative benefits and harms of different advanced wound care therapies. Future research also is needed to determine the effectiveness, comparative effectiveness, and harms of advanced wound care therapies as used in a broader spectrum of patients seen in clinical practice settings. These patients may have more severe and larger ulcers, more complicated comorbidities, or increased difficulty with treatment compliance than has been reported in the available literature.
A Cyberseminar session on this ESP Report was held on May 8, 2013. You can access the archived session here.
This report is a product of VA/HSR&D's Quality Enhancement Research Initiative's (QUERI) Evidence-Based Synthesis Program (ESP), which was established to provide timely and accurate synthesis of targeted healthcare topics of particular importance to VA managers and policymakers — and to disseminate these reports throughout VA.
Greer N, Foman N, Dorrian J, Fitzgerald P, MacDonald R, Rutks I, Wilt T. Advanced Wound Care Therapies for Non-Healing Diabetic, Venous, and Arterial Ulcers: A Systematic Review. VA-ESP Project #09-009; 2012.
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