Statin therapy for venous ulcers

Dear Editor, The recent paper by Evangelista et al.1 seems to offer the promise of an inexpensive, readily available, easy to administer and highly efficacious adjunctive therapy for the treatment of chronic venous leg ulcers. We congratulate the authors on this very provocative study in which subjects were randomized to receive either simvastatin 40 mg daily or a placebo pill, in addition to standard compression therapy. As with any surprisingly positive finding, the potential benefit of added simvastatin will require independent confirmation, which should address some potentially important methodological issues. Firstly, this was a small single-centre trial. Regulatory agencies require multicentre trials for confirmation of efficacy in order to prevent unintentional or conscious bias, outlier outcomes or other idiosyncratic site effects from significantly influencing overall results. A single-centre study has none of these safeguards in place and therefore can only be considered exploratory. Secondly, it would be difficult to imagine more favourable outcomes than those achieved in this trial. The authors report healing rates of 67% at 10 weeks for ulcers > 20 cm2 (> 5 cm in diameter) and 100% for ulcers ≤ 20 cm2. This result is compared with the placebo group where 0% and 50% achieved closure, respectively. These results are particularly surprising when one considers that these ulcers were not small and not young; the mean size for ulcers that closed was 12 cm2 and 31 cm2 for placebo and simvastatin groups with average chronicity of 2·4 years and 3·3 years, respectively. According to Margolis et al.,2 a wound > 10 cm2 and > 12 months old has only a 22% chance of healing after 24 weeks of good therapy with compression. If one compares the outcomes achieved for the placebo group with those from other studies with a compression-only group, it is apparent that the proportion healed is unusually high. Kirsner et al.3 reported 46% healed at 12 weeks for ulcers treated with four-layer compression. Although this seems similar to the 50% reported for the smaller ulcers (≤ 20 cm2) in the Evangelista et al. study, these ulcers were all < 12 cm2 (mean = 5·6 cm2) and ≤ 2 years old. As Evangelista et al. point out, larger longer-duration ulcers are more difficult to heal. Why were these large, long-duration ulcers healed with such comparative facility? It is possible that this study represented the first application of good care (i.e. consistent, good-quality compression, infection control, control of oedema). The study did not employ a run-in period to exclude those who would heal under standard care alone. It is also not clear from their paper whether subjects were required to be either statin naive, or to have discontinued prestudy statin usage and undergone a ‘washout’. This is important because subjects with hypercholesterolaemia were allowed to enrol. While the number of affected subjects is not given, it would be reasonable to assume based on previous work4 that at least 12–20% had serum cholesterol of ≥ 240 mg dL−1 and would be categorized as having hypercholesterolaemia. If those subjects with ‘high-borderline’ serum cholesterol (200–239 mg dL−1) and ≥ 2 risk factors are included, it is likely to be closer to 30% of subjects.4 Presumably, most (if not all) subjects were under statin treatment prior to the study. Were subjects allowed to continue taking their prestudy statins or were they required to discontinue use? Allowing subjects to continue these medications would introduce several difficulties, including nonstandardized dosing in the active treatment group and a serious confounding variable for those randomized to the placebo group. The alternative, requiring cessation of statins before enrolling, would present challenges, particularly for those randomized to the placebo group. From a practical standpoint it would also put a serious limitation on the generalizability of these results as statins are in widespread common usage, particularly in this target population. Moreover, a subject undergoing chronic statin therapy who develops a venous ulcer would seem to be in some sense a ‘nonresponder’ to statin treatment, at least in regard to venous ulcers. From our own phase II trial comparing HP802-247 with compression alone,3 we know that of those subjects enrolling who were concomitantly undergoing statin therapy (n = 48, mean duration prestudy = 50·5 months), the overall healing rate at 12 weeks was only modestly higher than for those not on a statin (65% vs. 59%, not significant). If those subjects who were randomized to compression only and not treated with HP802-247 are considered, the difference is even smaller (50% vs. 45%, not significant). Several other important factors affecting healing were identified including ulcer area, chronicity and bacterial load.5 An inexpensive, highly efficacious, adjunctive treatment for venous leg ulcers, which could be administered as a once-daily tablet, is surely a very exciting prospect. Confirmation will require replicating these results in larger multicentre studies with appropriate inclusion and exclusion criteria, study design and complete transparency of these key trial design components.