Letter by Violi and Pignatelli Regarding Article, “Effects of Random Allocation to Vitamin E Supplementation on the Occurrence of Venous Thromboembolism: Report From the Women’s Health Study”
To the Editor:
Vitamin E supplementation has been widely studied in interventional trials in patients with cardiovascular disease, but the results have been disappointing.1 These trials were planned on the assumption that vitamin E possesses antioxidant properties that may retard atherosclerosis. In the trial by Glynn et al,2 vitamin E supplementation was given to healthy women on the assumption that vitamin E possessed antithrombotic properties that could prevent the occurrence of venous thromboembolism. During a follow-up of 10 years, the trial demonstrated that vitamin E supplementation (600 IU every other day) reduced the risk of venous thromboembolism, indicating that it may have an antithrombotic effect in vivo; however, the underlying mechanism of this effect was not clarified. The authors report that vitamin E interferes with vitamin K–dependent clotting factor activation2 but fail to mention that, at concentrations achievable in the human circulation, vitamin E is also able to inhibit monocyte expression of tissue factor, a glycoprotein that converts factor X to Xa with a mechanism that may be dependent on its antioxidant properties.3 It is therefore possible that, in vivo, vitamin E may act at different steps of the coagulation cascade. This issue is of possible clinical relevance when one takes into account potential vitamin E interference with oral anticoagulants or antithrombotic drugs such as anti-Xa or thrombin inhibitors.
Another issue relates to the age of the population screened and its risk of venous thromboembolism. The trial included prevalently young women (≈60% were <50 years of age, and only 10% were >65 years of age). As mentioned by the authors, the risk of venous thromboembolism increases with advancing age, and in fact thromboembolism occurred more often in women >55 years of age than in those <55 years of age. Analysis of these 2 subgroups shows that the reduction of venous thromboembolism was weak (about 10%) in women <55 years but more marked (>25%) in those aged >55 years. This finding is consistent with the subgroup analysis indicating that vitamin E would be more effective in women at higher risk, such as those with a previous history of venous thromboembolism or with coexistent genetic disorders. Despite these considerations of potentially different effects of vitamin E in young and old women, we suggest that (1) the inclusion of a relatively low number of patients >65 years of age may have erased major advantage in the vitamin E-treated group, and (2) women <55 years of age receive only marginal benefit from vitamin E supplementation. These arguments may have an impact on clinical practice mainly by helping to avoid the indiscriminate use of vitamin E supplementation and thus preventing potential harmful effects.4
Glynn RJ, Ridker PM, Goldhaber SZ, Zee RY, Buring JE. Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism: report from the Women’s Health Study. Circulation. 2007; 116: 1497–1503.
Ferro D, Basili S, Praticó D, Iuliano L, FitzGerald GA, Violi F. Vitamin E reduces monocyte tissue factor expression in cirrhotic patients. Blood. 1999; 93: 2945–2950.