based on the iron (fe) and atherosclerosis study (feast)

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Based on the Iron (Fe) and Atherosclerosis Study (FeAST)

Based on the Iron (Fe) and Atherosclerosis Study (FeAST)

Leo R. Zacharski, MD; Bruce K. Chow, MS; Leo R. Zacharski, MD; Bruce K. Chow, MS; Paula S. Howes, MS, APRN; Galina Shamayeva, MS;Paula S. Howes, MS, APRN; Galina Shamayeva, MS;

John A. Baron, MD; Ronald L. Dalman, MD; John A. Baron, MD; Ronald L. Dalman, MD; David J. Malenka, MD; C. Keith Ozaki, MD; David J. Malenka, MD; C. Keith Ozaki, MD;

and Philip W. Lavori, PhDand Philip W. Lavori, PhD

Published in The Journal of the American Medical Association Published in The Journal of the American Medical Association

February 14, 2007February 14, 2007

Reduction of Iron Stores and Cardiovascular Outcomes in Patients with Peripheral Arterial Disease A Randomized Controlled Trial

Reduction of Iron Stores and Cardiovascular Outcomes in Patients with Peripheral Arterial Disease A Randomized Controlled Trial


FeAST Trial: BackgroundFeAST Trial: Background

• Accumulation of iron in excess of physiologic Accumulation of iron in excess of physiologic requirements has been implicated in risk of requirements has been implicated in risk of cardiovascular disease because of increased iron-cardiovascular disease because of increased iron-catalyzed free radical-mediated oxidative stress.catalyzed free radical-mediated oxidative stress.

• The objective of this study was to test the The objective of this study was to test the hypothesis that reducing body iron stores through hypothesis that reducing body iron stores through phlebotomy will influence outcomes in a cohort of phlebotomy will influence outcomes in a cohort of patients with symptomatic peripheral arterial patients with symptomatic peripheral arterial disease (PAD).disease (PAD).

• Accumulation of iron in excess of physiologic Accumulation of iron in excess of physiologic requirements has been implicated in risk of requirements has been implicated in risk of cardiovascular disease because of increased iron-cardiovascular disease because of increased iron-catalyzed free radical-mediated oxidative stress.catalyzed free radical-mediated oxidative stress.

• The objective of this study was to test the The objective of this study was to test the hypothesis that reducing body iron stores through hypothesis that reducing body iron stores through phlebotomy will influence outcomes in a cohort of phlebotomy will influence outcomes in a cohort of patients with symptomatic peripheral arterial patients with symptomatic peripheral arterial disease (PAD).disease (PAD).

Zacharski et al. JAMA; 2007 Feb. 297(6): 603-10.Zacharski et al. JAMA; 2007 Feb. 297(6): 603-10.


FeAST Trial: Study DesignFeAST Trial: Study Design

Primary Endpoint: All-cause mortalityPrimary Endpoint: All-cause mortality Secondary Endpoint: Death plus nonfatal myocardial infarction and Secondary Endpoint: Death plus nonfatal myocardial infarction and

strokestroke

Primary Endpoint: All-cause mortalityPrimary Endpoint: All-cause mortality Secondary Endpoint: Death plus nonfatal myocardial infarction and Secondary Endpoint: Death plus nonfatal myocardial infarction and

strokestroke

Control Groupn=641

Control Groupn=641

Iron-Reduction Group*n=636

Iron-Reduction Group*n=636

1277 patients with symptomatic but stable PAD Multicenter. Randomized. Controlled. Single-Blinded. Analysis by intent-to-treat.

Patients were stratified by hospital, age, and baseline smoking status, diagnosis of diabetes mellitus, ratio of high-density to low-density lipoprotein cholesterol level, and ferritin level.

Excluding those with conditions likely to cause acute-phase increase of the ferritin level or with a diagnosis of visceral malignancy within the preceding 5 years

1277 patients with symptomatic but stable PAD Multicenter. Randomized. Controlled. Single-Blinded. Analysis by intent-to-treat.

Patients were stratified by hospital, age, and baseline smoking status, diagnosis of diabetes mellitus, ratio of high-density to low-density lipoprotein cholesterol level, and ferritin level.

Excluding those with conditions likely to cause acute-phase increase of the ferritin level or with a diagnosis of visceral malignancy within the preceding 5 years

RR


* Phlebotomy reduced iron stores with removal of defined volumes of blood at 6 mo. intervals

Up to 3.5 years follow-upUp to 3.5 years follow-up


OutcomeOutcome Total Total (n=1277)(n=1277)

Control Control (n=641)(n=641)

Iron Iron ReductionReduction

(n=636)(n=636)HR (95% CI)HR (95% CI) P P

valuevalue

Primary Primary EndpointEndpoint 273 (21.4)273 (21.4) 148 (23.1)148 (23.1) 125 (19.7)125 (19.7) 0.85 (0.67-1.08)0.85 (0.67-1.08) 0.170.17

Secondary Secondary EndpointEndpoint 385 (30.1)385 (30.1) 205 (32)205 (32) 180 (28.3)180 (28.3) 0.88 (0.72-1.07)0.88 (0.72-1.07) 0.200.20

MIMI 119 (9.3)119 (9.3) 58 (9)58 (9) 61 (9.6)61 (9.6) 1.01 (0.70-1.47)1.01 (0.70-1.47) 0.950.95

StrokeStroke 61 (4.8)61 (4.8) 29 (4.5)29 (4.5) 32 (5)32 (5) 1.22 (0.71-2.10)1.22 (0.71-2.10) 0.460.46

FeAST Trial: Primary and Secondary Outcome EventsFeAST Trial: Primary and Secondary Outcome Events


Abbreviations: CI, confidence interval; HR, hazard ratio; MI, myocardial infarctionAbbreviations: CI, confidence interval; HR, hazard ratio; MI, myocardial infarction

Comparison of Control and Iron-Reduction Groups for Primary (All-Cause Comparison of Control and Iron-Reduction Groups for Primary (All-Cause Mortality) and Secondary (Death Plus Nonfatal MI and Stroke) Outcome EventsMortality) and Secondary (Death Plus Nonfatal MI and Stroke) Outcome Events


FeAST Trial: Kaplan-Meir Analysis of Primary Endpoint (All-Cause Mortality)

FeAST Trial: Kaplan-Meir Analysis of Primary Endpoint (All-Cause Mortality)

• No statistically No statistically significant significant differences differences between between treatment treatment groups was groups was observed for the observed for the primary primary endpoint of all-endpoint of all-cause mortality cause mortality (HR 0.85; 95% CI (HR 0.85; 95% CI 0.67-1.08; 0.67-1.08; p=0.17).p=0.17).



FeAST Trial: Kaplan-Meir Analysis of Secondary Endpoint (Death Plus Nonfatal MI, or Stroke)

FeAST Trial: Kaplan-Meir Analysis of Secondary Endpoint (Death Plus Nonfatal MI, or Stroke)

• There were no statistically There were no statistically significant differences significant differences between treatment groups between treatment groups for the secondary for the secondary endpoint (HR 0.88; 95% CI endpoint (HR 0.88; 95% CI 0.72-1.07; p=0.20).0.72-1.07; p=0.20).

• Neither the cumulative Neither the cumulative incidence nor the time to incidence nor the time to occurrence of other occurrence of other nonfatal peripheral, nonfatal peripheral, coronary, and cerebral coronary, and cerebral vascular events during vascular events during the follow-up differed the follow-up differed between groups.between groups.



FeAST Trial: LimitationsFeAST Trial: Limitations

• Because of lower than expected accrual, the study Because of lower than expected accrual, the study was underpowered overall and particularly was underpowered overall and particularly underpowered to definitively assess outcomes in underpowered to definitively assess outcomes in younger patients and smokers.younger patients and smokers.

• This study was single-blinded, and primary and This study was single-blinded, and primary and secondary endpoints were adjudicated by a secondary endpoints were adjudicated by a committee external to the study; nonetheless, committee external to the study; nonetheless, concerns remain about possible bias, particularly in concerns remain about possible bias, particularly in subgroup analyses.subgroup analyses.

• Because of lower than expected accrual, the study Because of lower than expected accrual, the study was underpowered overall and particularly was underpowered overall and particularly underpowered to definitively assess outcomes in underpowered to definitively assess outcomes in younger patients and smokers.younger patients and smokers.

• This study was single-blinded, and primary and This study was single-blinded, and primary and secondary endpoints were adjudicated by a secondary endpoints were adjudicated by a committee external to the study; nonetheless, committee external to the study; nonetheless, concerns remain about possible bias, particularly in concerns remain about possible bias, particularly in subgroup analyses.subgroup analyses.



FeAST Trial: Limitations (cont.)FeAST Trial: Limitations (cont.)

• Patients with very high ferritin levels were Patients with very high ferritin levels were excluded from the study, and the efficacy of iron excluded from the study, and the efficacy of iron reduction in individuals with extreme levels of reduction in individuals with extreme levels of iron stores is unknown.iron stores is unknown.

• Patients with very high ferritin levels were Patients with very high ferritin levels were excluded from the study, and the efficacy of iron excluded from the study, and the efficacy of iron reduction in individuals with extreme levels of reduction in individuals with extreme levels of iron stores is unknown.iron stores is unknown.



FeAST Trial: SummaryFeAST Trial: Summary

• Preplanned analyses of the primary (all-cause Preplanned analyses of the primary (all-cause mortality) and the secondary (death plus nonfatal MI mortality) and the secondary (death plus nonfatal MI and stroke) endpoints performed on the entire study and stroke) endpoints performed on the entire study cohort showed no effect of iron reduction.cohort showed no effect of iron reduction.

• However, there was a significant interaction with However, there was a significant interaction with age (1of 5 prespecified biological stratifying factors), age (1of 5 prespecified biological stratifying factors), suggesting that a beneficial effect might exist in suggesting that a beneficial effect might exist in younger patients, and observation that coincides younger patients, and observation that coincides with findings of others.with findings of others.

• Preplanned analyses of the primary (all-cause Preplanned analyses of the primary (all-cause mortality) and the secondary (death plus nonfatal MI mortality) and the secondary (death plus nonfatal MI and stroke) endpoints performed on the entire study and stroke) endpoints performed on the entire study cohort showed no effect of iron reduction.cohort showed no effect of iron reduction.

• However, there was a significant interaction with However, there was a significant interaction with age (1of 5 prespecified biological stratifying factors), age (1of 5 prespecified biological stratifying factors), suggesting that a beneficial effect might exist in suggesting that a beneficial effect might exist in younger patients, and observation that coincides younger patients, and observation that coincides with findings of others.with findings of others.



FeAST Trial: Summary (cont.)FeAST Trial: Summary (cont.)

• The FeAST data show that it should be possible to The FeAST data show that it should be possible to test definitively whether controlling iron levels may test definitively whether controlling iron levels may reduce disease risk and additional research is reduce disease risk and additional research is needed to further define ferrotoxic diseases, needed to further define ferrotoxic diseases, stratifying risk reduction with intervention, and clarify stratifying risk reduction with intervention, and clarify mechanisms, especially in younger patients.mechanisms, especially in younger patients.

• The FeAST data show that it should be possible to The FeAST data show that it should be possible to test definitively whether controlling iron levels may test definitively whether controlling iron levels may reduce disease risk and additional research is reduce disease risk and additional research is needed to further define ferrotoxic diseases, needed to further define ferrotoxic diseases, stratifying risk reduction with intervention, and clarify stratifying risk reduction with intervention, and clarify mechanisms, especially in younger patients.mechanisms, especially in younger patients.


based on the iron (fe) and atherosclerosis study (feast)

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