Does the Reduction of Total Body Iron Storage (TBIS) Alter Mortality in a Population of Patients With Advanced PVD? (FeAST)

January 18, 2013 updated by: US Department of Veterans Affairs

CSP #410 - The Iron (Fe) and Atherosclerosis Study (FeAST)

Veterans Affairs Cooperative Study #410, The Iron and Atherosclerosis Trial, FeAST, a 24-hospital prospective randomized single-blinded clinical trial of graded iron reduction was conducted between May 1, 1999 and April 30, 2005, and has now been completed. A total of 1,277 primarily male participants with peripheral arterial disease were entered. The primary outcome was all cause mortality and the secondary outcome combined death plus non-fatal myocardial infarction (MI) and stroke.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

The original JAMA abstract (2007) reported no overall effect of iron reduction intervention by phlebotomy. However, pre-planned analyses according to randomization variables at entry, including age and ferritin level, were described in the JAMA paper showing improved outcomes with iron reduction with younger age by quartile for the secondary endpoint (p for interaction =0.004) and also suggested a favorable effect in smokers (p for interaction 0.006). Age analyzed as a continuous variable using the Cox proportional hazards regression model and log relative hazard plots revealed that age interacted nonlinearly with treatment in both primary (p=0.04) and secondary (p<0.001) outcomes. The Cox model showed improved primary (HR 0.47, 95% CI 0.24-0.90, p=0.02) and secondary (HR 0.41, 95% CI 0.24-0.68, p<0.001) outcomes in youngest age quartile participants (age 43 to 61) randomized to iron reduction versus control. Thus, an interaction between age and level of body iron may have masked beneficial effects of iron reduction in the overall cohort.

Detailed analysis of the effect of age and ferritin levels published in the American Heart Journal confirmed that iron reduction significantly improved primary and secondary outcomes in youngest age quartile participants, as described above, displayed as Kaplan-Meier plots. Mean follow-up ferritin levels (MFFL) declined with increasing entry age in controls. Older age (p=0.026) and higher ferritin (p<0.001) at entry predicted poorer compliance with phlebotomy and rising MFFL in iron reduction participants. Iron reduction intervention also produced greater ferritin reduction in younger participants. Improved outcomes with lower MFFL occurred in iron reduction patients for both primary (HR 1.11, 95% CI 1.01-1.23, p=0.028) and secondary (HR 1.10, 95% CI 1.0-1.20, p=0.044) outcomes, and for the entire cohort: primary outcome (HR 1.11, 95% CI 1.01-1.23, p=0.037). 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=0.003; secondary outcome HR 1.22, 95% CI 0.99-1.50, p=0.067.

Thus, lower iron burden predicted improved outcomes overall and was enhanced with iron reduction by phlebotomy. Controlling iron burden may improve survival, and prevent or delay non-fatal myocardial infarction and stroke. These findings warrant confirmation using further studies.

A possible effect of iron levels on risk of cancer as well as vascular disease was recognized at trial inception. Participants with visceral malignancy within the preceding five years were excluded from this study. However, information was collected prospectively on the occurrence of new visceral malignancy and cause-specific mortality including death due to cancer. As reported in the Journal of the National Cancer Institute, a new visceral malignancy was diagnosed during follow-up in 60 control and 38 iron reduction participants, a 37% (HR 0.63; 95% CI = 0.42 - 0.95, p = 0.026) decrease in risk with iron reduction. Reduced cancer risk with iron reduction was confirmed on time-to-event analysis (HR = 0.65; 95% CI = 0.43 - 0.97, p = 0.036). Reduced risk was observed for several common tumor types. Iron reduction participants had lower cancer - specific mortality and lower all-cause mortality in participants diagnosed with cancer (HR = 0.39; 95% CI = 0.21 - 0.72, p = 0.003 and HR = 0.49; 95% CI = 0.29 - 0.83, p = 0.009 respectively), compared to control participants. MFFL during follow-up in those participants randomized to iron reduction who developed cancer were comparable to levels in control participants (t93 = 0.8, p = 0.428). The MFFL in participants randomized to iron reduction developing cancer was 127 ng/mL, 95% CI = 71.2 - 183.0. The MFFL was significantly lower in participants not developing cancer, 76.4 ng/mL, 95% CI = 71.4 - 81.4, p = 0.017). Participants randomized to iron reduction developing cancer appeared to be relatively non-compliant with intervention.

Analysis of data from the FeAST study continues to delineate interactions between iron status and smoking, lipid levels and statin use, diabetes and race. It has been shown that ferritin levels ranging from about 70 to 79 ng/mL are associated with lower mortality and levels of inflammatory markers. Statin use, while not a randomization variable, has been monitored and shown to relate to lower ferritin levels.

Study Type

Interventional

Enrollment (Actual)

1277

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Puerto Rico
      • San Juan, Puerto Rico, 00921
        • VA Medical Center, San Juan
  • United States
    • Alabama
      • Birmingham, Alabama, United States, 35233
        • VA Medical Center, Birmingham
    • Arkansas
      • No. Little Rock, Arkansas, United States, 72114-1706
        • Central Arkansas VHS Eugene J. Towbin Healthcare Ctr, Little Rock
    • California
      • Long Beach, California, United States, 90822
        • VA Medical Center, Long Beach
      • Palo Alto, California, United States, 94304-1290
        • VA Palo Alto Health Care System
    • Connecticut
      • West Haven, Connecticut, United States, 06516
        • VA Connecticut Health Care System (West Haven)
    • Florida
      • Gainesville, Florida, United States, 32608
        • North Florida/South Georgia Veterans Health System
      • Tampa, Florida, United States, 33612
        • James A. Haley Veterans Hospital, Tampa
    • Illinois
      • Hines, Illinois, United States, 60141-5000
        • Edward Hines, Jr. VA Hospital
    • Kentucky
      • Lexington, Kentucky, United States, 40502
        • VA Medical Center, Lexington
      • Louisville, Kentucky, United States, 40206
        • VA Medical Center, Louisville
    • Massachusetts
      • Boston, Massachusetts, United States, 02130
        • VA Medical Center, Jamaica Plain Campus
    • Nevada
      • Reno, Nevada, United States, 89502
        • VA Sierra Nevada Health Care System
    • New York
      • Albany, New York, United States, 12208
        • VA Stratton Medical Center, Albany
      • New York, New York, United States, 10010
        • New York Harbor HCS
    • North Carolina
      • Durham, North Carolina, United States, 27705
        • VA Medical Center, Durham
    • Ohio
      • Cleveland, Ohio, United States, 44106
        • VA Medical Center, Cleveland
    • Pennsylvania
      • Pittsburgh, Pennsylvania, United States, 15240
        • VA Pittsburgh Health Care System
    • Rhode Island
      • Providence, Rhode Island, United States, 02908
        • VA Medical Center, Providence
    • Texas
      • Houston, Texas, United States, 77030
        • Michael E. DeBakey VA Medical Center (152)
    • Utah
      • Salt Lake City, Utah, United States, 84148
        • VA Salt Lake City Health Care System, Salt Lake City
    • Vermont
      • White River Junction, Vermont, United States, 05009-0001
        • VA Medical & Regional Office Center, White River
    • Wisconsin
      • Madison, Wisconsin, United States, 53705
        • Wlliam S. Middleton Memorial Veterans Hospital, Madison
      • Milwaukee, Wisconsin, United States, 53295-1000
        • Zablocki VA Medical Center, Milwaukee

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

21 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. Males over the age of 21 years and post menopausal (either natural or surgical) females with a diagnosis of intermittent claudication who are not scheduled for major surgery and who can give informed consent will be entered.
  2. Hematocrit of 30% or greater for females and 35% or greater for males, normal liver function, serum creatinine less than 4 mg/dl. Patients with mild anemia and mild creatinine elevation will be entered (provided the anemia is not due to Fe deficiency found on screening laboratory tests) because such findings are commonly present chronically in PVD.
  3. Absence of a disturbance in Fe balance (e.g. hemosiderosis from any cause, hemochromatosis, atransferrinemia, PNH, Fe deficiency)
  4. Absence for at least six months of a disease that has caused bleeding (e.g. peptic ulcer, inflammatory bowel disease, hemorrhagic diathesis )
  5. Absence of associated neoplasm other than epithelial ( non-melanoma) tumors of skin or other co-morbid condition that is expected to be fatal within one year.
  6. Absence of an associated obvious inflammatory disorder (e.g. infection, connective tis-sue disease) capable of elevating ferritin levels acutely.
  7. Patients will not be excluded on the basis of either the existence or severity of either coronary- or cerebrovascular disease, medication use including non-steroidal anti-inflammatory drugs and anticoagulants, coronary angiographic findings, previous history of or possible future need for angioplasty or coronary bypass surgery, or elevated blood pressure.
  8. Patients must agree to not take any Fe supplements or vitamins while on study.

Exclusion Criteria:

1. Patients must have at least one lower extremity and must not be on another experimental therapy protocol for atherosclerotic vascular disease.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: DIAGNOSTIC
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: SINGLE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
OTHER: Arm 1
Usual care plus Ferritin reduction to a calculated nadir of 25 ng/mL by phlebotomy
Procedure: Ferritin reduction to 25 ng/ml by phlebotomy
NO_INTERVENTION: Arm 2
Usual care only; no intervention control

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Mortality
Time Frame: The minimum follow-up was 3.5 years and maximum follow-up was 6 years
The primary objective of this study is to evaluate the effectiveness of a reduction of Total Body Iron Stores (TBIS) in decreasing the rate of all cause mortality in patients with peripheral vascular disease (PVD).
The minimum follow-up was 3.5 years and maximum follow-up was 6 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

US Department of Veterans Affairs

Investigators

  • Study Chair: Zacharski R. Leo, VA Medical & Regional Office Center, White River

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

May 1, 1999

Primary Completion (ACTUAL)

April 1, 2005

Study Completion (ACTUAL)

September 1, 2005

Study Registration Dates

First Submitted

March 19, 2002

First Submitted That Met QC Criteria

March 19, 2002

First Posted (ESTIMATE)

March 20, 2002

Study Record Updates

Last Update Posted (ESTIMATE)

January 21, 2013

Last Update Submitted That Met QC Criteria

January 18, 2013

Last Verified

January 1, 2013

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 410

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Peripheral Vascular Diseases

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Saudi Arabia

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

3
Subscribe