Pharmacologic treatment of venous leg ulcers

In terms of prevalence, total cost and morbidity, venous leg ulcers are probably by far the most important type of ulcerations in the leg. The macrocirculatory defect leading to a raised ambulatory venous pressure is now accepted as a common initial pathologic pathway. Most current treatment modalities, such as surgery or external compression, are designed to control the macrovascular defect. However, it is the microcirculatory consequences of the venous hypertension that give rise to the trophic skin changes and ultimately to ulceration. At this microcirculatory level, pharmacotherapy may be a useful adjunct in the treatment of venous leg ulcers. The microcirculatory pathophysiologic changes include decreased fibrinolytic activity, elevated plasma fibrinogen, microcirculatory thrombi, and inappropriate activation of the white blood cells. The oxidative burst from the activated white cells probably plays a key role by releasing locally leukocyte-derived free radicals, proteolytic enzymes, cytokines, platelet-activating factor, and a number of other noxious mediators. An important additional component in recalcitrant venous ulcers is co-existing arterial disease, which is probably present in 15-20% of cases. Decreased arterial perfusion pressure will further aggravate the ischemic changes caused by the venous hypertension. Pentoxifylline downregulates leukocyte activation, reduces leukocyte adhesion, and also has fibrinolytic effects. A number of clinical studies have therefore been carried out to examine the clinical efficacy of pentoxifylline in treatment of venous leg ulcers. Probably the largest published placebo-controlled, double-blind randomized study was reported in 1990. In this study, 80 patients received either pentoxifylline 400 mg three times a day orally or matching placebo for 6 months or until their reference ulcer healed if this occurred sooner. Complete healing of the reference ulcer occurred in 23 of the 38 patients treated with pentoxifylline compared to 12 of the 42 patients treated with placebo. The odds ratio in favor of pentoxifylline was 1.81 (95 confidence intervals 1.20-2.71).