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AtherosclerosisPhase 3FeASTNCT00032357

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

A Phase 3 study testing Ferritin reduction to 25 ng/ml by phlebotomy in people with Atherosclerosis and Intermittent Claudication, run by US Department of Veterans Affairs at 24 sites in 2 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

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. Read more about this study

Who is it for?
Ages 21 years and olderHealthy volunteers can take part
What is being tested?
Ferritin reduction to 25 ng/ml by phlebotomy
Type of treatment
Surgery or procedure
Could I receive a placebo?
No, everyone receives an active treatment
How many people
1,277 participants
Where
24 sitesin 2 countries
Study dates
May 1999to Sep 2005
Phase
Phase 3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 21 years and older
  • All sexes
  • Healthy volunteers accepted
  • Adult, Older adult

Who may be able to join

  • 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.
  • 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.
  • Absence of a disturbance in Fe balance (e.g. hemosiderosis from any cause, hemochromatosis, atransferrinemia, PNH, Fe deficiency)
  • Absence for at least six months of a disease that has caused bleeding (e.g. peptic ulcer, inflammatory bowel disease, hemorrhagic diathesis )
  • 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.
  • Absence of an associated obvious inflammatory disorder (e.g. infection, connective tis-sue disease) capable of elevating ferritin levels acutely.
  • 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.
  • Patients must agree to not take any Fe supplements or vitamins while on study.

Who cannot join

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

Trial locations and contacts

24 sites in 2 countries.

24 sites in 2 countries

United States23 sites

  • VA Stratton Medical Center, Albany

    Albany, New York, 12208

  • VA Medical Center, Birmingham

    Birmingham, Alabama, 35233

  • VA Medical Center, Jamaica Plain Campus

    Boston, Massachusetts, 02130

  • VA Medical Center, Cleveland

    Cleveland, Ohio, 44106

  • VA Medical Center, Durham

    Durham, North Carolina, 27705

  • North Florida/South Georgia Veterans Health System

    Gainesville, Florida, 32608

  • Edward Hines, Jr. VA Hospital

    Hines, Illinois, 60141-5000

  • Michael E. DeBakey VA Medical Center (152)

    Houston, Texas, 77030

  • VA Medical Center, Lexington

    Lexington, Kentucky, 40502

  • VA Medical Center, Long Beach

    Long Beach, California, 90822

  • VA Medical Center, Louisville

    Louisville, Kentucky, 40206

  • Wlliam S. Middleton Memorial Veterans Hospital, Madison

    Madison, Wisconsin, 53705

  • Zablocki VA Medical Center, Milwaukee

    Milwaukee, Wisconsin, 53295-1000

  • New York Harbor HCS

    New York, New York, 10010

  • Central Arkansas VHS Eugene J. Towbin Healthcare Ctr, Little Rock

    No. Little Rock, Arkansas, 72114-1706

  • VA Palo Alto Health Care System

    Palo Alto, California, 94304-1290

  • VA Pittsburgh Health Care System

    Pittsburgh, Pennsylvania, 15240

  • VA Medical Center, Providence

    Providence, Rhode Island, 02908

  • VA Sierra Nevada Health Care System

    Reno, Nevada, 89502

  • VA Salt Lake City Health Care System, Salt Lake City

    Salt Lake City, Utah, 84148

  • James A. Haley Veterans Hospital, Tampa

    Tampa, Florida, 33612

  • VA Connecticut Health Care System (West Haven)

    West Haven, Connecticut, 06516

  • VA Medical & Regional Office Center, White River

    White River Junction, Vermont, 05009-0001

Other trials in United States

Puerto Rico1 site

  • VA Medical Center, San Juan

    San Juan, 00921

Other trials in Puerto Rico

About this study

Official title: 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.

Read the 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.

Being tested
Ferritin reduction to 25 ng/ml by phlebotomy
Keywords
Ferritin reduction, Peripheral Vascular Disease (PVD), phlebotomy, Reduction of Total Body Iron Storage(TBIS), Total Body Iron Storage(TBIS)
Medical subject headings
Atherosclerosis, Intermittent Claudication, Peripheral Vascular Diseases

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Ferritin reduction to 25 ng/ml by phlebotomyProcedure or surgery

Study groups in NCT00032357
Study groupRoleWhat they receive
Arm 1OtherUsual care plus Ferritin reduction to a calculated nadir of 25 ng/mL by phlebotomy
Receives: Procedure: Ferritin reduction to 25 ng/ml by phlebotomy
Arm 2No interventionUsual care only; no intervention control

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Mortality

    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).

    Measured: The minimum follow-up was 3.5 years and maximum follow-up was 6 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted20 Mar 2002 (estimated)
  2. Study startMay 1999
  3. Primary completionApr 2005
  4. Study completionSep 2005

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Diagnosis
Allocation
Randomised
Intervention model
Parallel groups
Masking
Single blind
Who is masked
Outcomes assessor
Enrolment
1,277 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00032357
Sponsor's protocol ID
410
Acronym
FeAST
Status last verified
Jan 2013
First submitted
19 Mar 2002
Last updated
21 Jan 2013
Results posted
No
Data monitoring committee
Yes

Publications

  • DePalma RG, Hayes VW, Cafferata HT, Mohammadpour HA, Chow BK, Zacharski LR, Hall MR. Cytokine signatures in atherosclerotic claudicants. J Surg Res. 2003 May 15;111(2):215-21. doi: 10.1016/s0022-4804(03)00075-1.

    PubMed 12850465

  • DePalma RG, Hayes VW, May PE, Cafferata HT, Mohammadpour HA, Brigg LA, Chow BK, Shamayeva G, Zacharski LR. Statins and biomarkers in claudicants with peripheral arterial disease: cross-sectional study. Vascular. 2006 Jul-Aug;14(4):193-200. doi: 10.2310/6670.2006.00039.

    PubMed 17026909

  • 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: a randomized controlled trial. JAMA. 2007 Feb 14;297(6):603-10. doi: 10.1001/jama.297.6.603.

    PubMed 17299195

  • DePalma RG, Hayes VW, Zacharski LR. Bloodletting: past and present. J Am Coll Surg. 2007 Jul;205(1):132-44. doi: 10.1016/j.jamcollsurg.2007.01.071. Epub 2007 May 17. No abstract available.

    PubMed 17617342

  • Depalma RG, Hayes VW, Chow BK, Shamayeva G, May PE, Zacharski LR. Ferritin levels, inflammatory biomarkers, and mortality in peripheral arterial disease: a substudy of the Iron (Fe) and Atherosclerosis Study (FeAST) Trial. J Vasc Surg. 2010 Jun;51(6):1498-503. doi: 10.1016/j.jvs.2009.12.068. Epub 2010 Mar 20.

    PubMed 20304584

  • Depalma RG, Zacharski LR. Iron reduction benefits: positive results from a "negative" prospective randomized controlled trial. Vasc Endovascular Surg. 2012 Oct;46(7):596-7. doi: 10.1177/1538574412456304. Epub 2012 Aug 17. No abstract available.

    PubMed 22903331

  • Zacharski LR, Shamayeva G, Chow BK. Effect of controlled reduction of body iron stores on clinical outcomes in peripheral arterial disease. Am Heart J. 2011 Nov;162(5):949-957.e1. doi: 10.1016/j.ahj.2011.08.013.

    PubMed 22093213

  • 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 Natl Cancer Inst. 2008 Jul 16;100(14):996-1002. doi: 10.1093/jnci/djn209. Epub 2008 Jul 8.

    PubMed 18612130

  • Zacharski LR, Chow BK, Howes PS, Lavori PW, Shamayeva G. Implementation of an iron reduction protocol in patients with peripheral vascular disease: VA cooperative study no. 410: the Iron (Fe) and Atherosclerosis Study (FeAST). Am Heart J. 2004 Sep;148(3):386-92. doi: 10.1016/j.ahj.2004.03.027.

    PubMed 15389223

  • Zacharski LR, Chow B, Lavori PW, Howes PS, Bell MR, DiTommaso MA, Carnegie NM, Bech F, Amidi M, Muluk S. The iron (Fe) and atherosclerosis study (FeAST): a pilot study of reduction of body iron stores in atherosclerotic peripheral vascular disease. Am Heart J. 2000 Feb;139(2 Pt 1):337-45. doi: 10.1067/mhj.2000.102909.

    PubMed 10650308

  • DePalma RG, Zacharski LR, Chow BK, Shamayeva G, Hayes VW. Reduction of iron stores and clinical outcomes in peripheral arterial disease: outcome comparisons in smokers and non-smokers. Vascular. 2013 Aug;21(4):233-41. doi: 10.1177/1708538113478776.

    PubMed 23518844

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Ferritin reduction to 25 ng/ml by phlebotomy in people with Atherosclerosis and Intermittent Claudication, run by US Department of Veterans Affairs at 24 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 8 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 21 Jan 2013. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 24 sites in United States, Puerto Rico. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Mortality (time frame: The minimum follow-up was 3.5 years and maximum follow-up was 6 years). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00032357, which also lists 11 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Jan 2013.

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