Protease-modulating matrix treatments for healing venous leg ulcers

Review question

We reviewed the evidence about the effects of treatments designed to lower the levels of protease in venous leg ulcers. Protease is an enzyme, a chemical produced by the body. High levels of protease in a wound are thought to slow down wound healing. We wanted to find out if treatments that remove protease from wounds could help venous leg ulcers to heal more quickly, and if these treatments were harmful in any way.


Venous leg ulcers are open skin wounds on the lower leg that can last weeks, months or even years. Leg ulcers can be painful, may become infected, and may affect mobility and quality of life. In 2012 in the UK, it cost about GBP 1700 per year to treat each person with an open venous leg ulcer.

The usual treatment for venous leg ulcers is compression therapy (for example, compression bandages), but even this does not work for everyone (about a third of people still have wounds that have not healed after six months). Therefore, we need to try additional treatments, and various dressings have been used alongside compression therapy. One of these is a 'protease-modulating matrix' (PMM) type of dressing. Research suggests that wounds are slow to heal when there are high levels of a substance called 'protease'. The PMM dressing is designed to remove these proteases from wound fluid, and this is expected to help the wound heal.

In this study, we investigated whether there is any evidence that PMM dressings heal leg ulcers more quickly than other types of dressings.

Study characteristics

In September 2016 we searched for as many relevant studies as we could find that had a reliable design (randomised controlled trials) and had compared PMM treatments with other treatments for venous leg ulcers. We found 12 studies involving a total of 784 people. Ten studies gave results we could use and all treatments were dressings. All these studies gave all the participants compression therapy as well as the dressings. Most of the people in the trials had wounds that were not getting better or had been there a long time.

Key results

Findings from four trials are unclear as to whether there is a benefit of PMM dressings on venous ulcer healing compared with other dressings. Five trials reported on wound side effects and their results are unclear as to whether there is a difference in rates of side effects between PMM dressings and other dressings. It is also unclear whether PMM dressings result in decreases in the amount of saline used and the time taken during dressing changes, and whether there is an effect on total costs.

Certainty of the evidence
Overall, the certainty of the evidence was judged to be low: most studies we found were small and could have been better conducted, so it was difficult to be sure how meaningful the results were. The next step would be to do more research of better quality to see whether PMM dressings do heal venous ulcers more quickly than other dressings.

This plain language summary is up to date as of September 2016.

Authors' conclusions: 

The evidence is generally of low certainty, particularly because of risk of bias and imprecision of effects. Within these limitations, we are unclear whether PMM dressing regimens influence venous ulcer healing relative to dressing regimens without PMM activity. It is also unclear whether there is a difference in rates of adverse events between PMM and non-PMM treatments. It is uncertain whether either resource use (products and staff time) or total costs associated with PMM dressing regimens are different from those for non-PMM dressing regimens. More research is needed to clarify the impact of PMM treatments on venous ulcer healing.

Read the full abstract...

Venous leg ulcers (VLUs) are open skin wounds on the lower leg that occur because of poor blood flow in the veins of the leg; leg ulcers can last from weeks to years, and are both painful and costly. Prevalence in the UK is about 2.9 cases per 10,000 people. First-line treatment for VLUs is compression therapy, but around 60% of people have unhealed ulcers after 12 weeks' treatment and about 40% after 24 weeks; therefore, there is scope for further improvement. Limited evidence suggests non-healing leg ulcers may have persisting elevated levels of proteases, which is thought to deter the later stages of healing; thus, timely protease-modulating matrix (PMM) treatments may improve healing by physically removing proteases from the wound fluid.


To determine the effects of protease-modulating matrix (PMM) treatments on the healing of venous leg ulcers, in people managed in any care setting.

Search strategy: 

In September 2016 we searched: the Cochrane Wounds Specialised Register; CENTRAL; Ovid MEDLINE; Ovid MEDLINE (In-Process & Other Non-Indexed Citations); Ovid Embase and EBSCO CINAHL Plus. We also searched clinical trials registries for ongoing and unpublished studies, and scanned reference lists of relevant included studies as well as reviews, meta-analyses and health technology reports to identify additional studies. There were no restrictions with respect to language, date of publication or study setting.

Selection criteria: 

We searched for published or unpublished randomised controlled trials (RCTs) that evaluated PMM treatments for VLUs. We defined PMM treatments as those with a purposeful intent of reducing proteases. Wound healing was the primary endpoint.

Data collection and analysis: 

Two review authors independently performed study selection, risk of bias assessment and data extraction.

Main results: 

We included 12 studies (784 participants) in this review; sample sizes ranged from 10 to 187 participants (median 56.5). One study had three arms that were all relevant to this review and all the other studies had two arms. One study was a within-participant comparison. All studies were industry funded. Two studies provided unpublished data for healing.

Nine of the included studies compared PMM treatments with other treatments and reported results for the primary outcomes. All treatments were dressings. All studies also gave the participants compression bandaging. Seven of these studies were in participants described as having 'non-responsive' or 'hard-to-heal' ulcers. Results, reported at short, medium and long durations and as time-to-event data, are summarised for the comparison of any dressing regimen incorporating PMM versus any other dressing regimen. The majority of the evidence was of low or very low certainty, and was mainly downgraded for risk of bias and imprecision.

It is uncertain whether PMM dressing regimens heal VLUs quicker than non-PMM dressing regimens (low-certainty evidence from 1 trial with 100 participants) (HR 1.21, 95% CI 0.74 to 1.97).

In the short term (four to eight weeks) it is unclear whether there is a difference between PMM dressing regimens and non-PMM dressing regimens in the probability of healing (very low-certainty evidence, 2 trials involving 207 participants).

In the medium term (12 weeks), it is unclear whether PMM dressing regimens increase the probability of healing compared with non-PMM dressing regimens (low-certainty evidence from 4 trials with 192 participants) (RR 1.28, 95% CI 0.95 to 1.71). Over the longer term (6 months), it is also unclear whether there is a difference between PMM dressing regimens and non-PMM dressing regimens in the probability of healing (low certainty evidence, 1 trial, 100 participants) (RR 1.06, 95% CI 0.80 to 1.41).

It is uncertain whether there is a difference in adverse events between PMM dressing regimens and non-PMM dressing regimens (low-certainty evidence from 5 trials, 363 participants) (RR 1.03, 95% CI 0.75 to 1.42). It is also unclear whether resource use is lower for PMM dressing regimens (low-certainty evidence, 1 trial involving 73 participants), or whether mean total costs in a German healthcare setting are different (low-certainty evidence, 1 trial in 187 participants). One cost-effectiveness analysis was not included because effectiveness was not based on complete healing.