Pharmacological adjuncts for chronic venous ulcer healing

Dear Editor, The problem of whether some systemic pharmacological adjuncts confer significant benefit to the healing process of chronic venous ulcers has been widely discussed in several narrative surveys and in a number of consensus conferences, systematic reviews and meta-analyses. The most relevant are the extensive and detailed survey by Nelson 1 and the multi-society consensus on the management of venous ulcers just published. 2 These outstanding analyses of the available data showed that only a few oral agents have supporting evidence as most likely effective adjuvants in this condition: namely pen-toxifylline, micronized flavonoids and sulodexide, a natural sulphated glycosaminoglycan with a number of biological and clinical activities on endothelial cell functions. 3 Just before the publication of the recent multi-society consensus, 2 a systematic review appeared in your Journal reconsidering most of the agents previously surveyed by other groups. 4 The authors concluded that, among the many systemic pharmacological agents studied to manage venous leg ulcers, pentoxifylline ''.. . is currently the only drug that has promising evidence to support its use.'' One of us, coordinator of the largest trial on sulo-dexide in venous ulcers, 5 that was preceded by a pilot study with similar design and equivalent results, 6 noticed with great surprise that, although each of the two trials resulted largely positive (OR for complete healing at 60 days: 2.04 (1.13–3.69) and 2.45 (1.0–5.67), respectively), the authors of the review stated that ''Pooled results from both these trials, however, have shown that sulodexide in comparison to placebo may not have beneficial effects as an adjunct to ulcer healing in addition to conventional therapy (RR 0.16 95% CI 0.06 to 0.26).'' We wondered whether there was any logical or statistical explanation for the fact that pooling the data of two similar studies, both significantly positive for the same drug, the result could be inverted, reversing the benefit shown in both individual studies into a pooled loss of benefit. Since a similar phenomenon (the Simpson's paradox) may rarely occur under special conditions, 7 we reexamined the statistics underlying the conclusion of the published review. Unfortunately, it was immediately apparent that the authors of the review made a critical and macroscopic statistical error. The figures given in the Varatharajan's paper on the pooled data from the two sulodexide trials were the absolute risk difference (RD: 0.16 (0.06; 0.26)), that they reported as relative risk (or risk ratio; RR), whereas the …