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

Atherosclerosis Clinical Trial

— FeAST  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00032357
• Other study ID #: 410
• Status: Completed
• Phase: Phase 3
• First received: March 19, 2002
• Last updated: January 18, 2013
• Start date: May 1999
• Est. completion date: September 2005

Study information

• Verified date: January 2013
• Source: VA Office of Research and Development
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical 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. 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1277
• Est. completion date: September 2005
• Est. primary completion date: April 2005
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 21 Years and older

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Outcomes Assessor), Primary Purpose: Diagnostic

Related Conditions & MeSH terms

• Atherosclerosis
• Intermittent Claudication
• Peripheral Arterial Disease
• Peripheral Vascular Diseases
• Vascular Diseases

Intervention

Procedure:
• Ferritin reduction to 25 ng/ml by phlebotomy

Locations

Country	Name	City	State
Puerto Rico	VA Medical Center, San Juan	San Juan
United States	VA Stratton Medical Center, Albany	Albany	New York
United States	VA Medical Center, Birmingham	Birmingham	Alabama
United States	VA Medical Center, Jamaica Plain Campus	Boston	Massachusetts
United States	VA Medical Center, Cleveland	Cleveland	Ohio
United States	VA Medical Center, Durham	Durham	North Carolina
United States	North Florida/South Georgia Veterans Health System	Gainesville	Florida
United States	Edward Hines, Jr. VA Hospital	Hines	Illinois
United States	Michael E. DeBakey VA Medical Center (152)	Houston	Texas
United States	VA Medical Center, Lexington	Lexington	Kentucky
United States	VA Medical Center, Long Beach	Long Beach	California
United States	VA Medical Center, Louisville	Louisville	Kentucky
United States	Wlliam S. Middleton Memorial Veterans Hospital, Madison	Madison	Wisconsin
United States	Zablocki VA Medical Center, Milwaukee	Milwaukee	Wisconsin
United States	New York Harbor HCS	New York	New York
United States	Central Arkansas VHS Eugene J. Towbin Healthcare Ctr, Little Rock	No. Little Rock	Arkansas
United States	VA Palo Alto Health Care System	Palo Alto	California
United States	VA Pittsburgh Health Care System	Pittsburgh	Pennsylvania
United States	VA Medical Center, Providence	Providence	Rhode Island
United States	VA Sierra Nevada Health Care System	Reno	Nevada
United States	VA Salt Lake City Health Care System, Salt Lake City	Salt Lake City	Utah
United States	James A. Haley Veterans Hospital, Tampa	Tampa	Florida
United States	VA Connecticut Health Care System (West Haven)	West Haven	Connecticut
United States	VA Medical & Regional Office Center, White River	White River Junction	Vermont

Sponsors (1)

Lead Sponsor	Collaborator
VA Office of Research and Development

Countries where clinical trial is conducted

United States,  Puerto Rico, 

References & Publications (10)

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. — View Citation

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 — View Citation

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. — View Citation

DePalma RG, Hayes VW, Zacharski LR. Bloodletting: past and present. J Am Coll Surg. 2007 Jul;205(1):132-44. Epub 2007 May 17. — View Citation

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. — View Citation

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 Hea — View Citation

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): — View Citation

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;1 — View Citation

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): — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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).	The minimum follow-up was 3.5 years and maximum follow-up was 6 years	No