NIHR Signal Skin grafts may help heal diabetic foot ulcers and reduce amputations

Published on 19 April 2016

Skin grafts and tissue replacement products can help heal diabetic foot ulcers in some cases, and may also slightly reduce the numbers of future amputations. Foot ulcers are common and can be hard to treat, but failure to heal them carries high risk for amputation and mortality.

This review showed skin grafts or tissue replacement moderately increased the healing rate of the most amenable diabetic foot ulcers in people with diabetes – that is, in those who had sufficient blood flow in their feet. Two trials reported slightly fewer amputations in people with diabetes compared to usual care at 12 weeks.

The review identified the most relevant trial evidence available. These trials showed some limitations. For example, most trials were linked with product manufacturers. However, given that the treatments are recognisable to patients and staff, it’s difficult to eliminate all potential causes of bias.

Currently recommended treatments of wound dressings and foot infection control don’t always achieve complete wound healing and are expensive for long term use, so this review added to understanding about better approaches. We still need more information about cost and long-term effectiveness of the treatments.

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Why was this study needed?

Foot complications are common in people with diabetes with around 10 to15% experiencing a diabetic foot ulcer at some point in their lives. NICE also estimate that around 50% of people die within five years of developing a diabetic foot ulcer and ulcers precede more than 80% of diabetes-related amputations.

They are also costly. A 2012 NHS Diabetes report estimated that around £650 million is spent on foot ulcers or amputations each year.

Despite the variety of current treatments for diabetic foot ulcers - including control of foot infection and wound dressings - up to 60% of ulcers fail to heal completely.

This review looked to see whether treatments involving skin grafts and tissue replacement would improve ulcer healing rates compared to usual care.

What did this study do?

This Cochrane systematic review included 17 randomised controlled trials involving 1,655 adults with type 1 or 2 diabetes. Fourteen trials compared skin grafts / tissue replacement with usual care, four compared tissue products against each other.

Skin grafts came from the person themselves, a different person; engineered or artificial skin; or from animals. Follow-up to assess ulcer healing ranged from six weeks to 14 months, but most were 12 weeks. In the 15 trials that described patients’ characteristics in detail, all studied people who had sufficient blood flow to their feet.

We can be confident the review identified the most relevant trials, but they were rated in the review as low-quality due to a lack of blinding of the outcomes assessors. Blinding is not feasible for these studies as the treatments are visible. There were links with manufacturers of skin products in 15 of the trials. No studies came from England and most (11) were from the US, so applicability to the UK may be an issue.

What did it find?

  • Fourteen trials found that skin grafts and tissue replacement products use in the trials increased the healing rate for people with diabetes by approximately 55% compared to usual care (risk ratio 1.55, 95% confidence interval [CI] 1.30 to 1.85). Complete ulcer healing at 6 to 16 weeks was 423 per 1,000 people using skin grafts or tissue replacement, significantly more than the 273 per 1,000 achieved in standard care. Despite this improvement, fewer than half of all ulcers were healed by 16 weeks.
  • Four trials directly comparing skin graft or tissue replacement products with one another found no specific type was more effective than another.
  • Two trials looking at the rate of lower limb amputations found around half the rate of amputations in the skin graft or tissue replacement groups (47 per 1,000, 95% CI 25 to 89) compared with usual care (109 per 1,000, 95%CI not reported). There was imprecision in reporting of amputations rates.
  • No trials reported significant differences in adverse events between skin graft or tissue replacement products compared to usual care, based on 16 trials.
  • No trials reported on quality of life or compared the cost benefits of skin grafts or tissue replacement compared with usual care.

What does current guidance say on this issue?

NICE’s 2015 guidance on Diabetic foot problems: prevention and management recommends that usual care includes one or more of the following treatments: offloading (keeping weight off the area), control of foot infection, control of ischaemia (poor blood supply to a part of the body, wound debridement (removal of dead tissue) and wound dressings.

It also recommends considering skin grafts or skin substitutes (tissue replacement) in addition to usual care for diabetic foot ulcers only when healing has not progressed and on the advice of the multidisciplinary foot care service.

What are the implications?

This review identifies evidence that skin grafts and tissue replacement may improve the healing rate of diabetic foot ulcers for some people, compared to usual care. This supports the NICE guideline’s cautious approach.

Limitations of the evidence include trials’ focus on people with sufficient blood flow to their feet - who may not be representative of all patients with diabetic foot ulcers. The average follow up of treatment was 12 weeks so longer-term effectiveness is not known. Having long term follow up is particularly important to assess risk of future amputation. Finally, we do not know the cost benefits of these interventions compared with standard care – differences in cost could be significant.

Better quality UK-relevant data on these interventions, including a cost benefit analysis would help commissioners of these services.  Bearing in mind how many people are diagnosed as having diabetes and the costs of treatment, patient selection of those people who stand to benefit from these grafts will be important.

Citation and Funding

Santema TB, Poyck PP, Ubbink DT. Skin grafting and tissue replacement for treating foot ulcers in people with diabetes. Cochrane Database Syst Rev. 2016;2:CD011255.

The project was funded by the National Institute for Health Research via Cochrane Infrastructure funding to Cochrane Wounds.

Bibliography

NICE. Diabetic foot problems: prevention and management. NG19. London. National Institute for Health and Care Excellence; 2015.

NHS Choices. How to look after your feet if you have diabetes. [internet]. Leeds: NHS Choices; 2015.

Why was this study needed?

Foot complications are common in people with diabetes with around 10 to15% experiencing a diabetic foot ulcer at some point in their lives. NICE also estimate that around 50% of people die within five years of developing a diabetic foot ulcer and ulcers precede more than 80% of diabetes-related amputations.

They are also costly. A 2012 NHS Diabetes report estimated that around £650 million is spent on foot ulcers or amputations each year.

Despite the variety of current treatments for diabetic foot ulcers - including control of foot infection and wound dressings - up to 60% of ulcers fail to heal completely.

This review looked to see whether treatments involving skin grafts and tissue replacement would improve ulcer healing rates compared to usual care.

What did this study do?

This Cochrane systematic review included 17 randomised controlled trials involving 1,655 adults with type 1 or 2 diabetes. Fourteen trials compared skin grafts / tissue replacement with usual care, four compared tissue products against each other.

Skin grafts came from the person themselves, a different person; engineered or artificial skin; or from animals. Follow-up to assess ulcer healing ranged from six weeks to 14 months, but most were 12 weeks. In the 15 trials that described patients’ characteristics in detail, all studied people who had sufficient blood flow to their feet.

We can be confident the review identified the most relevant trials, but they were rated in the review as low-quality due to a lack of blinding of the outcomes assessors. Blinding is not feasible for these studies as the treatments are visible. There were links with manufacturers of skin products in 15 of the trials. No studies came from England and most (11) were from the US, so applicability to the UK may be an issue.

What did it find?

  • Fourteen trials found that skin grafts and tissue replacement products use in the trials increased the healing rate for people with diabetes by approximately 55% compared to usual care (risk ratio 1.55, 95% confidence interval [CI] 1.30 to 1.85). Complete ulcer healing at 6 to 16 weeks was 423 per 1,000 people using skin grafts or tissue replacement, significantly more than the 273 per 1,000 achieved in standard care. Despite this improvement, fewer than half of all ulcers were healed by 16 weeks.
  • Four trials directly comparing skin graft or tissue replacement products with one another found no specific type was more effective than another.
  • Two trials looking at the rate of lower limb amputations found around half the rate of amputations in the skin graft or tissue replacement groups (47 per 1,000, 95% CI 25 to 89) compared with usual care (109 per 1,000, 95%CI not reported). There was imprecision in reporting of amputations rates.
  • No trials reported significant differences in adverse events between skin graft or tissue replacement products compared to usual care, based on 16 trials.
  • No trials reported on quality of life or compared the cost benefits of skin grafts or tissue replacement compared with usual care.

What does current guidance say on this issue?

NICE’s 2015 guidance on Diabetic foot problems: prevention and management recommends that usual care includes one or more of the following treatments: offloading (keeping weight off the area), control of foot infection, control of ischaemia (poor blood supply to a part of the body, wound debridement (removal of dead tissue) and wound dressings.

It also recommends considering skin grafts or skin substitutes (tissue replacement) in addition to usual care for diabetic foot ulcers only when healing has not progressed and on the advice of the multidisciplinary foot care service.

What are the implications?

This review identifies evidence that skin grafts and tissue replacement may improve the healing rate of diabetic foot ulcers for some people, compared to usual care. This supports the NICE guideline’s cautious approach.

Limitations of the evidence include trials’ focus on people with sufficient blood flow to their feet - who may not be representative of all patients with diabetic foot ulcers. The average follow up of treatment was 12 weeks so longer-term effectiveness is not known. Having long term follow up is particularly important to assess risk of future amputation. Finally, we do not know the cost benefits of these interventions compared with standard care – differences in cost could be significant.

Better quality UK-relevant data on these interventions, including a cost benefit analysis would help commissioners of these services.  Bearing in mind how many people are diagnosed as having diabetes and the costs of treatment, patient selection of those people who stand to benefit from these grafts will be important.

Citation and Funding

Santema TB, Poyck PP, Ubbink DT. Skin grafting and tissue replacement for treating foot ulcers in people with diabetes. Cochrane Database Syst Rev. 2016;2:CD011255.

The project was funded by the National Institute for Health Research via Cochrane Infrastructure funding to Cochrane Wounds.

Bibliography

NICE. Diabetic foot problems: prevention and management. NG19. London. National Institute for Health and Care Excellence; 2015.

NHS Choices. How to look after your feet if you have diabetes. [internet]. Leeds: NHS Choices; 2015.

Skin grafting and tissue replacement for treating foot ulcers in people with diabetes

Published on 13 February 2016

Santema, T. B.,Poyck, P. P.,Ubbink, D. T.

Cochrane Database Syst Rev Volume 2 , 2016

BACKGROUND: Foot ulceration is a major problem in people with diabetes and is the leading cause of hospitalisation and limb amputations. Skin grafts and tissue replacements can be used to reconstruct skin defects for people with diabetic foot ulcers in addition to providing them with standard care. Skin substitutes can consist of bioengineered or artificial skin, autografts (taken from the patient), allografts (taken from another person) or xenografts (taken from animals). OBJECTIVES: To determine the benefits and harms of skin grafting and tissue replacement for treating foot ulcers in people with diabetes. SEARCH METHODS: In April 2015 we searched: The Cochrane Wounds Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library); Ovid MEDLINE; Ovid MEDLINE (In-Process & Other Non-Indexed Citations); Ovid EMBASE and EBSCO CINAHL. We also searched clinical trial registries to identify ongoing studies. We did not apply restrictions to language, date of publication or study setting. SELECTION CRITERIA: Randomised clinical trials (RCTs) of skin grafts or tissue replacements for treating foot ulcers in people with diabetes. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed the quality of the included studies. MAIN RESULTS: We included seventeen studies with a total of 1655 randomised participants in this review. Risk of bias was variable among studies. Blinding of participants, personnel and outcome assessment was not possible in most trials because of obvious differences between the treatments. The lack of a blinded outcome assessor may have caused detection bias when ulcer healing was assessed. However, possible detection bias is hard to prevent due to the nature of the skin replacement products we assessed, and the fact that they are easily recognisable. Strikingly, nearly all studies (15/17) reported industry involvement; at least one of the authors was connected to a commercial organisation or the study was funded by a commercial organisation. In addition, the funnel plot for assessing risk of bias appeared to be asymmetrical; suggesting that small studies with 'negative' results are less likely to be published.Thirteen of the studies included in this review compared a skin graft or tissue replacement with standard care. Four studies compared two grafts or tissue replacements with each other. When we pooled the results of all the individual studies, the skin grafts and tissue replacement products that were used in the trials increased the healing rate of foot ulcers in patients with diabetes compared to standard care (risk ratio (RR) 1.55, 95% confidence interval (CI) 1.30 to 1.85, low quality of evidence). However, the strength of effect was variable depending on the specific product that was used (e.g. EpiFix(R) RR 11.08, 95% CI 1.69 to 72.82 and OrCel(R) RR 1.75, 95% CI 0.61 to 5.05). Based on the four included studies that directly compared two products, no specific type of skin graft or tissue replacement showed a superior effect on ulcer healing over another type of skin graft or tissue replacement.Sixteen of the included studies reported on adverse events in various ways. No study reported a statistically significant difference in the occurrence of adverse events between the intervention and the control group.Only two of the included studies reported on total incidence of lower limb amputations. We found fewer amputations in the experimental group compared with the standard care group when we pooled the results of these two studies, although the absolute risk reduction for amputation was small (RR 0.43, 95% CI 0.23 to 0.81; risk difference (RD) -0.06, 95% CI -0.10 to -0.01, very low quality of evidence). AUTHORS' CONCLUSIONS: Based on the studies included in this review, the overall therapeutic effect of skin grafts and tissue replacements used in conjunction with standard care shows an increase in the healing rate of foot ulcers and slightly fewer amputations in people with diabetes compared with standard care alone. However, the data available to us was insufficient for us to draw conclusions on the effectiveness of different types of skin grafts or tissue replacement therapies. In addition, evidence of long term effectiveness is lacking and cost-effectiveness is uncertain.

A diabetic foot ulcer was defined in the review as a wound of full thickness (into the subcutaneous tissue, the innermost layer of the skin) below the ankle, or as a lesion of the foot penetrating through the dermis (the inner layer of the skin), in people with type 1 or type 2 diabetes.

A foot ulcer is defined by NICE as a localised injury to the skin/and or underlying tissue, below the ankle, in a person with diabetes.

Skin grafts and tissue replacements (skin substitutes) can be categorised as:

  • autografts (taken from the patient); where the skin is taken and placed directly in the bed of the target ulcer (e.g. split-skin or full-thickness skin for pinch or mesh grafts).
  • allografts (taken from one person and given to another person) and xenografts (taken from animals); where skin is taken from other humans or animals with similar skin structure, placed directly in the bed of the target ulcer.
  • bioengineered tissue or artificial skin; where skin replacement products are created in a laboratory from cultures of skin components and cells (e.g. fibroblasts or keratinocytes) and then placed in the bed of the target ulcer.

Expert commentary

People living with diabetes have about a 15% lifetime risk of developing a foot ulcer. These take several weeks to heal, however, a third of ulcers never heal, recur in a year, or, sadly, lead to an amputation. This diabetic complication comes at a huge economic cost to patients and the NHS. The associated physical and emotional burden is also immense. To date, skin grafting and tissue replacement have not had a strong evidence-base. As a practising consultant in diabetes, I am always interested in effective therapies for patients and this study highlights that further research in this area is warranted.

Dr Mujahid Saeed, Consultant Physician in Diabetes at Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust

Expert commentary

Skin grafting is often avoided in diabetic foot ulceration in the belief that benefits in terms of healing or amputations are marginal. In this Cochrane review, Trientje et al analysed 17 studies and concluded that there was modest benefit from skin grafting compared to standard care in terms of increased rates of healing (RR 1.55) and marginal benefit on amputation rates in two studies reporting this outcome.

The quality of the studies was generally low. Outcome assessment was unblinded, most trials were industry sponsored and an analysis suggested that negative studies were less likely to be published.

Professor Simon Heller, Professor of Clinical Diabetes, Director of R&D, Sheffield Teaching Hospitals Foundation Trust