Medicine, Nursing and Health Sciences

Dr Carolina Weller NHMRC Research, Evaluation and Development FellowSenior Research FellowSchool of Public Health & Preventive Medicine

Low dose aspirin as an adjunct to 3L compression in healing chronic venous leg ulcers: what is the evidence?

Venous Leg Ulcers [VLU]

• most common cause of lower limb ulceration • prevalence 1.65 to 1.74%• common in adults aged ≥ 65 • growing in younger population

Passman J. Vasc. Surg. 2010

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OBESITY

expected to lead to a diabetic epidemic and reduction in life expectancy–cardiovascular-specific mortality rates ↓–life expectancy ↑

more people will be living with VLU and experiencing recurrence in future

The Australian Diabetes, Obesity and Lifestyle study 2013

VLU: a worldwide problem

~ 400,000 Australians [2010]

Almost $3 billion per year

UK National Healthcosts £2-3 billion annually

loss of 2 million working days per year

United States America

>650,000 patients treated/year

$1.3 billion per year

Europe (EWMA) predicted

€23 billion over next 10 years

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inflammation• inflammatory leucocyte response causes

cell dysfunction

• cellular and tissue dysfunction in vascular changes (varicose veins)

dermal changes

• oedema, hyperpigmentation, venous eczema, lipidermatosclerosis and ulceration

Chronic venous hypertension pathophysiology

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Best practice

• Compression increases healing rates

• Multi-component compression more effective than single

• Multi-component with an elastic bandage better

• Lacking agreement on optimum compression level

O'Meara et al. Compression for venous leg ulcers. Cochrane Database of Systematic Reviews. 2012Battler et al. Compression therapy in venous disease. Phlebology. 2008Partsch et al. Classification of compression bandages: practical aspects. Dermatol Surg. 2008Weller et al. Sub-bandage pressure difference of tubular form and short-stretch bandages: in-vivo RCT 2011

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Current treatment

• Compression bandage Limitations

• 40 - 70% will heal by 12 weeks with adherence to compression

• Many remain unhealed after two years

• Even if healed - VLU recurrence 30 -80% within 3 months post

healing

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Challenges to healingPatient factors

• Comorbidities • Socioeconomic• Adherence to compression

Wound factors• Size, duration• Wound bed condition

Resource factors• access to right care at right time • costs, reimbursement

Health care factors• Varied clinical skill and knowledge • Variable treatment • Variable referral time• No way to monitor patterns and quality of care

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Department of Health Aged Care Branch Falls Prevention Network

Meeting

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Identified theme Comments Recommendation

Reduce cost of compression bandages

‘Cost of stockings prohibitive for some patients

‘funding of dressing and bandage’‘lower cost of compression stockings and socks’

Improved application technique to enhance comfort

‘I realise compression is corner stone of treatment for venous ulcers but not many will tolerate much compression’

‘Simpler bandaging’ ‘bandages that patients will be willing to keep on and can afford’

Improved access to treatment including home visits and improved access to ABPI

‘increasing access to ABI for patients’‘Elderly find it difficult to attend clinic regularly due to transport problems and are unable to bandage legs by self’‘proper treatment-based on guidelines’

‘improve access to ABPI for patients’‘training for PNs’

Improved access to information by PNs and GPs

‘improved education for PNs and GPs re wound management’‘Improved knowledge of assessment and diagnosis’‘Confidence in recommending treatment’

‘need simple guidelines for GPs for leg ulcer management’

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Poor healing outcomes may be due to systemic inflammation

Impact of aspirin on VLU healing

Layton et al. Randomised trial of oral aspirin for chronic venous leg ulcers.

The Lancet 1994

del Río Solá et al. Influence of Aspirin Therapy in the Ulcer Associated With Chronic Venous Insufficiency.

Ann. Vasc. Surg. 2012

Layton 1994

n=20 (12 men)mean age 64 years (range 46–85) Intervention: ‘300mg aspirin daily plus compression’ or ‘placebo plus compression’ - four month period

•increased rate of healing in aspirin group compared with placebo (p<0.01)

•38% aspirin group healied compared with 0% placebo group (p<0.007)

•reduction in wound size, 52% aspirin group vs 26% of placebo (p<0.007)

•mechanism by which aspirin improved healing or its effects on recurrence was not investigated

Layton et al. Randomised trial of oral aspirin for chronic venous leg ulcers. The Lancet 1994

del Río Solá 2012

n= 51 (22 men)mean age 60 years (range 36–86) Intervention: ‘300mg aspirin daily plus compression’ or ‘only compression’ Follow up: five months to measure VLU recurrence

time to heal reduced by 46% average 10 week reduction in healing time in aspirin group

no statistical difference in complete healing (21/28 Aspirin and 17/23 control) but average time to healing was shorter in aspirin group

average time to recurrence aspirin group was 39 days [SD 6.0] control group 16.3 days [SD 7.5] (p= 0.007)

del Río Solá et al. Influence of Aspirin Therapy in the Ulcer Associated With Chronic Venous Insufficiency. Annual of Vascular Surgery 2012

How aspirin might work

– inhibits platelet aggregation– acts as an inhibitor of cyclooxygenase– results in the inhibition of the biosynthesis of

prostaglandins

– precise mechanism unclear

ASPirin in Venous Leg Ulcer study

Clinical effectiveness of aspirin as an adjunct to 3-Layer compression therapy in healing chronic venous leg ulcers: a randomised double-blinded placebo-controlled trial [the ASPiVLU study]

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3L compression research translation into clinical practice across clinical settings

Community General practice Home nursing servicesSub acute careHospitals

Interventions

Active Arm: 300 mg enteric coated aspirin daily for 12 months

Placebo Arm: enteric coated placebo daily for 12 months

All participants will receive 3L compression until healedHealed participants will be measured for compression hosiery and measured for recurrence during study period

Compression will consist of a padding layer and 3 layers of tubular compression (3L)

Weller et al. Wound Repair Regen. 2012Weller et al. et al. 3VSS2008. BMCTrials 2010

• Primary aim – to determine if aspirin as an adjunct to compression

improves healing

• Secondary aim– to determine the effects of aspirin on the rate of

target ulcer recurrence

Additional measures– serum inflammatory markers– adverse events– hospitalisations

Participants268 recruits6 speciality wound clinics• 3 Victoria

» Austin, Sunshine, Caulfield

• 1 New South Wales » Westmead

• 1 Queensland » Prince Charles

• 1 Tasmania » UTAS

Funding acknowledgments

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NHMRC Public Health Fellowship [2012-2016]

NHMRC Project Grant APP1069329 [2014-2017]

Further information

med-aspivlu@monash.edu

ASPiVLU web page

carolina.weller@monash.edu

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� Males and females

� Age 40 years and older

� target ulcer

– separated from other ulcers by at least 1 cm– present for at least six weeks– area ≥1 cm2 to ≤ 20 cm2

� ABPI measure of ≥ 0.7 mmHg to exclude significant arterial insufficiency

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Inclusion criteria

Exclusion criteria � Unable or unwilling to wear compression

� Unable to comply with study treatment.

� Aspirin intolerance

� Aspirin use for any reason within the last 3 months

� Anticoagulation therapy

� Bleeding disorder

� History of peptic ulcer, gastrointestinal bleeding or intracranial bleeding

� Severe liver disease

� Severe hypertension >180/110 mm Hg

� Undiagnosed anaemia

� Renal failure or severe renal impairment

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