Oral aspirin for venous leg ulcers

Background
Venous leg ulcers (VLUs) are the most common type of leg ulcers (sores) and are caused by poor blood flow in the veins of the legs (chronic venous insufficiency). Chronic venous insufficiency leads to high blood pressure in the veins (venous hypertension), which triggers many alterations in the skin of the leg. Leg ulcers are the end stage of these alterations. VLUs can occur spontaneously or after minor trauma, they are often painful and produce heavy exudation (loss of fluid). VLUs are a major health problem because they are quite common, tend to become chronic (long-lasting) and also have a high tendency to recur. They affect older people more frequently, have high costs of care, and a high individual and social burden for those affected.

Compression therapy, in the form of a firm bandage over the leg, which aids the flow of blood in the veins, is a well-established treatment for VLUs. However, studies show that compression has only moderate effects on healing, with up to 50% of VLUs remaining unhealed after two years of compression, possibly due to a prolonged inflammation process. A better understanding of the degenerative changes in the skin of the leg in people with VLUs and the chronic inflammation process involved in them, has led researchers to test different medicines that could improve the treatment of this condition. Aspirin has some well-known properties including: pain relief (analgesic), reducing inflammation and fever, and stopping blood cells from clumping together, which prevents formation of blood clots. Aspirin therapy may improve time to healing and decrease the number of recurrent VLU episodes. If proved effective, the low cost of aspirin therapy as an adjunct to compression would make it an affordable preventive agent for people with VLUs in all countries.

Review question

What are the benefits and harms of oral aspirin on the healing and recurrence of venous leg ulcers.

What we found

We identified only two randomised controlled trials that compared oral aspirin (300mg daily) plus compression with compression and placebo, or compression alone. One study conducted in UK included 20 participants (ten in the aspirin group and ten in the control group) and followed people for four months. This trial reported that the ulcer area had reduced (by 6.5 cm², a 39.4% reduction) in the aspirin group compared with no reduction in ulcer area in the control group, and that a higher proportion of the ulcers (38%) in the aspirin group had completely healed compared with none in the control group. Recurrence was not investigated in this study. Another study conducted in Spain included 51 participants (23 in the aspirin group and 28 in the control group) and followed people until their ulcers had healed. The study reported that the average time for healing was 12 weeks in the aspirin group and 22 weeks in the control group, and that there was no real difference between the proportion of people with ulcers healed (17 (74%) out 23 people in the aspirin group and 21 (75%) out 28 people in the control group). The average time for recurrence was longer in the aspirin group (39 days) compared with (16.3 days) in group of compression alone. Adverse events were not reported in either trial.

We considered these two studies too small and low quality for us to draw definitive conclusions about the benefits and harms of oral aspirin on the healing and recurrence of venous leg ulcers. The UK study provides only limited data about the potential benefits of daily oral aspirin therapy with compression due to a small sample size of only 20 participants and short follow up. The Spanish study provides limited data on 51 participants comparing aspirin and compression to a control group. The fact that no information was reported regarding placebo in the control group means the estimate of effect is uncertain. Further high quality studies are needed in this area.

This plain language summary is up to date as of 27 May 2015.

Authors' conclusions: 

Low quality evidence from two trials indicate that there is currently insufficient evidence for us to draw definitive conclusions about the benefits and harms of oral aspirin on the healing and recurrence of venous leg ulcers. We downgraded the evidence to low quality due to potential selection bias and imprecision due to the small sample size. The small number of participants may have a hidden real benefit, or an increase in harm. Due to the lack of reliable evidence, we are unable to draw conclusions about the benefits and harms of oral daily aspirin as an adjunct to compression in VLU healing or recurrence. Further high quality studies are needed in this area.

Read the full abstract...
Background: 

Venous leg ulcers (VLUs) or varicose ulcers are the final stage of chronic venous insufficiency (CVI), and are the most common type of leg ulcer. The development of VLUs on ankles and lower legs can occur spontaneously or after minor trauma. The ulcers are often painful and exudative, healing is often protracted and recurrence is common. This cycle of healing and recurrence has a considerable impact on the health and quality of life of individuals, and healthcare and socioeconomic costs. VLUs are a common and costly problem worldwide; prevalence is estimated to be between 1.65% to 1.74% in the western world and is more common in adults aged 65 years and older. The main treatment for a VLU is a firm compression bandage. Compression assists by reducing venous hypertension, enhancing venous return and reducing peripheral oedema. However, studies show that it only has moderate effects on healing, with up to 50% of VLUs unhealed after two years of compression. Non-adherence may be the principal cause of these poor results, but presence of inflammation in people with CVI may be another factor, so a treatment that suppresses inflammation (healing ulcers more quickly) and reduces the frequency of ulcer recurrence (thereby prolonging time between recurrent episodes) would be an invaluable intervention to complement compression treatments. Oral aspirin may have a significant impact on VLU clinical practice worldwide. Evidence for the effectiveness of aspirin on ulcer healing and recurrence in high quality RCTs is currently lacking.

Objectives: 

To assess the benefits and harms of oral aspirin on the healing and recurrence of venous leg ulcers.

Search strategy: 

In May 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. Additional searches were made in trial registers and reference lists of relevant publications for published or ongoing trials. There were no language or publication date restrictions.

Selection criteria: 

We included randomised controlled trials (RCTs) that compared oral aspirin with placebo or no drug intervention (in the presence or absence of compression therapy) for treating people with venous leg ulcers. Our main outcomes were time to complete ulcer healing, rate of change in the area of the ulcer, proportion of ulcers healed in the trial period, major bleeding, pain, mortality, adverse events and ulcer recurrence (time for recurrence and proportion of recurrence).

Data collection and analysis: 

Two review authors independently selected studies for inclusion, extracted data, assessed the risk of bias of each included trial and assessed overall quality of evidence for the main outcomes in the 'Summary of findings' table.

Main results: 

The electronic search located 62 studies. We included two RCTs of oral aspirin (300 mg/daily) given in addition to compression compared with compression and placebo, or compression alone. To date, the impact of aspirin on VLUs has been examined by only two randomised clinical trials, both with a small number of participants. The first RCT was conducted in the United Kingdom (n=20) and reported that daily administration of aspirin (300mg) in addition to compression bandages increased both the rate of healing, and the number of participants healed when compared to placebo in addition to compression bandaging over a four month period. Thirty-eight per cent of the participants given aspirin reported complete healing compared with 0% in the placebo group . Improvement (assessed by reduction in wound size) occurred in 52% of the participants taking aspirin compared with 26% in those taking placebo). The study identified potential benefits of taking aspirin as an adjunct to compression but the sample size was small, and neither the mechanism by which aspirin improved healing nor its effects on recurrence were investigated.

In 2012 an RCT in Spain (n=51) compared daily administration of aspirin (300mg) in addition to compression bandages with compression alone over a five month period. There was little difference in complete healing rates between groups (21/28 aspirin and 17/23 compression bandages alone) but the average time to healing was shorter (12 weeks in the treated group vs 22 weeks in the compression only group) and the average time for recurrence was longer in the aspirin group (39 days: [SD 6.0] compared with 16.3 days [SD 7.5] in the compression only group). Although this trial provides some limited data about the potential use of aspirin therapy, the sample size (only 20 patients) was too small for us to draw meaningful conclusions. In addition, patients were only followed up for 4 months and no information on placebo was reported.

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