Reduction of body iron stores and cardiovascular outcomes

February 13, 2007

The reduction of body iron stores through phlebotomy (blood removal) in patients with peripheral artery disease (PAD) does not appear to decrease the risk of death plus nonfatal cardiovascular events, according to a study published in the February 14 issue of JAMA.

PAD is a partial or total blockage of an artery, usually one leading to a leg or an arm. According to background information in the article, "accumulation of iron in excess of physiologic requirements has been implicated in the risk of several chronic diseases through increased iron-catalyzed free radical-mediated oxidative stress. Common diseases of aging that have been attributed to this mechanism include cardiovascular disease and cancer." The authors cite the "iron-heart" hypothesis of atherosclerotic cardiovascular disease to explain the age-related increase in myocardial infarction (MI) [heart attack] in women following menopause. Men have increasing levels of iron from childhood to late teens and their rates of MI increase earlier as compared to women.

Leo R. Zacharski, M.D., from the VA Medical Center, White River Junction, VT, and colleagues conducted a multicenter, randomized controlled clinical trial from May 1, 1999 and April 30, 2005 based on the Iron (Fe) and Atherosclerosis Study (FeAST), a pilot study that demonstrated the accuracy of a formula for calculating the amount of blood required to be removed to achieve the desired iron (ferritin) reduction safely and without causing iron deficiency. Patients with symptomatic PAD were assigned to a control group (n = 641) or to a group undergoing reduction of iron stores by phlebotomy with removal of defined volumes of blood at six-month intervals (n=636).

"There were no significant differences between treatment groups for the primary (all-cause death) or secondary (death plus nonfatal MI and stroke) study end points," the authors report. "All-cause deaths occurred in 148 patients (23 percent) in the control group and in 125 (20 percent) in the iron-reduction group. Death plus nonfatal myocardial infarction and stroke occurred in 205 patients (32 percent) in the control group and in 180 (28 percent) in the iron-reduction group." The researchers also examined whether effects of iron reduction differed across subgroups. They found apparent improvement with iron reduction among younger patients, those without diabetes and in smokers.

In conclusion the authors write, "The FeAST data show that it should be possible to test definitively whether controlling iron levels may reduce disease risk. Additional research is needed to further define ferrotoxic diseases, stratify risk reduction with intervention, and clarify mechanisms, particularly in younger patients."
-end-
(JAMA. 2007;297: 603-610. Available pre-embargo to the media at www.jamamedia.org.) Editor's Note: This study was funded by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development Clinical Science Research & Development Service. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Editorial: The Iron-Heart Hypothesis

In an accompanying editorial Frank B. Hu, M.D., Ph.D., from the Harvard School of Public Health, Boston, writes that results from this first randomized controlled clinical trial assessing iron-store reduction have been eagerly awaited to test the hypothesis that iron depletion through phlebotomy or other means can lower the risk for coronary heart disease (CHD).

"The results from this well-designed and executed trial generate more questions than answers." Dr. Hu questions whether the study was adequately powered, whether the study patients were a suitable population and whether the findings can be generalized to healthy individuals.

"Like any other theory in cardiovascular medicine, the iron-heart hypothesis will undergo many 'trials and tribulations' before it is proven or refuted. Fortunately, it is not necessary to wait for additional data to implement effective strategies that can prevent coronary arteries from getting 'rusty.' Even though the question of whether reduced iron stores and CHD risk are causally linked remains unanswered, there is solid evidence that regular exercise and maintaining a healthy weight can reduce both iron stores and risk of CHD." (JAMA. 2007;297:639-641. Available pre-embargo to the media at www.jamamedia.org) Editor's Note: No financial disclosures reported.

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