Effect of Reduction of Iron (Fe) Stores on Cardiovascular and Cancer Outcomes in Patients with Advanced Peripheral Arterial Disease (PAD): VA Cooperative Study #410, the Iron (Fe) and Atherosclerosis Study (FeAST).
Authors: Zacharski Leo R. , Chow Bruce , Howes Paula , Lavori Philip , Shamayeva Galina , Baron John , Dalman Ronald , Malenka David , Ozaki Keith 
Published: October 2019

Abstract
Background: Age-related accumulation of excess Fe has been implicated in risk of disease, including cardiovascular disease and malignancy, through Fe-catalyzed free radical-mediated mechanisms.
Methods: The effect of reducing body Fe stores through phlebotomy on disease risk and mortality was tested in a multi-center randomized, controlled, single-blinded clinical trial conducted between May 1, 1999 and April 30, 2005 in a cohort of 1,277 patients with symptomatic PAD. Patients with conditions likely to cause acute phase elevation of the ferritin level or with a diagnosis of visceral malignancy within the preceding five years were excluded. Patients were randomly assigned to control or reduction of Fe stores by graded phlebotomy (avoiding Fe deficiency) with stratification by hospital, age, baseline ferritin, diagnosis of diabetes mellitus, smoking status and HDL/LDL ratio. The primary outcome was all cause mortality; the secondary outcome was combined death plus non-fatal myocardial infarction and stroke. New non-fatal cardiovascular events and new disease diagnoses, including histologically confirmed visceral malignancy, were recorded during follow-up.
Results: There were no significant differences between Fe reduction and control groups for the primary (p=0.172) or secondary (p=0.202) study outcomes. The mean age at entry was 67 years. Patients in the youngest age quartile randomized to Fe reduction had a 53.6% reduction in the primary endpoint (p = 0.019) and a 57% reduction in the secondary endpoint (p <0.001) compared to control patients. Kaplan - Meier analysis of the secondary endpoint revealed a significantly reduced hazard ratio with Fe reduction that was graded in patients within the youngest age quartile (p <0.001) and that persisted after excluding patients dying of cancer (p = 0.007). Patients randomized to Fe reduction had a 36.7% lower risk of cancer occurrence (p = 0.023) and a 68.6% lower cancer mortality (p = 0.003) compared to control patients. Reduced cancer risk was observed for most tumor types and occurred over the entire patient age range.
Conclusions: Fe reduction in patients with symptomatic PAD did not confer an overall benefit in cardiovascular disease risk and mortality. Apparent improvement in cardiovascular outcomes with Fe reduction in the youngest age quartile suggests a role for Fe relatively early in the course of disease but confirmation in studies of specific patient subsets is needed. Fe reduction decreased cancer risk and mortality, an effect that was not age-related. Ferritin levels found commonly in adults are associated with disease risk while levels characteristic of childhood and pre-menopausal women (below about 80 ng/ml) are associated with reduced risk. These results suggest strategies for low-cost and non-toxic disease prevention and treatment through patient monitoring, selective and graded Fe reduction, and attention to optimal Fe nutrition.