Summary of Results of a Controlled Clinical Trial of Iron Reduction
We searched for adverse effects of excess iron in a group of patients that already had atherosclerosis (vascular disease) but not previous malignancy. Patients studied were given standard of care and then randomly assigned to a control group (no iron reduction) or to have their iron reduced by blood drawing to levels found normally in menstruating women. Such a study was possible because: (a) there is a simple blood test for the amount of iron in the body, the ferritin level; (b) we know the level of iron (ferritin) in menstruating women that corresponds to low risk; (c) excessive iron can be removed safely by measured blood drawing; and (d) patients could be followed for several years to determine whether they were better with lower iron levels.
Investment of time and resources in conducting a controlled clinical trial was considered worthwhile because, if benefits of iron reduction were confirmed, it should be possible to: (a) define what levels of iron were safe; (b) monitor iron levels during health in a manner comparable to testing for cholesterol and (c) control iron accumulation with aging by proper diet without the need for expensive drugs or sophisticated technology. Efforts were rewarded by improved patient outcome with iron reduction as described in the scientific narrative that follows.
THE IRON AND ATHEROSCLEROSIS (FeAST) STUDY: A 24 hospital, 6 year, randomized, controlled, single-blinded clinical trial of measured iron reduction was conducted in 1,277 patients (primarily male veterans) aged 43 to 87 with vascular disease but no prior malignancy. The hypothesis was that reduction of body iron stores to levels characteristic of childhood and pre-menopausal women (without causing iron deficiency) would improve clinical outcomes. Patients were randomized to control versus iron reduction by calibrated phlebotomy and followed for a mean of 4.5 years per patient.
Results
Malignancy: New visceral malignancy was recorded prospectively by organ site and histology with cause-specific mortality including death from cancer. Iron reduction resulted in a 37% lower cancer risk (p = 0.025), reduced cancer risk on Kaplan-Meier (p = 0.036) and Cumulative Incidence analysis (p = 0.019), and reduced cancer-specific (p = 0.003) and all-cause mortality in patients diagnosed with cancer (p = 0.009). Reduced risk of lung, colorectal, head and neck, and prostate cancers could not be explained in any other way. Risk reduction correlated with compliance with intervention and minimal cancer risk occurred with ferritin levels below about 50 ng/ml (levels that are normal in children and pre-menopausal women). Benefits of iron reduction were observed within 6 months of randomization regardless of age. These results correspond to pre-clinical data and support findings showing significantly reduced risk of hepatocellular carcinoma in patients with hepatitis C treated with phlebotomy to reduce iron compared to a comparable cohort not iron-reduced.
Vascular disease: While comparison of all treated and untreated patients did not show improvement in outcomes, improved outcomes by age quartile were statistically significant for the secondary endpoint (death plus non-fatal myocardial infarction and stroke, p for interaction = 0.004). A steep age-related benefit from iron reduction was observed in the youngest age quartile for both primary (all cause mortality, p = 0.02) and secondary (death plus non-fatal myocardial infarction and stroke, p < 0.001) endpoints. Age analyzed as a continuous variable was significantly associated with improved outcome for both the primary (p = 0.04) and secondary (p = 0.001) endpoints.
INTERPRETATION: These unprecedented results correspond to data from basic and clinical cohort studies, and support the concept that uncompensated free radical damage catalyzed by excess iron may contribute to cancer and vascular disease. Iron reduction appeared to be vaso-protective if implemented relatively early. The youngest quartile of patients in this study, age 43 to 61, corresponds to the age of transition from pre- to post-menopausal status in women. These results suggest that iron reduction may be primarily a means of disease prevention rather than treatment althought the latter is not ruled out.
REFERENCES:
- Zacharski LR, Chow BK, Howes PS, Shamayeva G, Baron JA, Dalman RL, Malenka DJ, Ozaki CK, Lavori PW. Reducing iron stores lowers cancer risk in patients with peripheral arterial disease. Blood 110: 783a, November 16, 2007, abstract 2665.
- Zacharski LR, Chow BK, Howes PS, Shamayeva G, Baron JA, Dalman RL, Malenka DJ, Ozaki CK, Lavori PW. Decreased cancer risk after iron reduction in patients with peripheral arterial disease: results from a randomized trial. J Nat’l Cancer Inst, in press, 2008.
- Zacharski LR, Chow BK, Howes PS, Shamayeva G, Baron JA, Dalman RL, Malenka DJ, Ozaki CK, Lavori PW. Reduction of Iron Stores and Cardiovascular Outcomes in Patients with Peripheral Arterial Disease. JAMA 2007;297:603-10.
- Zacharski LR, Chow BK. Iron reduction and cardiovascular outcomes. Letter-to-editor, JAMA 2007;297:2075-6.
