Reduction of iron stores and clinical outcomes in peripheral arterial disease: outcome comparisons in smokers and non-smokers

Abstract

A prospective randomized trial suggested that iron (ferritin) reduction improved outcomes in smokers. The present study reanalyzed the trial results in smokers compared with non-smokers. Randomization of 1262 men with peripheral arterial disease (540 smokers and 722 non-smokers) to iron reduction (phlebotomy) or control groups permitted analysis of the effects of iron reduction and smoking on primary (all-cause mortality) and secondary (death plus non-fatal myocardial infarction or stroke) endpoints. Iron reduction resulted in significant improvement in the primary (hazard ratio [HR] 0.661, 95% confidence interval [CI] 0.45, 0.97; P = 0.036) and secondary (HR 0.64, 95% CI 0.46, 0.88; P = 0.006) endpoints compared with controls in smokers but not in non-smokers. Smokers required removal of a greater volume of blood to attain targeted ferritin reduction as compared with non-smokers (P = 0.003) and also exhibited differing characteristics from non-smokers, including significantly less statin use. Phlebotomy-related outcomes favored smokers over non-smokers. Biological linkages responsible for this unique effect offer promising lines for future iron reduction studies (ClinicalTrial.Gov Identifier: NCT00032357).

Racial Differences in Iron Measures and Outcomes Observed during an Iron Reduction Trial in Peripheral Arterial Disease

“…Analyses reported previously showed that significantly improved clinical outcomes with ferritin reduction in the entire cohort [13][14][15][16] were more pronounced based on compliance in age group 43-61 years 13 and in smokers. 16 Striking effects of statin administration on measures of iron status and ratios of cholesterol fractions were reported. 26,27 The present study explored possible racial differences in study parameters and outcomes that may help clarify the basis for racial disparities in health outcomes.…”

“…The Consort Diagram 14 and methodological details of study protocols, informed consent, randomization and intervention procedures, outcomes assessment, and study administration have been reported. [13][14][15][16]24,25 Enrolment regardless of age, sex, or race applied uniform randomization, intervention, and follow-up procedures. Analyses reported previously showed that significantly improved clinical outcomes with ferritin reduction in the entire cohort [13][14][15][16] were more pronounced based on compliance in age group 43-61 years 13 and in smokers.…”

“…Study design excluded individuals with an hematocrit less than 35%, a ferritin greater than 400ng/ mL, clinical conditions capable of causing an acute-phase elevation of ferritin levels, a diagnosis of visceral malignancy within the past five years and disorders of iron metabolism including iron deficiency. [13][14][15][16]24,25 All participants received standard of care treatment for PAD including statins introduced for PAD treatment during the trial. For participants randomized to iron reduction, the entry ferritin level, the preferred method for assessing body iron stores, 24,30,31 was used to calculate the amount of blood drawn to achieve the required decrement in serum ferritin [(initial ferritin-25)×10=mL of blood to be removed].…”

“…[9][10][11][12] A prospective randomized clinical trial of iron reduction by graded phlebotomy in individuals with advanced peripheral arterial disease (PAD) showed that lower follow-up levels of body iron represented by reduced serum ferritin levels were associated with significantly improved clinical outcomes particularly in younger age groups and in smokers. [13][14][15][16] Analysis of cross sectional data from this trial according to race showed that iron status, effects of iron reduction on health outcomes, and effects of statin administration on measures of iron status and ratios of cholesterol fractions differed strikingly between Black and White participants. We suggest that racial differences in iron status may contribute, along with other factors, to unfavorable health outcomes in African Americans.…”

Iron Reduction Benefits

“…7 Unequivocal benefits of iron reduction in younger individuals, in participants reaching ferritin levels below 70 ng/mL and in smokers now have been shown with reasonable degrees of certainty. 1,3,4,8 Current recommendations for expanded statin use in asymptomatic normolipidemic individuals 9-10 with a single risk factor for CVD raise provocative issues of cost and safety. [11][12][13] Statins are recommended for all patients with peripheral vascular disease and some consider their use essential.…”