Published results from a controlled clinical trial in patients with peripheral arterial disease found improved outcomes with iron (ferritin) reduction among middle-aged subjects but not the entire cohort. The mechanism of the age-specific effect was explored.

Randomization to iron reduction (phlebotomy, n = 636) or control (n = 641) stratified by prognostic variables permitted analysis of effects of age and ferritin on primary (all-cause mortality) and secondary (death, nonfatal myocardial infarction, and stroke) outcomes.

Iron reduction improved outcomes in youngest age quartile patients (primary outcome hazard ratio [HR] 0.44, 95% CI 0.21-0.92, P = .028; secondary outcome HR 0.34, 95% CI 0.19-0.61, P < .001). Mean follow-up ferritin levels (MFFL) declined with increasing entry age in controls. Older age (P = .035) and higher ferritin (P < .001) at entry predicted poorer compliance with phlebotomy and rising MFFL in iron-reduction patients. Intervention produced greater ferritin reduction in younger patients. Improved outcomes with lower MFFL were found in iron-reduction patients (primary outcome HR 1.11, 95% CI 1.01-1.23, P = .028; secondary outcome HR 1.10, 95% CI 1.0-1.20, P = .044) and the entire cohort (primary outcome HR 1.11, 95% CI 1.01-1.23, P = .037). Improved outcomes occurred with MFFL below versus above the median of the entire cohort means (primary outcome HR 1.48, 95% CI 1.14-1.92, P = .003; secondary outcome HR 1.22, 95% CI 0.99-1.50, P = .067).

Lower iron burden predicted improved outcomes overall and was enhanced by phlebotomy. Controlling iron burden may improve survival and prevent or delay nonfatal myocardial infarction and stroke.