Abstract & Commentary
Comment by Harold L. Karpman, MD, Clinical Professor of Medicine, UCLA School of Medicine, and Associate Editor, Internal Medicine Alert
Synopsis: In patients with vascular disease or diabetes mellitus, long-term vitamin E supplementation does not prevent cancer or major cardiovascular events and may increase the risk for heart failure.
Source: HOPE-TOO Trial Investigators. JAMA. 2005;293:1338-1347.
During the past 15 years, epidemiological, biological and experimental studies on atherosclerosis have supported the prevailing view that oxidation of low-density lipoprotein and certain other cellular targets may contribute significantly to both atherogenesis and carcinogenesis.1,2 Therefore, it would seem to follow that antioxidants would protect against atherosclerosis by limiting low-density lipoprotein oxidation in the arterial wall.3-5 As a result, the effectiveness of various antioxidant vitamins has been tested in 8 major trials with nearly 140,000 randomized participants. The data published from these trials have suggested that antioxidant vitamins were essentially of no benefit in preventing cardiovascular disease or cancer except in various subgroups such as patients with advanced renal failure undergoing hemodialysis6-8 or certain patients with macular degeneration.9
Because most of the prior clinical trials testing the effects of vitamin E and other antioxidant vitamins and/or their combinations on clinical manifestations of cardiovascular disease and cancer were only 3 to 6 years in length, the HOPE investigators10,11 extended the term of their original study which lasted 5½ years for another 4 years and reported the results of the HOPE-TOO trial in the March 16, 2005, issue of JAMA. The patients in this randomized, double-blind, placebo-controlled international trial numbered 3994 and were followed for a median duration of 7.0 years. Vitamin E supplementation in a dose of 400 IU given to patients with vascular disease or diabetes over the long term of this study was not found to prevent cancer or major cardiovascular events and, in fact, vitamin E administration actually appeared to increase the risk for developing congestive heart failure.
Comment
The HOPE-TOO trial results do not necessarily negate prevailing views that oxidation of low density lipoprotein and certain other cellular targets may contribute importantly to atherogenesis and carcinogenesis; however, the hope for therapeutic benefit from vitamin E and/or other antioxidant vitamins has now been clearly diminished by a compelling body of clinical trial evidence all of which have demonstrated little value of vitamin E administration in these areas of medicine. In fact, the HOPE-TOO trial results demonstrated that subjects receiving vitamin E were at a significantly increased risk of developing cardiac decompensation or of being hospitalized for heart failure and, in addition, the trial results revealed subtle but non-significant trends toward increased ischemic complications in patients with atherosclerosis. It should be noted that these heart failure findings were unexpected and were not previously noted in published results of other trials and, therefore, a meta-analysis may be necessary to determine if this was a finding specific only to the HOPE-TOO study. Although the precise explanation for these possibly harmful effects of vitamin E was not clear, it should be noted that these negative results were at least partially confirmed by a recent metaanalysis which reported an increase in mortality in trials using high-dose (ie, greater than or equal to 400 IU/d) vitamin E.12
In summary, it would now appear appropriate for physicians to avoid using vitamin E supplements in patients with cardiovascular disease or diabetes mellitus in order to avoid the potential for harm suggested by the findings of the HOPE-TOO study. Since, as indicated above, oxidation of low density lipoprotein and other cellular targets are almost certainly an important factor in the development of atherosclerosis and/or cancer, research will have to find other ways to control the effects of these oxidative processes other then the so-called antioxidant vitamins or approach the control of these disease processes with methods that are not involved with altering oxidative processes.
References
1. Stampfer MJ, et al. N Engl J Med. 1993;328: 1444-1449.
2. Rimm EB, et al. N Engl J Med. 1993;328:1450-1456.
3. Sparrow CP, et al. J Clin Invest. 1992;89:1885-1891.
4. Carew TE, et al. Proc Natl Acad Sci USA. 1987;84: 7725-7729.
5. Sasahara M, et al. J Clin Invest. 1994;94:155-164.
6. Lindner A, et al. N Engl J Med. 1974;290:697-701.
7. Giray B, et al. Clin Chim Acta. 2003;338:91-98.
8. Boaz M, et al. Lancet. 2000;356:1213-1218.
9. Age-related Eye Disease Study Research Group. Arch Ophthalmol. 2001;119:1417-1436.
10. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342:154-160.
11. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342:145-153.
12. Miller ER III, et al. Ann Intern Med. 2005;142:37-46.
In patients with vascular disease or diabetes mellitus, long-term vitamin E supplementation does not prevent cancer or major cardiovascular events and may increase the risk for heart failure.
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