Adjunctive aspirin for venous ulcer healing

Venous leg ulceration affects approximately 1% ¹ of the adult population and takes a median of three months to heal with four layer bandaging. ² Pharmacotherapy to aid healing has recently been reviewed^3,4 with only Pentoxifylline (a blood viscosity lowering agent, with vasodilator properties) demonstrating clinical benefit. ⁵ The recent National Institute for Health Research (NIHR) call (HTA no. 12/147) in the UK in 2012 for a randomised placebo controlled pilot study for adjunctive aspirin for venous ulcer healing with a minimum follow-up period of six months has raised a few eyebrows. Could a drug that has been superseded by clopidogrel as first-line treatment for ischaemic stroke and peripheral arterial disease according to NICE guidelines, ⁶ now find a role in the management of venous ulceration?

The scientific rationale for the use of aspirin is an irreversible cyclooxygenase-mediated reduction in PGE₂ and thromboxane A₂ – involved in inflammation and platelet aggregation, respectively.^7–9 Aspirin has been evaluated in three clinical studies in venous ulcer patients to date.

The seminal 1994 pilot randomised controlled trial ¹⁰ raised as many questions as answers. In this pragmatic, UK study, 20 patients with pure venous ulcers of >2 cm² for a mean duration of 10 years were randomised to class 3c compression bandages with either aspirin 300 mg or placebo once daily. Sixty percent of this patient cohort had multiple ulcers, all of which were evaluated. The primary outcome measure was total ulcer(s) surface area on the affected limb over four months. The study reported some unusual findings. First, no patients healed at four months in the control group, contrasting with results of subsequent trials. ² Second, 38% more ulcers healed in the aspirin group (four patients; p < 0.007; confidence intervals have not been stated), an impressive treatment effect. Yet it has taken 18 years for the NIHR to fund this trial, making some ask why the delay has occurred?

The same research group conducted a double-blind randomised placebo controlled study investigating the effect of aspirin in addition to standardised treatment with compression bandaging on haemostatic activity in the treatment of 20 patients with venous ulcers >2 cm² for a mean duration of 13.8 and 11.2 years in males and females, respectively. A shortened coagulation rate was found in patients in comparison to healthy controls but of pertinence to this editorial, an increased rate of ulcer healing (assessed by percentage reduction in ulcer size) occurred in patients receiving aspirin (47% of original ulcer size) compared with the placebo-treated group (69% of original ulcer size) at four months (p = 0.002). ¹¹

Despite reporting interesting findings, the numbers recruited in both these latter two studies are too small to reliably conclude on the effect of aspirin on the healing of venous ulceration.

A Spanish group in 2012 performed another randomised controlled pilot study. ¹² In this study, 51 patients were randomised to compression bandaging (40 mmHg) with or without aspirin 300 mg daily. There were methodological issues including a lack of placebo and no information regarding blinding. There was a reduction in average time to healing from 22 to 12 weeks with aspirin. On multivariate analysis, however, aspirin was not an independent predictor of healing (p = 0.315). In fact, only wound area at baseline predicted shorter time to healing.

Therefore, although beneficial effects for aspirin are claimed in three small studies, there is a clear rationale to settle this question once and for all. Investigators should, we recommend, use time to healing as a primary endpoint (as this is economically important), use a population with pure venous ulcers (in those with atherosclerosis aspirin may have a separate effect), use a placebo, blind the assessors and follow patients for a minimum of six months. Covariates to inform randomisation should include ulcer size, an important confounder. Additionally the Eschar trial showed that varicose vein surgery did not affect ulcer healing rates, but more recent studies have suggested that foam sclerotherapy has a beneficial effect. ¹³ In the NIHR trial, there is no plan at present to stratify for aspirin usage. The role of endovenous treatment on ulcer healing rates is yet unproven, hence the need for the NIHR-funded trial.

A recent Cochrane review on the use of Pentoxifylline for the treatment of venous ulcers included 12 randomised trials involving 864 participants and demonstrated that it is an effective adjunct to compression bandaging for the treatment of venous ulcers and may even be effective in the absence of compression bandaging. ⁵ If there is a similar benefit to Pentoxifylline, it is likely that aspirin would prove cost-effective as it costs 1 p/day (€0.01/$0.02) as opposed to 20 p/day (€0.23/$0.30). We wait with anticipation to see if aspirin can alter outcomes for our patients with venous ulceration.