FeAST Study Elucidates Health Benefits of Iron Reduction

By Bruce Jancin

< previous article | Table of Contents | next article >

DENVER — The mechanism by which increased stored bodily iron raises the risks of both cardiovascular events and cancer in patients with peripheral artery disease appears to involve iron-catalyzed oxidative stress as reflected in elevated inflammatory cytokines and biomarkers, Dr. Ralph G. DePalma said at the Vascular Annual Meeting.

He presented a new prespecified substudy of the Iron (Fe) and Atherosclerosis Study (FeAST), a multicenter single-blind trial in which 1,277 cancer-free patients with advanced stable peripheral artery disease (PAD) were randomized to calibrated reduction of iron stores by phlebotomy or to a control group.

The FeAST hypothesis was that accumulated bodily iron in excess of physiologic requirements increases risks of cancer and cardiovascular disease, and that reducing iron stores by phlebotomy without causing anemia would favorably influence clinical outcomes. This indeed proved to be the case, noted Dr. DePalma, national director of surgery in the Department of Veterans Affairs Central Office, Washington, D.C.

During a mean 4.5 years of prospective follow-up at 24 participating VA hospitals, patients in the phlebotomy group were 35% less likely than controls to develop a new visceral cancer. Moreover, among patients diagnosed with visceral cancer, those in the phlebotomy group were 61% less likely to die of cancer than were controls with cancer. Mean serum ferritin levels in PAD patients who developed cancer were significantly higher than in those who remained cancer-free, by a margin of 127 to 76 ng/mL (J. Natl. Cancer Inst. 2008;100:996-1,002).

The effect of reducing iron stores on cardiovascular outcomes was more convoluted. In the full FeAST cohort, with a mean age of 67 years at entry, no significant differences were found between treatment arms for the primary study end point of all-cause mortality or the secondary end point of death plus nonfatal myocardial infarction and stroke. But that’s only part of the story.

In a preplanned analysis based on age as a continuous variable, a nonlinear interaction between iron reduction and the primary and secondary study end points was seen. Patients in the youngest age quartile—that is, those aged 43-61—who were assigned to iron reduction had significant 53% and 59% reductions in all-cause mortality and death plus nonfatal MI and stroke, respectively (JAMA 2007;297:603-10).

Dr. DePalma’s new substudy involved 100 FeAST participants in whom blood levels of several substances were measured every 6 months during follow-up: interleukin-6, -2, and -10; tumor necrosis factor-alpha receptors 1 and 2; and high-sensitivity C-reactive protein.

Mean serum ferritin in the 77 survivors was 83.6 ng/mL, compared with 132.5 ng/mL in the 23 nonsurvivors. The key finding was that the higher ferritin levels in the nonsurvivors were significantly correlated with increased levels of interleukin-6, TNF-alpha receptor 2, and CRP.

“I believe that the ferritin level stimulates IL-6, which is a ubiquitous inflammatory cytokine made by almost every tissue in the body. The elevated ferritin provokes an inflammatory response, which in turn determines what happens at the level of the plaque,” the surgeon explained.

Excess bodily iron could be the missing link that helps explain the imperfect correlation between serum lipids and cardiovascular events. “We all know perfectly well that a lot of patients have unstable plaques and big-time complications while their lipids are relatively normal,” he observed.

In all, 53 participants were on statin therapy at baseline, and another 31 started on it during follow-up. In a multivariate analysis, statin therapy resulted in a mean 29 ng/mL reduction in serum ferritin independent of phlebotomy. “This has important implications in terms of statins’ pleotropic actions,” Dr. DePalma noted.

Although he said that further studies are needed to better define the role of bodily iron reduction in the risks of cardiovascular disease and cancer, he added that FeAST has several clinical implications: Perhaps ferritin and IL-6 levels should be routinely monitored as cancer and cardiovascular disease risk factors. Consideration also should be given to frequent blood donation by men and nonmenstruating women, he continued. And reduced dietary iron intake by less consumption of red meat and iron-fortified foods may be appropriate.

FeAST was funded by the Department of Veterans Affairs. Dr. DePalma reported having no financial conflicts of interest.

< previous article | Table of Contents | next article >

Society for Vascular Surgery - 633 N. St. Clair, 24th Floor; Chicago, IL 60611; Phone: 312-334-2300 or 800-258-7188; Fax: 312-334-2320; Email: vascular@vascularsociety.org
© 2010 VascularWeb. All rights reserved. Use of the VascularWeb site constitutes acceptance of all of the policies, rules and regulations for the site.